Input: The 4.


Input: 7 kb CTSC gene consists of two exons.


Input: Sequence analysis of CTSC from subjects affected with PLS from five consanguineous Turkish families identified four different mutations.

PLS


Input: An exon 1 nonsense mutation (856C--> T) introduces a premature stop codon at amino acid 286.


Input: Three exon 2 mutations were identified, including a single nucleotide deletion (2692delA) of codon 349 introducing a frameshift and premature termination codon, a 2 bp deletion (2673-2674delCT) that results in introduction of a stop codon at amino acid 343, and a G--> A substitution in codon 429 (2931G--> A) introducing a premature termination codon.


Input: All PLS patients were homozygous for cathepsin C mutations inherited from a common ancestor.

PLS


Input: Parents and sibs heterozygous for cathepsin C mutations do not show either the palmoplantar hyperkeratosis or severe early onset periodontitis characteristic of PLS.

palmoplantar hyperkeratosis

periodontitis

PLS


Input: A more complete understanding of the functional physiology of cathepsin C carries significant implications for understanding normal and abnormal skin development and periodontal disease susceptibility

periodontal disease


Input: Mutational analysis of the HGO gene in Finnish alkaptonuria patients.

alkaptonuria


Input: Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been shown to be caused by loss of function mutations in the homogentisate-1, 2-dioxygenase gene (HGO).

Alkaptonuria

AKU

inborn error of metabolism


Input: So far 17 mutations have been characterised in AKU patients of different ethnic origin.

AKU


Input: We describe three novel mutations (R58fs, R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and polymorphism analysis of the HGO gene in five Finnish AKU pedigrees.

AKU

AKU


Input: The three novel AKU mutations are most likely specific for the Finnish population and have originated recently..

AKU


Input: The identical 5' splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect.

attenuated APC


Input: Inherited mutations of the APC gene predispose carriers to multiple adenomatous polyps of the colon and rectum and to colorectal cancer.

APC

adenomatous polyps of the colon and rectum

colorectal cancer


Input: Mutations located at the extreme 5 end of the APC gene, however, are associated with a less severe disease known as attenuated adenomatous polyposis coli (AAPC).

APC

attenuated adenomatous polyposis coli

AAPC


Input: Many individuals with AAPC develop relatively few colorectal polyps but are still at high risk for colorectal cancer.

AAPC

colorectal polyps

colorectal cancer


Input: We report here the identification of a 5 APC germline mutation in five separately ascertained AAPC families from Newfoundland, Canada.

APC

AAPC


Input: This disease-causing mutation is a single basepair change (G to A) in the splice-acceptor region of APC intron 3 that creates a mutant RNA without exon 4 of APC.

APC


Input: The observation of the same APC mutation in five families from the same geographic area demonstrates a founder effect.

APC


Input: Furthermore, the identification of this germline mutation strengthens the correlation between the 5 location of an APC disease-causing mutation and the attenuated polyposis phenotype..

APC

attenuated polyposis


Input: Alstrom syndrome: further evidence for linkage to human chromosome 2p13.

Alstrom syndrome


Input: Alstrom syndrome is a rare autosomal recessive disorder characterized by retinal degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin-dependent diabetes mellitus.

Alstrom syndrome

autosomal recessive disorder

retinal degeneration

sensorineural hearing loss

obesity

non-insulin-dependent diabetes mellitus


Input: The gene for Alstrom syndrome (ALMS1) has been previously localized to human chromosome 2p13 by homozygosity mapping in two distinct isolated populations-French Acadian and North African.

Alstrom syndrome


Input: Pair-wise analyses resulted in maximum lod (logarithm of the odds ratio) scores of 3.


Input: 84 and 2.


Input: 9, respectively.


Input: To confirm these findings, a large linkage study was performed in twelve additional families segregating for Alstrom syndrome.

Alstrom syndrome


Input: A maximum two-point lod score of 7.


Input: 13 (theta = 0. 00) for marker D2S2110 and a maximum cumulative multipoint lod score of 9.


Input: 16 for marker D2S2110 were observed, further supporting linkage to chromosome 2p13.


Input: No evidence of genetic heterogeneity was observed in these families.


Input: Meiotic recombination events have localized the critical region containing ALMS1 to a 6.


Input: 1-cM interval flanked by markers D2S327 and D2S286.


Input: A fine resolution radiation hybrid map of 31 genes and markers has been constructed.


Input: Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation.

Pendred syndrome

PDS


Input: Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter, and positive perchlorate discharge test.

