Input: We show herein that CTLA-4 is present in enlarged, abnormal vesicles in CHS T cells and is not properly expressed at the cell surface after T cell activation, whereas its surface expression is not impaired.

CHS


Input: It is therefore proposed that the defective surface expression of CTLA-4 by CHS T cells is involved in the generation of lymphoproliferative disease.

CHS

lymphoproliferative disease


Input: This observation may provide insight into the role of CTLA-4 in humans..


Input: Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher Disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not.

Pelizaeus-Merzbacher Disease


Input: The Clinical European Network on Brain Dysmyelinating Disease.

Brain Dysmyelinating Disease


Input: Pelizaeus-Merzbacher Disease (PMD) is an X-linked developmental defect of myelination affecting the central nervous system and segregating with the proteolipoprotein (PLP) locus.

Pelizaeus-Merzbacher Disease

PMD

X-linked developmental defect of myelination


Input: Investigating 82 strictly selected sporadic cases of PMD, we found PLP mutations in 77%; complete PLP-gene duplications were the most frequent abnormality (62%), whereas point mutations in coding or splice-site regions of the gene were involved less frequently (38%).

PMD


Input: We analyzed the maternal status of 56 cases to determine the origin of both types of PLP mutation, since this is relevant to genetic counseling.


Input: In the 22 point mutations, 68% of mothers were heterozygous for the mutation, a value identical to the two-thirds of carrier mothers that would be expected if there were an equal mutation rate in male and female germ cells.


Input: In sharp contrast, among the 34 duplicated cases, 91% of mothers were carriers, a value significantly (chi2 = 9. 20, P <. 01) in favor of a male bias, with an estimation of the male/female mutation frequency (k) of 9.


Input: 3 3.


Input: Moreover, we observed the occurrence of de novo mutations between parental and grandparental generations in 17 three-generation families, which allowed a direct estimation of the k value (k = 11).


Input: Again, a significant male mutation imbalance was observed only for the duplications.


Input: Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.

Prader-Willi and Angelman syndromes


Input: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively.

Prader-Willi syndrome

PWS

Angelman syndrome

AS

neurobehavioral disorders


Input: At a de novo frequency of approximately.


Input: 67-1/10, 000 births, these deletions represent a common structural chromosome change in the human genome.


Input: To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster.


Input: Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions.


Input: Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints.


Input: The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues.


Input: One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event.

PWS

AS


Input: We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion.


Input: Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.


Input: Linkage analysis in a large Brazilian family with van der Woude syndrome suggests the existence of a susceptibility locus for cleft palate at 17p11. 2-11. 1.

van der Woude syndrome

cleft palate


Input: van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H).

van der Woude syndrome

VWS

pits and/or sinuses of the lower lip

cleft lip/palate

CL/P

cleft palate

CP

bifid uvula

hypodontia

H


Input: The expression of VWS, which has incomplete penetrance, is highly variable.

VWS


Input: Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk < 40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci.

CL/P

CP

CP

VWS

clefts


Input: To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS.

VWS

CP

VWS


Input: Our results suggest that a gene at 17p11.


Input: 2-11 2-11.


Input: 1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes.

VWS

CP


Input: If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene.

VWS


Input: New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy.


Input: The gene for ataxia-telangiectasia, ATM, spans about 150 kb of genomic DNA.

ataxia-telangiectasia


Input: ATM mutations are found along the entire gene, with no evidence of a mutational hot spot.


Input: Using DNA as the starting material, we screened the ATM gene in 92 A-T patients, using an optimized single-strand conformation polymorphism (SSCP) technique that detected all previously known mutations in the polymerase chain reaction (PCR) segments being analyzed.

A-T


Input: To expedite screening, we sequentially loaded the SSCP gels with three different sets of PCR products that were pretested to avoid overlapping patterns.


Input: Many of the DNA changes we detected were intragenic polymorphisms.


Input: Of an expected 177 unknown mutations, we detected approximately 70%, mostly protein truncating mutations (that would have been detectable by protein truncation testing if RNA starting material had been available).


Input: Mutations have now been defined for every exon of the ATM gene.


Input: Herein, we present 35 new mutations and 34 new intragenic polymorphisms or rare variants within the ATM gene.


Input: This is the most comprehensive compilation of ATM polymorphisms assembled to date.


Input: Defining polymorphic sites as well as mutations in the ATM gene will be of great importance in designing automated methods for detecting mutations..


Input: A novel frameshift mutation in the McLeod syndrome gene in a Japanese family.

McLeod syndrome


Input: We report a novel mutation in the XK gene (XK) in a Japanese patient with McLeod syndrome.

McLeod syndrome


Input: A 50-year-old man showed progressive muscular atrophy, choreic movement, elevated level of serum creatinine kinase, and acanthocytosis.

muscular atrophy

choreic movement

acanthocytosis


Input: The expression level of all the Kell antigens in erythrocyte was decreased and molecular analysis revealed a single-base (T) deletion at the nucleotide position 1095 in XK.


Input: This deletion caused a frameshift in translation, leading to a premature stop codon at the amino acid position 408.


Input: We conclude this single-base deletion causes defective Kx protein, which is responsible for the McLeod phenotype in this patient..

McLeod


Input: Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.


Input: BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers.

tumor

familial breast and ovarian cancers


Input: Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin.


Input: Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50.


Input: Formation of irradiation-induced foci positive for BRCA1, hRad50, hMre11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wild-type BRCA1.

breast cancer


Input: Ectopic expression of wild-type, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent, methyl methanesulfonate.


Input: These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex..


Input: Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study.

phenylalanine hydroxylase deficiency

Maternal Phenylketonuria


Input: OBJECTIVE To examine the relationship of phenylalanine hydroxylase (PAH) genotypes to biochemical phenotype and cognitive development in maternal phenylketonuria (PKU).

maternal phenylketonuria

PKU


Input: METHODOLOGY PAH gene mutations were examined in 222 hyperphenylalaninemic females enrolled in the Maternal PKU Collaborative Study (MPKUCS).

hyperphenylalaninemic

Maternal PKU


Input: A total of 84 different mutations were detected, and complete genotype was obtained in 199 individuals.


Input: Based on previous knowledge about mutation-phenotype associations, 78 of the mutations could be assigned to one of four classes of severity (severe PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia [MHP]).

PKU

PKU

PKU

mild hyperphenylalaninemia

MHP


Input: Then, 189 MPKUCS subjects were grouped according to the various combinations of mutation classifications.


Input: The sample sizes were large enough for statistical testing in four groups with at least one mutation that completely abolishes enzyme activity.


Input: These patients are considered functionally hemizygous.


Input: RESULTS The biochemical phenotype predicted from the genotype in functionally hemizygous patients was related significantly to the assigned phenylalanine level.


Input: Cognitive performance (IQ) was also significantly related to genotype.


Input: The IQ of PAH-deficient mothers with a severe PKU mutation in combination with a MHP mutation or a mild PKU mutation was 99 and 96, respectively, whereas the IQ of PKU mothers with two severe PKU mutations or with one severe and one moderate PKU mutation was 83 and 84, respectively.

PAH-deficient

PKU

MHP

PKU

PKU

PKU

PKU


Input: Of the patients with PKU, 92% had been treated during childhood.

PKU


Input: Those who were untreated or treated late had lower than average IQ scores for their group of mutation combinations.


Input: Females with moderate or mild PKU who were treated early and treated for > 6 years showed IQ scores 10 points above average for their group.

PKU


Input: CONCLUSIONS The reproductive outcome in maternal phenylketonuria is dependent on prenatal metabolic control and postnatal environmental circumstances.

maternal phenylketonuria


Input: Both factors depend on the intellectual resources of the mother with PKU.

PKU


Input: The significant relationship among genotype, biochemical phenotype, and cognitive performance observed in the present study is of importance for the development of an optimal strategy for future treatment of females with PKU who plan pregnancy..

PKU


Input: Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis.

Spinal xanthomatosis

cerebrotendinous xanthomatosis


Input: We describe seven Dutch patients from six families with a slowly progressive, mainly spinal cord syndrome that remained for many years the sole expression of cerebrotendinous xanthomatosis (CTX).

spinal cord syndrome

cerebrotendinous xanthomatosis

CTX


Input: MRI demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord.

white matter abnormalities


Input: Post-mortem examination of one of the patients showed extensive myelin loss in these columns.


Input: An array of genotypes was found in these patients.


Input: We conclude that spinal xanthomatosis is a clinical and radiological separate entity of CTX that should be included in the differential diagnosis of chronic myelopathy..

spinal xanthomatosis

CTX

chronic myelopathy


Input: A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and angelman syndromes.

Prader-Willi and angelman syndromes


Input: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) result from the loss of function of imprinted genes in human chromosome 15q11-q13.

Prader-Willi syndrome

PWS

Angelman syndrome

AS


Input: The central part of mouse chromosome 7 is homologous to human 15q11-q13, with conservation of both gene order and imprinted features.


Input: We report here the characterization of a transgene insertion (Epstein-Barr virus Latent Membrane Protein 2A, LMP2A) into mouse chromosome 7C, which has resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent.

PWS

AS


Input: Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analyses indicate that the transgene-induced mutation has generated a complete deletion of the PWS/AS-homologous region but has not deleted flanking loci.

PWS

AS


Input: Because the intact chromosome 7, opposite the deleted homolog, maintains the correct imprint in somatic cells of PWS and AS mice and establishes the correct imprint in male and female germ cells of AS mice, homologous association and replication asynchrony are not part of the imprinting mechanism.

PWS

AS

AS


Input: This heritable-deletion mouse model will be particularly useful for the identification of the etiological genes and mechanisms, phenotypic basis, and investigation of therapeutic approaches for PWS..

PWS


Input: Linkage analysis of 5 novel van der Woude syndrome kindreds to 1q32-q41 markers further supports locus homogeneity of the disease trait.

van der Woude syndrome


Input: van der Woude syndrome (vWS, MIM 119300) is a rare autosomal dominant clefting condition with cardinal features of mucous cysts (lower-lip pits) and clefts to the lip and/or palate.

van der Woude syndrome

vWS

autosomal dominant clefting condition

mucous cysts

lower-lip pits

clefts to the lip and/or palate


Input: The vWS gene has been assigned to a locus in 1q32-q41 by linkage analysis and physical mapping.

vWS


Input: We have investigated 5 novel vWS families through probands attended for cleft lip and/or palate repair at the Department of Maxillofacial Surgery of Hopital Trousseau, Paris, in order to tentatively refine the genetic map of the vWS region in 1q32-q41 and possibly identify unlinked pedigrees.

vWS

cleft lip and/or palate

vWS


Input: Linkage analysis was carried out to 6 microsatellite markers (D1S249, D1S425, D1S491, D1S205, D1S414, D1S425), yielding a maximum cumulative LOD score of Z = 3.


Input: 27 at theta = 0.


Input: 00 for D1S245.


Input: The innermost four markers were found to be tightly linked to one another, with no evidence for recombination.


Input: Our results support linkage of vWS within a region of tightly linked markers and do not favour locus heterogeneity of the disease trait.

vWS


Input: Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation.

Wilson disease

intracellular copper accumulation

late-onset hepatic nodular transformation


Input: The Atp7b protein is a copper-transporting ATPase expressed predominantly in the liver and to a lesser extent in most other tissues.


Input: Mutations in the ATP7B gene lead to Wilson disease, a copper toxicity disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neuro-logical abnormalities.

Wilson disease

copper toxicity disorder

hepatic and neuro-logical abnormalities


Input: Using homologous recombination to disrupt the normal translation of ATP7B, we have generated a strain of mice that are homozygous mutants (null) for the Wilson disease gene.

Wilson disease


Input: The ATP7B null mice display a gradual accumulation of hepatic copper that increases to a level 60-fold greater than normal by 5 months of age.


Input: An increase in copper concentration was also observed in the kidney, brain, placenta and lactating mammary glands of homo-zygous mutants, although milk from the mutant glands was copper deficient.

copper deficient


Input: Morphological abnormalities resembling cirrhosis developed in the majority of the livers from homozygous mutants older than 7 months of age.

Morphological abnormalities

cirrhosis


Input: Progeny of the homozygous mutant females demonstrated neurological abnormalities and growth retardation characteristic of copper deficiency.

neurological abnormalities

growth retardation

copper deficiency


Input: Copper concentration in the livers of the newborn homozygous null mutants was decreased dramatically.


Input: In summary, inactivation of the murine ATP7B gene produces a form of cirrhotic liver disease that resembles Wilson disease in humans and the toxic milk phenotype in the mouse..

cirrhotic liver disease

Wilson disease


Input: French Machado-Joseph disease patients do not exhibit gametic segregation distortion: a sperm typing analysis.

Machado-Joseph disease


Input: Segregation distortion has been reported to occur in a number of the trinucleotide repeat disorders.

trinucleotide repeat disorders


Input: On the basis of a sperm typing study performed in patients of Japanese descent with Machado-Joseph disease (MJD), it was reported that disease alleles are preferentially transmitted during meiosis.

Machado-Joseph disease

MJD


Input: We performed a sperm typing study of five MJD patients of French descent and analysis of the pooled data shows a ratio of mutant to normal alleles of 379 436 (46. 5 53. 5%), which does not support meiotic segregation distortion.

MJD


Input: To confirm these results, sperm typing analysis was also performed using a polymorphic marker, D14S1050, closely linked to the MJD1 gene.


Input: Among 910 sperm analyzed, the allele linked to the disease chromosome was detected in 50.


Input: 3% of the samples and the allele linked to the normal chromosome was found in 49.


Input: 6% of the sperm.


Input: The difference in frequency of these two alleles is not significant (P = 0. 8423).


Input: Likelihood-based analysis of segregation distortion in the single sperm data using the SPERMSEG program also showed no support for segregation distortion at the gamete level in this patient population.


Input: The previous report on the Japanese patients also suggested that disease allele stability may be influenced by a trans effect of an intragenic polymorphism (987 G/C) in the wild-type allele.


Input: All of the French patients were heterozygous for this polymorphism.


Input: However, analysis of the variance in repeat number in sperm from the French MJD patients overlapped significantly with the variance in repeat number observed in the C/C homozygous Japanese patients.

MJD


Input: Missense mutation in the alternative splice region of the PAX6 gene in eye anomalies.

eye anomalies


Input: The PAX6 gene is involved in ocular morphogenesis, and PAX6 mutations have been detected in various types of ocular anomalies, including aniridia, Peters anomaly, corneal dystrophy, congenital cataract, and foveal hypoplasia.

ocular anomalies

aniridia

Peters anomaly

corneal dystrophy

congenital cataract

foveal hypoplasia


Input: The gene encodes a transcriptional regulator that recognizes target genes through its paired-type DNA-binding domain.


Input: The paired domain is composed of two distinct DNA-binding subdomains, the N-terminal subdomain (NTS) and the C-terminal subdomain (CTS), which bind respective consensus DNA sequences.


Input: The human PAX6 gene produces two alternative splice isoforms that have the distinct structure of the paired domain.


Input: The insertion, into the NTS, of 14 additional amino acids encoded by exon 5a abolishes the DNA-binding activity of the NTS and unmasks the DNA-binding ability of the CTS.


Input: Thus, exon 5a appears to function as a molecular switch that specifies target genes.


Input: We ascertained a novel missense mutation in four pedigrees with Peters anomaly, congenital cataract, Axenfeldt anomaly, and/or foveal hypoplasia, which, to our knowledge, is the first mutation identified in the splice-variant region.

Peters anomaly

congenital cataract

Axenfeldt anomaly

foveal hypoplasia


Input: A T--> A transition at the 20th nucleotide position of exon 5a results in a Val--> Asp (GTC--> GAC) substitution at the 7th codon of the alternative splice region.


Input: Functional analyses demonstrated that the V54D mutation slightly increased NTS binding and decreased CTS transactivation activity to almost half..


Input: Penetrances of BRCA1 1675delA and 1135insA with respect to breast cancer and ovarian cancer.

breast cancer

ovarian cancer


Input: For genetic counseling and predictive testing in families with inherited breast-ovarian cancer, penetrances and expressions of the underlying mutations should be known.

inherited breast-ovarian cancer


Input: We have previously reported two BRCA1 founder mutations in the Norwegian population.


Input: Index cases for the present study were found two different ways through a series of consecutive ovarian cancers (n = 16) and through our family cancer clinic (n = 14).

ovarian cancers

cancer


Input: Altogether, 20 of the patients had BRCA1 1675delA, and 10 had 1135insA.


Input: Their relatives were described with respect to absence/presence of breast and/or ovarian cancer.

breast and/or ovarian cancer


Input: Of 133 living female relatives, 83 (62%) were tested for the presence of a mutation.


Input: No difference, in penetrance and expression, between the two mutations were found, whereas differences according to method of ascertainment were seen.


Input: The overall findings were that disease started to occur at age 30 years and that by age 50 years 48% of the mutation-carrying women had experienced breast and/or ovarian cancer.

breast and/or ovarian cancer


Input: More ovarian cancers than breast cancers were recorded.

ovarian cancers

breast cancers


Input: Both penetrance and expression (breast cancer vs. ovarian cancer) were different from those in reports of the Ashkenazi founder mutations.

breast cancer

ovarian cancer


Input: Whether the reported differences reflect true differences and/or methodological problems is discussed.


Input: An observed excess of mutation carriers could not be accounted for by methodological problems; possible explanations were a " true " low penetrance or preferential segregation..


Input: The dermatofibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB.

dermatofibrosarcoma protuberans


Input: Dermatofibrosarcoma protuberans (DFSP) displays chromosomal rearrangements involving chromosome 17 and 22, which fuse the collagen type Ialpha1 (COLIA1) gene to the platelet-derived growth factor (PDGF) B-chain (PDGFB) gene.

Dermatofibrosarcoma protuberans

DFSP


Input: To characterize the functional and structural properties of the COLIA1/PDGFB fusion protein, we generated a stable NIH3T3 cell line that contained a tumor-derived chimeric gene resulting from a COIA1 intron 7-PDGFB intron 1 fusion.


Input: Expression of the fusion protein led to morphological transformation and increased growth rate of these cells.


Input: The PDGF receptor kinase inhibitor CGP57148B reversed the transformed phenotype and reduced the growth rate of COLIA1/PDGFB-expressing cells but had no effects on control cells.


Input: The presence of dimeric COLIA1/PDGFB precursors was demonstrated through PDGFB immunoprecipitations of metabolically labeled cells and also by PDGFB immunoprecipitations followed by immunoblotting with COLIA1 antibodies.


Input: Pulse-chase studies demonstrated that the COLIA1/PDGFB precursor was processed to an end product that was indistinguishable from wild-type PDGF-BB.


Input: Finally, COLIA1/PDGFB-expressing cells generated tumors after s.

tumors


Input: c c. injection into nude mice, and tumor growth was reduced by treatment with CGP57148B.

tumor


Input: We conclude that the COLIA1/PDGFB fusion associated with DFSP contributes to tumor development through ectopic production of PDGF-BB and the formation of an autocrine loop.

DFSP

tumor


Input: Our findings, thus, suggest that PDGF receptors could be a target for pharmacological treatment of DFSP and giant cell fibroblastoma, e. g., through the use of PDGF receptor kinase inhibitors such as CGP57148B.

DFSP

giant cell fibroblastoma


Input: Identification of a common PEX1 mutation in Zellweger syndrome.

Zellweger syndrome


Input: The Zellweger spectrum of disease, encompassing Zellweger syndrome and the progressively milder phenotypes of neonatal adrenoleukodystrophy and infantile Refsum disease, is due to a failure to form functional peroxisomes.