Pendred syndrome

congenital sensorineural hearing loss

thyroid goiter


Input: Recently, this autosomal recessive disorder was shown to be caused by mutations in the PDS gene, which encodes an anion transporter called pendrin.

autosomal recessive disorder

PDS


Input: Molecular analysis of the PDS gene was performed in two consanguineous large families from Southern Tunisia comprising a total of 23 individuals affected with profound congenital deafness; the same missense mutation, L445W, was identified in all affected individuals.

PDS

congenital deafness


Input: A widened vestibular aqueduct was found in all patients who underwent computed tomography (CT) scan exploration of the inner ear.

widened vestibular aqueduct


Input: In contrast, goiter was present in only 11 affected individuals, who interestingly had a normal result of the perchlorate discharge test whenever performed.

goiter


Input: The present results question the sensitivity of the perchlorate test for the diagnosis of Pendred syndrome and support the use of a molecular analysis of the PDS gene in the assessment of individuals with severe to profound congenital hearing loss associated with inner ear morphological anomaly even in the absence of a thyroid goiter..

Pendred syndrome

PDS

congenital hearing loss

inner ear morphological anomaly

thyroid goiter


Input: Knobloch syndrome involving midline scalp defect of the frontal region.

Knobloch syndrome

midline scalp defect of the frontal region


Input: We report on a 4-year-old boy with Knobloch syndrome.

Knobloch syndrome


Input: He has vitreoretinal degeneration, high myopia, cataract, telecanthus, hypertelorism, and a high-arched palate.

vitreoretinal degeneration

high myopia

cataract

telecanthus

hypertelorism

high-arched palate


Input: He also has a defect of the anterior midline scalp with involvement of the frontal bone as documented by a computed tomography (CT) scan.

defect of the anterior midline scalp


Input: The brain was normal on CT scan and magnetic resonance imaging.


Input: We present a review of the 23 published cases with this syndrome.


Input: Our patient illustrates the importance of investigating for underlying ocular and central nervous system pathology whenever midline scalp defects are present..

midline scalp defects


Input: The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder.

ataxia-telangiectasia-like disorder


Input: We show that hypomorphic mutations in hMRE11, but not in ATM, are present in certain individuals with an ataxia-telangiectasia-like disorder (ATLD).

ataxia-telangiectasia-like disorder

ATLD


Input: The cellular features resulting from these hMRE11 mutations are similar to those seen in A-T as well as NBS and include hypersensitivity to ionizing radiation, radioresistant DNA synthesis, and abrogation of ATM-dependent events, such as the activation of Jun kinase following exposure to gamma irradiation.

A-T

NBS

hypersensitivity to ionizing radiation


Input: Although the mutant hMre11 proteins retain some ability to interact with hRad50 and Nbs1, formation of ionizing radiation-induced hMre11 and Nbs1 foci was absent in hMRE11 mutant cells.


Input: These data demonstrate that ATM and the hMre11/hRad50/Nbs1 protein complex act in the same DNA damage response pathway and link hMre11 to the complex pathology of A-T..

A-T


Input: Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis.

familial expansile osteolysis


Input: Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling.

Familial expansile osteolysis

FEO

autosomal dominant bone disorder

increased bone remodelling


Input: The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity.

osteolytic lesions


Input: Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.

FEO


Input: 2-21 2-21.


Input: 3 in a large Northern Irish family.


Input: The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region.


Input: RANK is essential in osteoclast formation.


Input: We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB).

FEO

familial Paget disease of bone

PDB


Input: One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule.


Input: Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide.


Input: Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.


Input: Cardiac Na (+) channel dysfunction in Brugada syndrome is aggravated by beta (1)-subunit.

Brugada syndrome


Input: BACKGROUND Mutations in the gene encoding the human cardiac Na (+) channel alpha-subunit (hH1) are responsible for chromosome 3-linked congenital long-QT syndrome (LQT3) and idiopathic ventricular fibrillation (IVF).

congenital long-QT syndrome

idiopathic ventricular fibrillation

IVF


Input: An auxiliary beta (1)-subunit, widely expressed in excitable tissues, shifts the voltage dependence of steady-state inactivation toward more negative potentials and restores normal gating kinetics of brain and skeletal muscle Na (+) channels expressed in Xenopus oocytes but has little if any functional effect on the cardiac isoform.


Input: Here, we characterize the altered effects of a human beta (1)-subunit (hbeta (1)) on the heterologously expressed hH1 mutation (T1620M) previously associated with IVF.