Zellweger spectrum of disease

Zellweger syndrome

neonatal adrenoleukodystrophy

infantile Refsum disease


Input: Cell fusion complementation studies demonstrated that these diseases are genetically heterogeneous, with two-thirds of all patients lying within a single complementation group, CG1.


Input: Molecular genetic and cell biology studies have shown that PEX1 is deficient in many CG1 patients.


Input: However, previous studies have focused on mildly affected patients and there is still no report of two mutant PEX1 alleles in any Zellweger syndrome patient.

Zellweger syndrome


Input: Furthermore, mutations in the PMP70 gene have also been identified in two Zellweger syndrome patients from CG1, raising the possibility that CG1 patients may represent a mixture of PEX1-deficient and PMP70-deficient individuals.

Zellweger syndrome


Input: To address the molecular basis of disease in Zellweger syndrome patients from CG1, we examined all 24 PEX1 exons in four patients, including both patients that have mutations in PMP70.

Zellweger syndrome


Input: PEX1 mutations were detected in all four patients, including a 1-bp insertion (c. 2097insT) in exon 13 that was present in three of the four patients.


Input: Subsequent studies demonstrated that this mutation is present in one-half of all CG1 patients and correlates with the Zellweger syndrome phenotype.

Zellweger syndrome


Input: As this mutation leads to a loss of protein function its frequency makes it the most common cause of Zellweger syndrome, helping to explain the high percentage of patients that belong to CG1.

Zellweger syndrome


Input: Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes.

Wiskott-Aldrich syndrome


Input: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency characterized by thrombocytopenia, eczema, and recurrent infections, and caused by mutations in the WAS protein (WASP) gene.

Wiskott-Aldrich syndrome

WAS

X-linked recessive immunodeficiency

thrombocytopenia

eczema

WAS


Input: WASP contains several functional domains through which it interacts with proteins involved in intracellular signaling and regulation of the actin cytoskeleton.


Input: In this report, 17 WASP gene mutations were identified, 12 of which are novel.


Input: DNA of affected males and obligate carriers was PCR amplified and analyzed by SSCA, heteroduplex analysis, and direct sequencing.


Input: The effects of the mutations at the mRNA and protein level were ascertained by RT-PCR and Western blot analyses.


Input: All missense mutations were located in exons 1-4.


Input: Most of the nonsense, frameshift and splice site mutations were found in exons 6-11.


Input: Mutations that alter splice sites led to the synthesis of several types of mRNAs, a fraction of which represented the normally spliced product.


Input: The presence of normally spliced transcripts was correlated with a milder phenotype.


Input: When one such case was studied by Western blotting, reduced amounts of normal-size WASP were present.


Input: In other cases as well, a correlation was found between the amount of normal or mutant WASP present and the phenotypes of the affected individuals.


Input: No protein was detected in two individuals with severe WAS.

WAS


Input: Reduced levels of a normal-size WASP with a missense mutation were seen in two individuals with XLT.

XLT


Input: It is concluded that mutation analysis at the DNA level is not sufficient for predicting clinical course.


Input: Studies at the transcript and protein level are needed for a better assessment..


Input: Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice.


Input: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene, leading to the absence of the dystrophin protein in striated muscle.

Duchenne muscular dystrophy

DMD


Input: A significant number of these mutations are premature stop codons.


Input: On the basis of the observation that aminoglycoside treatment can suppress stop codons in cultured cells, we tested the effect of gentamicin on cultured muscle cells from the mdx mouse-an animal model for DMD that possesses a premature stop codon in the dystrophin gene.

DMD


Input: Exposure of mdx myotubes to gentamicin led to the expression and localization of dystrophin to the cell membrane.


Input: We then evaluated the effects of differing dosages of gentamicin on expression and functional protection of the muscles of mdx mice.


Input: We identified a treatment regimen that resulted in the presence of dystrophin in the cell membrane in all striated muscles examined and that provided functional protection against muscular injury.

muscular injury


Input: To our knowledge, our results are the first to demonstrate that aminoglycosides can suppress stop codons not only in vitro but also in vivo.


Input: Furthermore, these results raise the possibility of a novel treatment regimen for muscular dystrophy and other diseases caused by premature stop codon mutations.

muscular dystrophy


Input: This treatment could prove effective in up to 15% of patients with DMD..

DMD


Input: Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs.

ataxia-telangiectasia


Input: Ataxia-telangiectasia (A-T) is characterized by a markedly increased sensitivity to ionizing radiation, increased incidence of cancer, and neurodegeneration, especially of the cerebellar Purkinje cells.

Ataxia-telangiectasia

A-T

cancer

neurodegeneration


Input: Ionizing radiation oxidizes macromolecules and causes tissue damage through the generation of reactive oxygen species (ROS).


Input: We therefore hypothesized that A-T is due to oxidative damage resulting from loss of function of the A-T gene product.

A-T

A-T


Input: To assess this hypothesis, we employed an animal model of A-T, the mouse with a disrupted Atm gene.

A-T


Input: We show that organs which develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected.


Input: These observations provide a mechanistic basis for the A-T phenotype and lay a rational foundation for therapeutic intervention..

A-T


Input: Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation.

multiple epiphyseal dysplasia

club foot

double layered patella


Input: We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia.

diastrophic dysplasia

recessive disorders achondrogenesis 1B

atelosteogenesis 2

diastrophic dysplasia


Input: The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with other DTDST mutations.


Input: We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia.

multiple epiphyseal dysplasia


Input: He was treated for club foot and hip dysplasia at birth.

club foot

hip dysplasia


Input: Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood.

multiple epiphyseal dysplasia

double layered patella


Input: Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent.

Cleft palate

swelling of the ear pinna

hitch hiker thumb


Input: He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders.

DTDST disorders


Input: Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring.

recessive disorder


Input: Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204).

Multiple epiphyseal dysplasia


Input: A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900).

MED


Input: This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at the DTDST locus..


Input: Homozygosity for a novel DTDST mutation in a child with a' broad bone-platyspondylic' variant of diastrophic dysplasia.

diastrophic dysplasia


Input: Atypical or variant forms of well-known chondrodysplasias may pose diagnostic problems.

chondrodysplasias


Input: We report on a girl with clinical features suggesting diastrophic dysplasia but with unusual radiographic features including severe platyspondyly, wide metaphyses, and fibular overgrowth, which are partially reminiscent of metatropic dysplasia.

diastrophic dysplasia

platyspondyly

metatropic dysplasia


Input: The diagnosis was clarified by molecular analysis of the DTDST gene, which revealed homozygosity for a previously undescribed mutation leading to a Q454P substitution in the 10th transmembrane domain of the DTDST sulfate transporter.


Input: Molecular analysis may be of particular value in such atypical cases..


Input: The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson' s' two-hit' hypothesis.

familial adenomatous polyposis


Input: APC is often cited as a prime example of a tumor suppressor gene.

tumor


Input: Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis).

tumors

FAP

familial adenomatous polyposis


Input: Most sporadic colorectal cancers also have two APC mutations.

sporadic colorectal cancers

APC


Input: Clues from attenuated polyposis, missense germline variants with mild disease and the somatic mutation cluster region (codons 1, 250-1, 450) indicate, however, that APC mutations might not result in simple loss of protein function.

attenuated polyposis

APC


Input: We have found that FAP patients with germline APC mutations within a small region (codons 1, 194-1, 392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose second hits tend to occur by truncating mutations in the mutation cluster region.

FAP

APC

colorectal adenomas

FAP


Input: Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1, 300 providing the greatest advantage.

APC


Input: Allelic loss is selected strongly in cells with one mutation near codon 1, 300.


Input: A different germline-somatic APC mutation association exists in FAP desmoids.

APC

FAP desmoids


Input: APC is not, therefore, a classical tumor suppressor.

tumor


Input: Our findings also indicate a new mechanism for disease severity if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow..

tumors

tumors


Input: Mxi1 mutations in human neurofibrosarcomas.

neurofibrosarcomas


Input: Mxi1 is thought to negatively regulate Myc function and may therefore be a potential tumor suppressor gene.

tumor


Input: Little effort has yet been made to find alterations involving this gene in human solid tumors.

solid tumors


Input: We screened 31 human gastric cancers, 7 esophageal cancers, 85 bone and soft tissue tumors of various types, including 4 neurofibrosarcomas.

gastric cancers

esophageal cancers

bone and soft tissue tumors

neurofibrosarcomas


Input: We also examined 29 human tumor cell lines consisting of 12 esophageal cancers, 7 glioma/glioblastomas and 10 others for Mxi1 mutations in exons 1, 2, 4 (HLH domain), 5 and 6.

tumor

esophageal cancers

glioma

glioblastomas


Input: Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and subsequent sequencing revealed three distinct polymorphisms in the intron-exon boundary upstream from exon 6.


Input: We discovered a missense mutation, GCA to GTA (Ala 54 Val), in exon 2 in a neurofibrosarcoma patient (case 1), two missense mutations, AAA to CAA (Lys 118 Gln) and GAA to GGA (Glu 154 Gly) in exon 5 of another neurofibrosarcoma patient (case 2), and 3 amino acid substitutions, GTG to GCG (Val 179 Ala), GTT to GCT (Val 181 Ala) and TTC to CTC (Phe 186 Leu), in a third neurofibrosarcoma patient (case 3).

neurofibrosarcoma

neurofibrosarcoma

neurofibrosarcoma


Input: In case 3, loss of heterozygosity was also demonstrated by informative (TTC) 3/(TTC) 2 polymorphism.


Input: Our data demonstrate that mutations occur in the Mxi1 gene in neurofibrosarcoma.

neurofibrosarcoma


Input: Missense mutations in the functional domain of Mxi1 in these cases may be involved in the pathogenesis of neurofibrosarcoma..

neurofibrosarcoma


Input: A population-based study of the clinical expression of the hemochromatosis gene.

hemochromatosis


Input: BACKGROUND AND METHODS Hereditary hemochromatosis is associated with homozygosity for the C282Y mutation in the hemochromatosis (HFE) gene on chromosome 6, elevated serum transferrin saturation, and excess iron deposits throughout the body.

Hereditary hemochromatosis

hemochromatosis

excess iron deposits


Input: To assess the prevalence and clinical expression of the HFE gene, we conducted a population-based study in Busselton, Australia.


Input: In 1994, we obtained blood samples for the determination of serum transferrin saturation and ferritin levels and the presence or absence of the C282Y mutation and the H63D mutation (which may contribute to increased hepatic iron levels) in 3011 unrelated white adults.


Input: We evaluated all subjects who had persistently elevated transferrin-saturation values (45 percent or higher) or were homozygous for the C282Y mutation.


Input: We recommended liver biopsy for subjects with serum ferritin levels of 300 ng per milliliter or higher.


Input: The subjects were followed for up to four years.


Input: RESULTS Sixteen of the subjects (0. 5 percent) were homozygous for the C282Y mutation, and 424 (14. 1 percent) were heterozygous.


Input: The serum transferrin saturation was 45 percent or higher in 15 of the 16 who were homozygous; in 1 subject it was 43 percent.


Input: Four of the homozygous subjects had previously been given a diagnosis of hemochromatosis, and 12 had not.

hemochromatosis


Input: Seven of these 12 patients had elevated serum ferritin levels in 1994; 6 of the 7 had further increases in 1998, and 1 had a decrease, although the value remained elevated.


Input: The serum ferritin levels in the four other homozygous patients remained in the normal range.


Input: Eleven of the 16 homozygous subjects underwent liver biopsy; 3 had hepatic fibrosis, and 1, who had a history of excessive alcohol consumption, had cirrhosis and mild microvesicular steatosis.

hepatic fibrosis

excessive alcohol consumption

cirrhosis

microvesicular steatosis


Input: Eight of the 16 homozygous subjects had clinical findings that were consistent with the presence of hereditary hemochromatosis, such as hepatomegaly, skin pigmentation, and arthritis.

hereditary hemochromatosis

hepatomegaly

skin pigmentation

arthritis


Input: CONCLUSIONS In a population of white adults of northern European ancestry, 0.


Input: 5 percent were homozygous for the C282Y mutation in the HFE gene.


Input: However, only half of those who were homozygous had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained normal over a four-year period.

hemochromatosis


Input: Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis.


Input: The clinical use of molecular analyses in recessive disorders relies on the exact characterization of both mutant alleles in the affected patient.

recessive disorders


Input: This can be problematic when only part of the gene is examined or when relevant DNA alterations are not recognized by standard methods.


Input: We present a child in whom phenylketonuria was apparently caused by homozygosity for the mutation E390G in exon 11 of the phenylalanine hydroxylase (PAH) gene.

phenylketonuria


Input: However, the clinical severity of the disease was not quite as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene.


Input: Presence of a large deletion involving exons 9, 10 and 11 of the phenylalanine hydroxylase gene was confirmed by long-range PCR.


Input: Diagnostic DNA analyses should include a comprehensive examination of the whole relevant gene in the patient and confirmation of carrier status in both parents..


Input: Early onset of X-linked Emery-Dreifuss muscular dystrophy in a boy with emerin gene deletion.

X-linked Emery-Dreifuss muscular dystrophy


Input: A boy developed contractures of the Achilles tendons at 3 years and of the postcervical muscles at 7 years, although neither contractures of the elbows nor cardiac abnormality were recognized by the age of 9 years.

contractures of the Achilles tendons

contractures of the elbows

cardiac abnormality


Input: Muscle computed tomography scanning revealed changes characteristic of muscle involvement.


Input: Emerin was not detected in the biopsied muscle, and RT-PCR and PCR-based genomic DNA analyses of the emerin gene demonstrated no amplification product in the patient.


Input: These results confirmed the diagnosis of X-linked Emery-Dreifuss muscular dystrophy (EDMD), and reinforce the necessity of molecular genetic diagnosis of the membrane protein emerin in younger patients with possible EDMD before appearance of the typical symptoms, to avoid sudden cardiac death..

X-linked Emery-Dreifuss muscular dystrophy

EDMD

EDMD

sudden cardiac death


Input: Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations.

Duchenne/Becker muscular dystrophy


Input: The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD/BMD) shows a marked reduction in b-wave amplitude.

Duchenne and Becker muscular dystrophy

DMD

BMD


Input: Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype mice with 5 defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged implicit times for both the b-wave and oscillatory potentials, and mice with 3 defects have a phenotype similar to that seen in DMD/BMD patients.

DMD

DMD

BMD


Input: The mouse studies suggest a key role for the carboxyl terminal dystrophin isoform, Dp260, in retinal electrophysiology.


Input: We have undertaken a systematic evaluation of DMD/BMD patients through clinical examination and review of the literature in order to determine whether the position-specific effects of mutations noted in the mouse are present in man.

DMD

BMD


Input: We have found that, in man, a wider variation of DMD defects correlate with reductions in the b-wave amplitude.

DMD defects


Input: Individuals with normal ERGs have mutations predominantly located 5 of the transcript initiation site of Dp260.


Input: Our results suggest that the most important determinant in the ERG b-wave phenotype is the mutation position, rather than muscle disease severity.

muscle disease


Input: Forty-six per cent of patients with mutations 5 of the Dp260 transcript start site have abnormal ERGs, as opposed to 94% with more distal mutations.


Input: The human genotype-phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission..


Input: Cis and trans effects of the myotonic dystrophy (DM) mutation in a cell culture model.

myotonic dystrophy

DM


Input: The mutation causing myotonic dystrophy (DM) has been identified as a CTG expansion in the 3-untranslated region (3-UTR) of the DM protein kinase gene (DMPK), but the mechanism (s) of pathogenesis remain unknown.

myotonic dystrophy

DM

DM


Input: Studies using DM patient materials have often produced confusing results.

DM


Input: Therefore, to study the effects of the DM mutation in a controlled environment, we have established a cell culture model system using C2C12 mouse myoblasts.

DM


Input: By expressing chimeric reporter constructs containing a reporter gene fused to a human DMPK 3-UTR, we identified both cis and trans effects that are mediated by the DM mutation.

DMPK


Input: Our data show that a mutant DMPK 3-UTR, with as few as 57 CTGs, had a negative cis effect on protein expression and resulted in the aggregation of reporter transcripts into discrete nuclear foci.


Input: We determined by deletion analysis that an expanded (CTG) (n) tract alone was sufficient to mediate these cis effects.


Input: Furthermore, in contrast to the normal DMPK 3-UTR mRNA, a mutant DMPK 3-UTR mRNA with (CUG) (200) selectively inhibited myogenic differentiation of C2C12 myoblasts.


Input: Genetic analysis and the Cre-loxP system were used to clearly demonstrate that the myoblast fusion defect could be rescued by eliminating the expression of the mutant DMPK 3-UTR transcript.


Input: Characterization of spontaneous deletion events mapped the inhibitory effect to the (CTG) (n) expansion and/or the 3 end of the DMPK 3-UTR.


Input: These results provide evidence that the DM mutation acts in cis to reduce protein production (consistent with DMPK haploinsufficiency) and in trans as a riboregulator to inhibit myogenesis..

DM

DMPK haploinsufficiency


Input: Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis.

Coats' disease

unilateral retinal telangiectasis


Input: Coats disease is characterized by abnormal retinal vascular development (so-called retinal telangiectasis) which results in massive intraretinal and subretinal lipid accumulation (exudative retinal detachment).

Coats disease

abnormal retinal vascular development

retinal telangiectasis

intraretinal and subretinal lipid accumulation

exudative retinal detachment


Input: The classical form of Coats disease is almost invariably isolated, unilateral and seen in males.

Coats disease


Input: A female with a unilateral variant of Coats disease gave birth to a son affected by Norrie disease.

Coats disease

Norrie disease


Input: Both carried a missense mutation within the NDP gene on chromosome Xp11.


Input: 2 2.


Input: Subsequently analysis of the retinas of nine enucleated eyes from males with Coats disease demonstrated in one a somatic mutation in the NDP gene which was not present within non-retinal tissue.

Coats disease


Input: We suggest that Coats telangiectasis is secondary to somatic mutation in the NDP gene which results in a deficiency of norrin (the protein product of the NDP gene) within the developing retina.

Coats telangiectasis

deficiency of norrin


Input: This supports recent observations that the protein is critical for normal retinal vasculogenesis.


Input: Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in a Li-Fraumeni syndrome family.

Li-Fraumeni syndrome


Input: Li-Fraumeni syndrome is an autosomal dominant disorder that is characterized by various types of cancer in childhood and adult cases.

Li-Fraumeni syndrome

autosomal dominant disorder

cancer


Input: Although hereditary TP53 mutation is very rare in different human cancers, it has been frequently reported in Li-Fraumeni syndrome.

cancers

Li-Fraumeni syndrome


Input: On the other hand, hereditary mutations of TP57KIP2, P15INK4B, and P16INK4A, which affect the cell cycle similar to TP53, were observed in some types of cancer.

cancer


Input: In a Turkish family with the diagnosis of Li-Fraumeni syndrome, we analyzed the mutation pattern of TP53, P57KIP2, P15INK4B, and P16INK4A in the peripheral blood, and loss of heterozygosity (homo/hemizygous deletion) pattern of TP53 and P15INK4B/P16INK4A in two tumor tissues.

Li-Fraumeni syndrome

tumor


Input: The propositus had a seminoma, his daughter a medulloblastoma, and one of his healthy cousins, a TP53 codon 292 missense point mutation (AAA--> ATA; Lys--> Ile) in the peripheral blood cells.

seminoma

medulloblastoma


Input: Tumor tissue obtained from the propositus with the seminoma revealed loss of heterozygosity in the TP53 gene.

seminoma


Input: In the analyses of tumor tissues from the propositus and his daughter, a P16INK4A codon 94 missense point mutation (GCG--> GAG; Ala--> Glu) was observed with the hereditary TP53 mutation.

tumor


Input: P16INK4A codon 94 mutation observed in our family is a novel mutation in Li-Fraumeni syndrome.

Li-Fraumeni syndrome


Input: No other gene alteration in TP53, P57KIP2, P15INK4B, and P16INK4A was observed.


Input: Existence of the P16INK4A mutation and the hereditary TP53 mutation with or without loss of heterozygosity in the TP53 gene (seminoma/medulloblastoma) may be evidence for a common mechanism involved in tumorogenesis.

seminoma

medulloblastoma

tumorogenesis


Input: The gene alterations in TP53 and P16INK4A genes may be used as tumor markers in our family..

tumor


Input: A novel mutation in the sodium/iodide symporter gene in the largest family with iodide transport defect.

iodide transport defect


Input: We previously reported nine children with an autosomally recessive form of congenital hypothyroidism due to an iodide transport defect in a large Hutterite family with extensive consanguinity living in central Canada.

congenital hypothyroidism

iodide transport defect


Input: Since the original report, we have diagnosed congenital hypothyroidism by newborn TSH screening in 9 additional children from the family.

congenital hypothyroidism


Input: We performed direct sequencing of the PCR products of each NIS (sodium/iodide symporter) gene exon with flanking introns amplified from genomic DNA extracted from peripheral blood cells of the patients.


Input: We identified a novel NIS gene mutation, G395R (Gly395--> Arg; GGA--> AGA), in 10 patients examined in the present study.


Input: All of the parents tested were heterozygous for the mutation, suggesting that the patients were homozygous.


Input: The mutation was located in the 10th transmembrane helix.


Input: Expression experiments by transfection of the mutant NIS complimentary DNA into COS-7 cells showed no perchlorate-sensitive iodide uptake, confirming that the mutation is the direct cause of the iodide transport defect in these patients.

iodide transport defect


Input: A patient who showed an intermediate saliva/serum technetium ratio (14. 0; normal, > or = 20) and was considered to have a partial or less severe defect in the previous report (IX-24) did not have a NIS gene mutation.


Input: It is now possible to use gene diagnostics of this unique NIS mutation to identify patients with congenital hypothyroidism due to an iodide transport defect in this family and to determine the carrier state of potential parents for genetic counseling and arranging rapid and early diagnosis of their infants.

congenital hypothyroidism

iodide transport defect


Input: Molecular analysis in familial neurohypophyseal diabetes insipidus: early diagnosis of an asymptomatic carrier.

familial neurohypophyseal diabetes insipidus


Input: Familial neurohypophyseal diabetes insipidus (FNDI) is an inherited deficiency of the hormone arginine vasopressin (AVP) and is transmitted as an autosomal dominant trait.

Familial neurohypophyseal diabetes insipidus

FNDI

deficiency of the hormone arginine vasopressin


Input: In the present study we have analyzed the AVP-neurophysin II (AVP-NPII) gene in a Spanish kindred.


Input: Studies were performed on seven members (four clinically affected) of the family.


Input: Patients were diagnosed at the Hospital Universitario Gregorio Maranon (Madrid, Spain).


Input: The entire coding region of the AVP-NPII gene of all family members was amplified by PCR and sequenced.


Input: All affected individuals presented a missense mutation (G1757--> A) that replaces glycine at position 23 with arginine within the NPII domain.


Input: The substitution was confirmed by restriction endonuclease analysis and was present in heterozygosis.


Input: Additionally, one of the asymptomatic relatives (a girl 8 months old at the time of study) was identified as carrier of the same mutation and developed the disease 3 months later.


Input: The alteration found in the second exon of the gene in this family seems to be responsible for the disease, as all individuals harboring the mutation had been previously diagnosed or have eventually developed FNDI.

FNDI


Input: Identification of the molecular defect underlying FNDI in affected families is a powerful tool for early asymptomatic diagnosis in infants..

FNDI


Input: Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia.

Friedreich ataxia


Input: Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs.

Friedreich ataxia

FRDA

inherited ataxias

autosomal recessive degenerative disorder

progressive gait and limb ataxia

absence of deep tendon reflexes

extensor plantar responses

loss of position and vibration sense


Input: FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients.

FRDA

FRDA


Input: The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients.

FRDA

FRDA


Input: Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron.


Input: Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients.

FRDA


Input: Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V (max)) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V (max) and the number of GAA repeats in the smaller allele.

FRDA


Input: Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition..

FRDA

mitochondrial disorder


Input: Identification of a novel R21X mutation in the liver-type arginase gene (ARG1) in four Portuguese patients with argininemia.

argininemia


Input: Argininemia is a rare autossomal recessive disorder caused by deficiency in the cytosolic liver-type arginase enzyme (L-arginine urea-hydrolase; E. C. 3. 5. 3. 1).

Argininemia

autossomal recessive disorder

deficiency in the cytosolic liver-type arginase enzyme


Input: In order to investigate the molecular basis for argininemia in four unrelated Portuguese patients (two from northern Portugal and two from Madeira Island) we performed a DNA sequence analysis of all the exons and exon/intron boundaries of the liver-type arginase gene (ARG1).

argininemia


Input: All patients were found to be homozygous for a newly identified C-> T transition in codon 21 (exon 2) substituting arginine for a premature stop codon (R21X CGA to TGA) and generating a NlaIII restriction site.


Input: Restriction digestion following PCR amplification of ARG1 exon 2 confirmed the presence of the mutation.


Input: Mutation of the sterol 27-hydroxylase gene (CYP27) results in truncation of mRNA expressed in leucocytes in a Japanese family with cerebrotendinous xanthomatosis.

cerebrotendinous xanthomatosis


Input: OBJECTIVES A Japanese family with cerebrotendinous xanthomatosis (CTX) was investigated for a sequence alteration in the sterol 27-hydroxylase gene (CYP27).

cerebrotendinous xanthomatosis

CTX


Input: The expression of CYP27 has been mostly explored using cultured fibroblasts, prompting the examination of the transcripts from blood leucocytes as a simple and rapid technique.


Input: METHODS An alteration in CYP27 of the proband was searched for by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and subsequent sequencing.


Input: Samples of RNA were subjected to reverse transcription PCR (RT-PCR) and the product of the proband was amplified with nested primers and sequenced.


Input: RESULTS A homozygous G to A transition at the 5 end of intron 7 was detected in the patient.


Input: In RT-PCR analysis, only a truncated transcript was detected in the patient, whereas both normal and truncated transcripts were detected in the siblings.


Input: The sequencing of the patients cDNA fragment disclosed a direct conjuction of exon 6 and exon 8.


Input: CONCLUSION The mutation at splice donor site and the truncation of mRNA were identical with those of a recently reported Italian patient, although different in symptomatology.


Input: The application of blood leucocytes can be a simple technique on analysing a constructive abnormality of CYP27 mRNA..

abnormality of CYP27


Input: Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1.

Wolfram syndrome


Input: Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and progressive optic atrophy.

Wolfram syndrome

autosomal recessive neurodegenerative disorder

juvenile-onset diabetes mellitus

optic atrophy


Input: mtDNA deletions have been described, and a gene (WFS1) recently has been identified, on chromosome 4p16, encoding a predicted 890 amino acid transmembrane protein.


Input: Direct DNA sequencing was done to screen the entire coding region of the WFS1 gene in 30 patients from 19 British kindreds with Wolfram syndrome.

Wolfram syndrome


Input: DNA was also screened for structural rearrangements (deletions and duplications) and point mutations in mtDNA.


Input: No pathogenic mtDNA mutations were found in our cohort.


Input: We identified 24 mutations in the WFS1 gene 8 nonsense mutations, 8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations.


Input: Of these, 23 were novel mutations, and most occurred in exon 8.


Input: The majority of patients were compound heterozygotes for two mutations, and there was no common founder mutation.


Input: The data were also analyzed for genotype-phenotype relationships.


Input: Although some interesting cases were noted, consideration of the small sample size and frequency of each mutation indicated no clear-cut correlations between any of the observed mutations and disease severity.


Input: There were no obvious mutation hot spots or clusters.


Input: Hence, molecular screening for Wolfram syndrome in affected families and for Wolfram syndrome-carrier status in subjects with psychiatric disorders or diabetes mellitus will require complete analysis of exon 8 and upstream exons..

Wolfram syndrome

Wolfram syndrome

psychiatric disorders

diabetes mellitus


Input: Late-onset familial Mediterranean fever (FMF): a subset with distinct clinical, demographic, and molecular genetic characteristics.

familial Mediterranean fever

FMF


Input: To determine the prevalence and characterize demographic, clinical, and genetic features of familial Mediterranean fever (FMF) of late onset, all patients experiencing their first FMF attack at age 40 years or more were identified using the computerized registry of our FMF clinic, and then thoroughly interviewed and examined.

familial Mediterranean fever

FMF

FMF

FMF


Input: The control group consisted of 40 consecutive FMF patients, who arrived at the FMF clinic for their regular follow-up visit and were 40 years of age or older at the time of the examination.

FMF

FMF


Input: The severity of the disease in patients and controls was determined using a modified score, developed previously.


Input: Mutational analysis in the FMF gene was performed using a commercial kit.

FMF


Input: Only 20 of 4000 (0. 5%) patients had late-onset FMF.

FMF


Input: These patients were mostly men, of non-North African origin, P < 0.


Input: 05 compared to controls.


Input: All had abdominal attacks and in most these were the only manifestation of their disease, P < 0.


Input: 001 001.


Input: None had chronic or prolonged manifestations of FMF, for example, amyloidosis, chronic arthritis, or protracted myalgia, P < 0.

FMF

amyloidosis

chronic arthritis

myalgia


Input: The response to treatment was good despite using low colchicine dose, P < 0.


Input: The overall severity score indicated a mild disease, P < 0.


Input: Mutational analysis revealed absence of M694V homozygosity, P < 0.


Input: 01, compared to our regular FMF population.

FMF


Input: We conclude that the onset of FMF in a late age defines a milder form of disease with typical clinical, demographic, and molecular genetic characteristics

FMF


Input: A highly accurate, low cost test for BRCA1 mutations.


Input: The hereditary breast and ovarian cancer syndrome is associated with a high frequency of BRCA1 mutations.

hereditary breast and ovarian cancer syndrome


Input: However, the widespread use of BRCA1 testing has been limited to date by three principal concerns the fear of loss of health and life insurance, the uncertain clinical value of a positive test result, and the current lack of an inexpensive and sensitive screening test for BRCA1 mutations.


Input: We have developed an inexpensive system for gene mutational scanning, based on a combination of extensive multiplex PCR amplification and two dimensional electrophoresis.


Input: The efficiency of this system, as a screening test for BRCA1 mutations, was evaluated in a panel of 60 samples from high risk women, 14 of which contained a previously identified mutation in BRCA1.


Input: All 14 mutations were identified, as well as an additional five that had previously escaped detection.


Input: In addition to the 19 mutations, a total of 15 different polymorphic variants were scored, most of which were recurring.


Input: All were confirmed by nucleotide sequencing.


Input: The cost of screening per sample was calculated to be approximately US $70 for the manual technique used in this study, and may be reduced to approximately US $10 with the introduction of commercially available PCR robotics and fluorescent imaging.


Input: Implementation of this method of mutation screening in the research and clinical setting should permit rapid accrual of quantitative data on genotype-phenotype associations for the evaluation of diagnostic testing..


Input: Maternal uniparental disomy for chromosome 14 in a boy with a normal karyotype.

Maternal uniparental disomy for chromosome 14


Input: We report on a boy with a maternal uniparental disomy for chromosome 14 (UPD (14)).

maternal uniparental disomy for chromosome 14

UPD


Input: At 7 years of age he was referred to us by the paediatrician because of symptoms of Prader-Willi syndrome (PWS).

Prader-Willi syndrome

PWS


Input: He showed short stature, obesity, mild developmental delay, cryptorchidism, and some mild dysmorphic features.

short stature

obesity

developmental delay

cryptorchidism

dysmorphic features


Input: The history further indicated intrauterine growth retardation at the end of the pregnancy.

intrauterine growth retardation


Input: His mother was 44 years of age at the time of his birth.


Input: After birth he showed hypotonia with poor sucking, for which gavage feeding was needed.

hypotonia


Input: Motor development was delayed.


Input: After 1 year he became obese despite a normal appetite.

obese


Input: Recurrent middle ear infections, a high pain threshold, and a great skill with jigsaw puzzles were reported.

middle ear infections


Input: There were no behavioural problems or sleep disturbance.


Input: Chromosomal analysis was normal (46, XY).


Input: DNA analysis for Prader-Willi syndrome showed no abnormalities.

Prader-Willi syndrome


Input: Two years later he was re-examined because we thought his features fitted the PWS-like phenotype associated with maternal UPD (14).

PWS

UPD


Input: At that time precocious puberty was evident.


Input: DNA analysis showed maternal heterodisomy for chromosome 14.

maternal heterodisomy


Input: In all the previously described 11 cases with maternal UPD (14), a Robertsonian translocation involving chromosome 14 was detected cytogenetically before DNA analysis.

UPD


Input: This is the first report of diagnosis of maternal UPD (14) based on clinical features.

UPD


Input: This finding underlines the importance of DNA analysis for maternal UPD (14) in patients with a similar PWS-like phenotype even without previous identification of a Robertsonian translocation involving chromosome 14..

PWS


Input: Clinical and genetic study of Friedreich ataxia in an Australian population.

Friedreich ataxia


Input: Friedreich ataxia is an autosomal recessive disorder caused by mutations in the FRDA gene that encodes a 210-amino acid protein called frataxin.

Friedreich ataxia

autosomal recessive disorder

FRDA


Input: An expansion of a GAA trinucleotide repeat in intron 1 of the gene is present in more than 95% of mutant alleles.


Input: Of the 83 people we studied who have mutations in FRDA, 78 are homozygous for an expanded GAA repeat; the other five patients have an expansion in one allele and a point mutation in the other.


Input: Here we present a detailed clinical and genetic study of a subset of 51 patients homozygous for an expansion of the GAA repeat.


Input: We found a correlation between the size of the smaller of the two expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity.

scoliosis

foot deformity


Input: There was no significant correlation between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms.

cardiomyopathy

diabetes mellitus

loss of proprioception

bladder symptoms


Input: The larger allele size correlated with bladder symptoms and the presence of foot deformity.

bladder symptoms

foot deformity


Input: The duration of disease is correlated with wheelchair use and the presence of diabetes, scoliosis, bladder symptoms and impaired proprioception, and vibration sense but no other complications studied..

diabetes

scoliosis

bladder symptoms

impaired proprioception


Input: Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change.

retinoschisis


Input: Juvenile retinoschisis is an X-linked recessive disease caused by mutations in the XLRS1 gene.

Juvenile retinoschisis

X-linked recessive disease


Input: We screened 31 new unrelated patients and families for XLRS1 mutations in addition to previously reported mutations for 60 of our families (Retinoschisis Consortium, Hum Mol Genet 1998; 7 1185-1192).

Retinoschisis


Input: Twenty-three different mutations including 12 novel ones were identified in 28 patients.


Input: Mutations identified in this study include 19 missense mutations, two nonsense mutations, one intragenic deletion, four microdeletions, one insertion, and one intronic sequence substitution that is likely to result in a splice site defect.


Input: Two novel mutations, c.


Input: 38T--> C (L13P) and c.


Input: 667T--> C (C223R), respectively, present the first genetic evidence for the functional significance of the putative leader peptide sequence and for the functional significance at the carboxyl terminal of the XLRS1 protein beyond the discoidin domain.


Input: Mutations in 25 of the families were localized to exons 4-6, emphasizing the critical functional significance of the discoidin domain of the XLRS1 protein


Input: Growth hormone treatment increases CO (2) response, ventilation and central inspiratory drive in children with Prader-Willi syndrome.

Prader-Willi syndrome


Input: We studied whether the beneficial effects of growth hormone (GH) treatment on growth and body composition in PWS are accompanied by an improvement in respiratory function.

PWS


Input: We measured resting ventilation, airway occlusion pressure (P (0. 1)) and ventilatory response to CO (2) in nine children, aged 7-14 years, before and 6-9 months after the start of GH treatment.


Input: During GH treatment, resting ventilation increased by 26%, P (0. 1) by 72% and the response to CO (2) by 65% (P < 0. 002, < 0. 04 and < 0. 02, respectively).


Input: This observed increase in ventilatory output was not correlated to changes in body mass index.


Input: CONCLUSION Treatment of children with Prader-Willi syndrome (PWS) seems to have a stimulatory effect on central respiratory structures.

Prader-Willi syndrome

PWS


Input: The observed increase in ventilation and inspiratory drive may contribute to the improved activity level reported by parents of PWS children during growth hormone therapy

PWS


Input: G130V, a common FRDA point mutation, appears to have arisen from a common founder.

FRDA


Input: Friedreich ataxia (FRDA) is the most common inherited ataxia.

Friedreich ataxia

FRDA

inherited ataxia


Input: About 98% of mutant alleles have an expansion of a GAA trinucleotide repeat in intron 1 of the affected gene, FRDA.


Input: The other 2% are point mutations.


Input: Of the 17 point mutations so far described, three appear to be more common.


Input: One of these is the G130V mutation in exon 4 of FRDA.


Input: G130V, when present with an expanded GAA repeat on the other allele, is associated with an atypical FRDA phenotype.

FRDA


Input: Haplotype analysis was undertaken on the four families who have been described with this mutation.


Input: The results suggest a common founder for this mutation.


Input: Although marked differences in extragenic marker haplotypes were seen in one family, similar intragenic haplotyping suggests the same mutation founder for this family with the differences explicable by two recombination events..


Input: Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene.


Input: Most fragile X syndrome patients have expansion of a (CGG) (n) sequence with > 200 repeats (full mutation) in the FMR1 gene responsible for this condition.

fragile X syndrome


Input: Hypermethylation of the expanded repeat and of the FMR1 promoter is almost always present and apparently suppresses transcription, resulting in absence of the FMR1 protein.


Input: We recently showed that transcriptional reactivation of FMR1 full mutations can be achieved by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC).


Input: The level of histone acetylation is another important factor in regulating gene expression; therefore, we treated lymphoblastoid cell lines of non-mosaic full mutation patients with three drugs capable of inducing histone hyperacetylation.


Input: We observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate and trichostatin A, as shown by RT-PCR.


Input: However, we report that combining these drugs with 5-azadC results in a 2-to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a marked synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations..


Input: Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.

von Hippel-Lindau

VHL

VHL


Input: von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer syndrome predisposing to a variety of tumor types that include retinal hemangioblastomas, hemangioblastomas of the central nervous system, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, endolymphatic sac tumors, and epididymal cystadenomas [W.

von Hippel-Lindau (VHL) disease

autosomal dominantly inherited cancer syndrome

tumor

hemangioblastomas

hemangioblastomas

renal cell carcinomas

pancreatic cysts and tumors

pheochromocytomas

endolymphatic sac tumors

epididymal cystadenomas


Input: M.


Input: Linehan et al., J.


Input: Am. Med. Assoc., 273 564-570, 1995; E. A. Maher and W. G. Kaelin, Jr., Medicine (Baltimore), 76 381-391, 1997; W. M. Linehan and R. D. Klausner, In B. Vogelstein and K. Kinzler (eds.), The Genetic Basis of Human Cancer, pp.


Input: 455-473, McGraw-Hill, 1998].


Input: The VHL gene was localized to chromosome 3p25-26 and cloned [F. Latif et al., Science (Washington DC), 260 1317-1320, 1993].

VHL


Input: Germline mutations in the VHL gene have been detected in the majority of VHL kindreds.

VHL

VHL


Input: The reported frequency of detection of VHL germline mutations has varied from 39 to 80% (J. M. Whaley et al., Am. J. Hum. Genet., 55 1092-1102, 1994; Clinical Research Group for Japan, Hum. Mol. Genet., 4 2233-2237, 1995; F. Chen et al., Hum. Mutat., 5 66-75, 1995; E. R. Maher et al., J. Med. Genet., 33 328-332, 1996; B. Zbar, Cancer Surv., 25 219-232, 1995).

VHL


Input: Recently a quantitative Southern blotting procedure was found to improve this frequency (C. Stolle et al., Hum. Mutat., 12 417-423, 1998).


Input: In the present study, we report the use of fluorescence in situ hybridization (FISH) as a method to detect and characterize VHL germline deletions.

VHL


Input: We reexamined a group of VHL patients shown previously by single-strand conformation and sequencing analysis not to harbor point mutations in the VHL locus.

VHL

VHL


Input: We found constitutional deletions in 29 of 30 VHL patients in this group using cosmid and P1 probes that cover the VHL locus.

VHL

VHL


Input: We then tested six phenotypically normal offspring from four of these VHL families two were found to carry the deletion and the other four were deletion-free.

VHL


Input: In addition, germline mosaicism of the VHL gene was identified in one family.

VHL


Input: In sum, FISH was found to be a simple and reliable method to detect VHL germline deletions and practically useful in cases where other methods of screening have failed to detect a VHL gene abnormality

VHL


Input: Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations.

cancer


Input: The hSNF5/INI1 gene which encodes a member of the SWI/SNF chromatin ATP-dependent remodeling complex, is a new tumor suppressor gene localized on chromosome 22q11.

tumor


Input: 2 and recently shown to be mutated in malignant rhabdoid tumors.

malignant rhabdoid tumors


Input: We have searched for hSNF5/INI1 mutations in 229 tumors of various origins using a screening method based on denaturing high-performance liquid chromatography.

tumors


Input: A total of 31 homozygous deletions and 36 point alterations were identified.


Input: Point mutations were scattered along the coding sequence and included 15 nonsense, 15 frameshift, three splice site, two missense and one editing mutations.


Input: Mutations were retrieved in most rhabdoid tumors, whatever their sites of occurrence, indicating the common pathogenetic origin of these tumors.

rhabdoid tumors

tumors


Input: Recurrent hSNF5/INI1 alterations were also observed in choroid plexus carcinomas and in a subset of central primitive neuroectodermal tumors (cPNETs) and medulloblastomas.

choroid plexus carcinomas

neuroectodermal tumors

medulloblastomas


Input: In contrast, hSNF5/INI1 point mutations were not detected in breast cancers, Wilms tumors, gliomas, ependymomas, sarcomas and other tumor types, even though most analyzed cases harbored loss of heterozygosity at 22q11.

breast cancers

Wilms tumors

gliomas

ependymomas

sarcomas

tumor


Input: 2 loci.


Input: These results suggest that rhabdoid tumors, choroid plexus carcinomas and a subset of medulloblastomas and cPNETs share common pathways of oncogenesis related to hSNF5/INI1 alteration and that hSNF5/INI1 mutations define a genetically homogeneous family of highly aggressive cancers mainly occurring in young children and frequently, but not always, exhibiting a rhabdoid phenotype

rhabdoid tumors

choroid plexus carcinomas

medulloblastomas

cancers

rhabdoid


Input: Ataxin-3 with an altered conformation that exposes the polyglutamine domain is associated with the nuclear matrix.


Input: Spinocerebellar ataxia type-3 or Machado-Joseph disease (SCA3/MJD) is a member of the CAG/polyglutamine repeat disease family.

Spinocerebellar ataxia type-3

Machado-Joseph disease

MJD

CAG/polyglutamine repeat disease


Input: In this family of disorders, a normally polymorphic CAG repeat becomes expanded, resulting in expression of an expanded polyglutamine domain in the disease gene product.


Input: Experimental models of polyglutamine disease implicate the nucleus in pathogenesis; however, the link between intranuclear expression of expanded polyglutamine and neuronal dysfunction remains unclear.

polyglutamine disease

neuronal dysfunction


Input: Here we demonstrate that ataxin-3, the disease protein in SCA3/MJD, adopts a unique conformation when expressed within the nucleus of transfected cells.

MJD


Input: The monoclonal antibody 1C2 is known preferentially to bind expanded polyglutamine, but we find that it also binds a fragment of ataxin-3 containing a normal glutamine repeat.


Input: In addition, expression of ataxin-3 within the nucleus exposes the glutamine domain of the full-length non-pathological protein, allowing it to bind the monoclonal antibody 1C2.


Input: Fractionation and immunochemical experiments indicate that this novel conformation of intranuclear ataxin-3 is not due to proteolysis, suggesting instead that association with nuclear protein (s) alters the structure of full-length ataxin-3 which exposes the polyglutamine domain.


Input: This conformationally altered ataxin-3 is bound to the nuclear matrix.


Input: The pathological form of ataxin-3 with an expanded polyglutamine domain also associates with the nuclear matrix.


Input: These data suggest that an early event in the pathogenesis of SCA3/MJD may be an altered conformation of ataxin-3 within the nucleus that exposes the polyglutamine domain..

MJD


Input: The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region.

Prader-Willi


Input: Prader-Willi syndrome (PWS) is a complex neurogenetic disorder.

Prader-Willi syndrome

PWS

neurogenetic disorder


Input: The phenotype is likely to be a contiguous gene syndrome involving genes which are paternally expressed only, located in the human 15q11-q13 region.

contiguous gene syndrome


Input: Four mouse models of PWS have been reported but these do not definitively allow the delineation of the critical region and the associated genes involved in the aetiology of PWS.

PWS

PWS


Input: Moreover, targeted mutagenesis of mouse homologues of the human candidate PWS genes does not appear to result in any of the features of PWS.

PWS

PWS


Input: Therefore, the isolation of new genes in this region remains crucial for a better understanding of the molecular basis of PWS.

PWS


Input: In this manuscript, we report the characterization of MAGEL2 and its mouse homologue Magel2.


Input: These are located in the human 15q11-q13 and mouse 7C regions, in close proximity to NDN/Ndn.


Input: By northern blot analysis we did not detect any expression of MAGEL2/Magel2 but by RT-PCR analysis, specific expression was detected in fetal and adult brain and in placenta.


Input: Both genes are intronless with tandem direct repeat sequences contained within a CpG island in the 5-untranscribed region.


Input: The transcripts encode putative proteins that are homologous to the MAGE proteins and NDN.


Input: Moreover, MAGEL2/Magel2 are expressed only from the paternal allele in brain, suggesting a potential role in the aetiology of PWS and its mouse model, respectively..

PWS


Input: cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene.


Input: Alveolar rhabdomyosarcoma is an aggressive pediatric cancer of striated muscle characterized in 60% of cases by a t (2; 13) (q35; q14).

Alveolar rhabdomyosarcoma

pediatric cancer of striated muscle


Input: This results in the fusion of PAX3, a developmental transcription factor required for limb myogenesis, with FKHR, a member of the forkhead family of transcription factors.


Input: The resultant PAX3-FKHR gene possesses transforming properties; however, the effects of this chimeric oncogene on gene expression are largely unknown.


Input: To investigate the actions of these transcription factors, both Pax3 and PAX3-FKHR were introduced into NIH 3T3 cells, and the resultant gene expression changes were analyzed with a murine cDNA microarray containing 2, 225 elements.


Input: We found that PAX3-FKHR but not PAX3 activated a myogenic transcription program including the induction of transcription factors MyoD, Myogenin, Six1, and Slug as well as a battery of genes involved in several aspects of muscle function.


Input: Notable among this group were the growth factor gene Igf2 and its binding protein Igfbp5.


Input: Relevance of this model was suggested by verification that three of these genes (IGFBP5, HSIX1, and Slug) were also expressed in alveolar rhabdomyosarcoma cell lines.

alveolar rhabdomyosarcoma


Input: This study utilizes cDNA microarrays to elucidate the pattern of gene expression induced by an oncogenic transcription factor and demonstrates the profound myogenic properties of PAX3-FKHR in NIH 3T3 cells..


Input: Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism.

hemochromatosis

HFE deficiency


Input: The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified.

hemochromatosis


Input: Indeed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function.


Input: As yet, our understanding of HFE function in iron homeostasis is only partial; an even more open question is its possible role in the immune system.


Input: To advance on both of these avenues, we report the deletion of HFE alpha1 and alpha2 putative ligand binding domains in vivo.


Input: HFE-deficient animals were analyzed for a comprehensive set of metabolic and immune parameters.

HFE-deficient


Input: Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load.

hemochromatosis


Input: The primary defect could, indeed, be traced to an augmented duodenal iron absorption.


Input: In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis.


Input: Finally, an extensive phenotyping of primary and secondary lymphoid organs including the gut provides no compelling evidence for an obvious immune-linked function for HFE..


Input: Somatic rearrangement of chromosome 14 in human lymphocytes.


Input: Ataxia-telangiectasia is a rare genetic disorder associated with immune deficiency, chromosome instability, and a predisposition to lymphoid malignancy.

Ataxia-telangiectasia

genetic disorder

immune deficiency

chromosome instability

lymphoid malignancy


Input: We have detected chromosomally anomalous clones of lymphocytes in eight patients with this disorder.


Input: Chromosome banding disclosed that the clones are consistently marked by structural rearrangement of the long arm (q) of chromosome 14.


Input: A translocation involving 14q was found in clones obtained from seven of the eight patients whereas a ring 14 chromosome was found in a clone obtained from the other.


Input: These findings as well as data obtained by others for patients with ataxia-telangiectasia suggest that structural rearrangement of 14q is the initial chromosomal change in lymphocyte clones of patients with this disorder.

ataxia-telangiectasia


Input: Chromosomes of lymphocytes from one of the patients were studied before and after the onset of chronic lymphocytic leukemia.

chronic lymphocytic leukemia


Input: Before leukemia was diagnosed, the patient had a lymphocyte clone with a 14q translocation.

leukemia


Input: This clone appears to have given rise to the leukemic cells.

leukemic


Input: We hypothesize that structural rearrangement of 14q is directly related to abnormal growth of lymphocytes and that it may be a step toward the development of lymphoid malignancies.

lymphoid malignancies


Input: Increasing evidence, provided by others, for the nonrandom involvement of 14q in African-type Burkitts lymphoma and other lymphoid neoplasms further strengthens this hypothesis..

Burkitts lymphoma

lymphoid neoplasms


Input: Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome.

Frasier syndrome


Input: We report new mutations in exon 9 of the WT1 gene that did not alter the ratio of +/-KTS splice isoforms in two unrelated patients with Frasier syndrome (FS).

Frasier syndrome

FS


Input: The mutation of intron 9 inducing defective alternative splicing was reported to be responsible for this syndrome.


Input: The mutations found in our cases occurred in the same exon of the WT1 gene as detected in Denys-Drash syndrome (DDS) and could not be explained by the previously proposed mechanism.

Denys-Drash syndrome

DDS


Input: The results suggest that the two syndromes originate from the same WT1 gene abnormality.

WT1 gene abnormality


Input: From a molecular biological point of view, we concluded that the two diseases were not separable, and that FS should be included as an atypical form of DDS..

FS

DDS


Input: Splice-site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome.

PDS

deafness

Pendred syndrome


Input: Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter).

Pendred syndrome

recessive inherited disorder

developmental abnormalities of the cochlea

sensorineural hearing loss

diffuse thyroid enlargement

goiter


Input: This disorder may account for up to 10% of cases of hereditary deafness.

hereditary deafness


Input: The disease gene (PDS) has been mapped to chromosome 7q22-q31, and encodes a chloride-iodide transport protein.

PDS


Input: We performed mutation analysis of individual exons of the PDS gene in one Spanish family that shows intrafamilial variability of the deafness phenotype (two patients with profound and one with moderate-severe deafness).

PDS

deafness

deafness


Input: We identified a new splice-site mutation affecting intron 4 of the PDS gene, at nucleotide position 639 + 7.

PDS


Input: RNA analysis from lymphocytes of the affected patients showed that mutation 639 + 7A--> G generates a new donor splice site, leading to an mRNA with an insertion of six nucleotides from intron 4 of PDS.


Input: Since the newly created donor splice site is likely to compete with the normal one, variations of the levels of normal and aberrant transcripts of the PDS gene in the cochlea may explain the variability in the deafness presentation..

PDS

deafness


Input: The molecular basis of Sjogren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene.

Sjogren-Larsson syndrome


Input: Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity, and deficient activity of fatty aldehyde dehydrogenase (FALDH).

Sjogren-Larsson syndrome

SLS

autosomal recessive disorder

ichthyosis

mental retardation

spasticity

deficient activity of fatty aldehyde dehydrogenase


Input: To define the molecular defects causing SLS, we performed mutation analysis of the FALDH gene in probands from 63 kindreds with SLS.

SLS

SLS


Input: Among these patients, 49 different mutations-including 10 deletions, 2 insertions, 22 amino acid substitutions, 3 nonsense mutations, 9 splice-site defects, and 3 complex mutations-were found.


Input: All of the patients with SLS were found to carry mutations.

SLS


Input: Nineteen of the missense mutations resulted in a severe reduction of FALDH enzyme catalytic activity when expressed in mammalian cells, but one mutation (798G--> C [K266N]) seemed to have a greater effect on mRNA stability.


Input: The splice-site mutations led to exon skipping or utilization of cryptic acceptor-splice sites.


Input: Thirty-seven mutations were private, and 12 mutations were seen in two or more probands of European or Middle Eastern descent.


Input: Four single-nucleotide polymorphisms (SNPs) were found in the FALDH gene.


Input: At least four of the common mutations (551C--> T, 682C--> T, 733G--> A, and 798 + 1delG) were associated with multiple SNP haplotypes, suggesting that these mutations originated independently on more than one occasion or were ancient SLS genes that had undergone intragenic recombination.

SLS


Input: Our results demonstrate that SLS is caused by a strikingly heterogeneous group of mutations in the FALDH gene and provide a framework for understanding the genetic basis of SLS and the development of DNA-based diagnostic tests..

SLS

SLS


Input: Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.

periodontal disease

palmoplantar keratosis


Input: Papillon-Lefevre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients.

Papillon-Lefevre syndrome

keratosis palmoplantaris

periodontopathia

PLS

autosomal recessive disorder

periodontitis


Input: Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss.

tooth loss


Input: Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life.

Palmoplantar keratosis

hyperkeratosis


Input: Keratosis also affects other sites such as elbows and knees.

Keratosis


Input: Most PLS patients display both periodontitis and hyperkeratosis.

PLS

periodontitis

hyperkeratosis


Input: Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset.

palmoplantar keratosis

periodontitis

periodontitis


Input: The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9).


Input: Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.


Input: 2-cM interval between D11S4082 and D11S931.


Input: The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval.


Input: We defined the genomic structure of CTSC and found mutations in all eight families.


Input: In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

PLS


Input: Confirmation of linkage of Van der Woude syndrome to chromosome 1q32: evidence of association with STR alleles suggests possible unique origin of the disease mutation.

Van der Woude syndrome


Input: Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression.

Van der Woude syndrome

VWS

autosomal dominant craniofacial disorder


Input: Its clinical features are variably expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia.

cleft lip

cleft palate

lip pits

hypodontia


Input: All VWS families studied to date map the disease gene to a < 2 cM region of chromosome 1q32, with no evidence of locus heterogeneity.

VWS


Input: The aim of this study is to refine the localization of the VWS gene and to further assess possible heterogeneity.

VWS


Input: We analyzed four multiplex VWS families.

VWS


Input: All available members were clinically assessed and genotyped for 19 short tandem repeat markers on chromosome 1 in the VWS candidate gene region.

VWS


Input: We performed two-point and multipoint limit of detection (LOD) score analyses using a high penetrance autosomal dominant model.


Input: All families showed positive LOD scores without any recombination in the candidate region.


Input: The largest two-point LOD score was 5.


Input: 87 87.


Input: Our assay method for short tandem repeat (STR) markers provided highly accurate size estimation of marker allele fragment sizes, and therefore enabled us to determine the specific alleles segregating with the VWS gene in each of our four families.

VWS


Input: We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the US.

VWS


Input: These results suggest the possibility of a unique origin for a mutation responsible for many or most cases of VWS.

VWS


Input: A point mutation Thr (799) Met on the alpha (2) integrin leads to the formation of new human platelet alloantigen Sit (a) and affects collagen-induced aggregation.


Input: A new platelet-specific alloantigen, termed Sit (a), was identified in a severe case of neonatal alloimmune thrombocytopenia.

neonatal alloimmune thrombocytopenia


Input: The Sit (a) alloantigen is of low frequency (1/400) in the German population.


Input: Immunochemical studies demonstrated that the Sit (a) epitopes reside on platelet glycoprotein (GP) Ia.


Input: Nucleotide sequence analysis of GPIa cDNA derived from Sit (a)-positive platelets showed C (2531)--> T (2531) point mutation, resulting in Thr (799) Met dimorphism.


Input: Analysis of genomic DNA from 22 Sit (a)-negative normal individuals showed that the Thr (799) is encoded by ACG (2532) (90. 9%) or ACA (2532) (9. 1%).


Input: To establish a DNA typing technique, we elucidated the organization of the GPIa gene adjacent to the polymorphic bases.


Input: The introns (421 bp and 1. 2 kb) encompass a 142-bp exon with the 2 polymorphic bases 2531 and 2532.


Input: Polymerase chain reaction-restriction fragment length polymorphism analysis on DNA derived from 100 donors using the restriction enzyme Mae III showed that the Met (799) form of GPIa is restricted to Sit (a) (+) phenotype.


Input: Analysis of stable Chinese hamster ovary transfectants expressing allele-specific recombinant forms of GPIa showed that anti-Sit (a) exclusively reacted with the Glu (505) Met (799), but not with the Glu (505) Thr (799) and the Lys (505) Thr (799) isoforms.


Input: In contrast, anti-Br (a) (HPA-5b) only recognized the Lys (505) Thr (799) form, whereas anti-Br (b) (HPA-5a) reacted with both Glu (505) Thr (799) and Glu (505) Met (799) isoforms.


Input: These results demonstrated that the Met (799) is responsible for formation of the Sit (a) alloantigenic determinants, whereas amino acid 505 (Lys or Glu) specifically controls the expression of Br (a) and Br (b) epitopes, respectively.


Input: Platelet aggregation responses of Sit (a) (+) individuals were diminished in response to collagen, indicating that the Thr (799) Met mutation affects the function of the GPIa/IIa complex


Input: Mutations of the cathepsin C gene are responsible for Papillon-Lefevre syndrome.

Papillon-Lefevre syndrome


Input: Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar hyperkeratosis and severe early onset periodontitis that results in the premature loss of the primary and secondary dentitions.

Papillon-Lefevre syndrome

PLS

autosomal recessive disorder

palmoplantar hyperkeratosis

periodontitis


Input: A major gene locus for PLS has been mapped to a 2.

PLS


Input: 8 cM interval on chromosome 11q14.


Input: Correlation of physical and genetic maps of this interval indicate it includes at least 40 ESTs and six known genes including the lysosomal protease cathepsin C gene (CTSC).


Input: The CTSC message is expressed at high levels in a variety of immune cells including polymorphonuclear leucocytes, macrophages, and their precursors.


Input: By RT-PCR, we found CTSC is also expressed in epithelial regions commonly affected by PLS, including the palms, soles, knees, and oral keratinised gingiva.

PLS