IVF


Input: METHODS AND RESULTS When expressed alone in Xenopus oocytes, T1620M exhibited no persistent currents, in contrast to the LQT3 mutant channels, but the midpoint of steady-state inactivation (V (1/2)) was significantly shifted toward more positive potentials than for wild-type hH1.


Input: Coexpression of hbeta (1) did not significantly alter current decay or recovery from inactivation of wild-type hH1; however, it further shifted the V (1/2) and accelerated the recovery from inactivation of T1620M.


Input: Oocyte macropatch analysis revealed that the activation kinetics of T1620M were normal.


Input: CONCLUSIONS It is suggested that coexpression of hbeta (1) exposes a more severe functional defect that results in a greater overlap in the relationship between channel inactivation and activation (window current) in T1620M, which is proposed to be a potential pathophysiological mechanism of IVF in vivo.

IVF


Input: One possible explanation for our finding is an altered alpha-/beta (1)-subunit association in the mutant..


Input: Meiotic segregation analysis of RB1 alleles in retinoblastoma pedigrees by use of single-sperm typing.

retinoblastoma


Input: In hereditary retinoblastoma, different epidemiological studies have indicated a preferential paternal transmission of mutant retinoblastoma alleles to offspring, suggesting the occurrence of a meiotic drive.

hereditary retinoblastoma

retinoblastoma


Input: To investigate this mechanism, we analyzed sperm samples from six individuals from five unrelated families affected with hereditary retinoblastoma.

hereditary retinoblastoma


Input: Single-sperm typing techniques were performed for each sample by study of two informative short tandem repeats located either in or close to the retinoblastoma gene (RB1).

retinoblastoma


Input: The segregation probability of mutant RB1 alleles in sperm samples was assessed by use of the SPERMSEG program, which includes experimental parameters, recombination fractions between the markers, and segregation parameters.


Input: A total of 2, 952 single sperm from the six donors were analyzed.


Input: We detected a significant segregation distortion in the data as a whole (P =. 0099) and a significant heterogeneity in the segregation rate across donors (. 0092).


Input: Further analysis shows that this result can be explained by segregation distortion in favor of the normal allele in one donor only and that it does not provide evidence of a significant segregation distortion in the other donors.


Input: The segregation distortion favoring the mutant RB1 allele does not seem to occur during spermatogenesis, and, thus, meiotic drive may result either from various mechanisms, including a fertilization advantage or a better mobility in sperm bearing a mutant RB1 gene, or from the existence of a defectively imprinted gene located on the human X chromosome.


Input: Friedreich ataxia: an overview.

Friedreich ataxia


Input: Friedreich ataxia, an autosomal recessive neurodegenerative disease, is the most common of the inherited ataxias.

Friedreich ataxia

autosomal recessive neurodegenerative disease

inherited ataxias


Input: The recent discovery of the gene that is mutated in this condition, FRDA, has led to rapid advances in the understanding of the pathogenesis of Friedreich ataxia.

Friedreich ataxia


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


Input: This leads to reduced levels of the protein, frataxin.


Input: There is mounting evidence to suggest that Friedreich ataxia is the result of accumulation of iron in mitochondria leading to excess production of free radicals, which then results in cellular damage and death.

Friedreich ataxia


Input: Currently there is no known treatment that alters the natural course of the disease.


Input: The discovery of the FRDA gene and its possible function has raised hope that rational therapeutic strategies will be developed..

FRDA


Input: X-linked retinoschisis with point mutations in the XLRS1 gene.

X-linked retinoschisis


Input: BACKGROUND X-linked retinoschisis (XLRS) is a relatively rare vitreoretinal dystrophy that causes visual loss in young men.

X-linked retinoschisis

XLRS

vitreoretinal dystrophy

visual loss


Input: Recently, a gene responsible for this disease, designated XLRS1, was identified, and several deleterious gene mutations were reported.


Input: OBJECTIVE To analyze Japanese patients clinically diagnosed as having XLRS formutational changes in the XLRS1 gene.

XLRS


Input: METHODS Ten patients with XLRS underwent full ophthalmologic examination, including slitlamp biomicroscopy and dilated funduscopy.

XLRS


Input: Genomic DNA was isolated from leukocytes, and all exons of the XLRS1 gene were amplified by polymerase chain reaction and analyzed using a direct sequencing method.


Input: RESULTS Point mutations in the XLRS1 gene were identified in all 10 patients.


Input: The mutations were identical in each of 2 pairs of brothers.


Input: Six of the point mutations represented missense mutations, 1 was a nonsense mutation, and 1 was a frameshift mutation.


Input: Five of the mutations are newly reported herein.


Input: CONCLUSIONS The discovery of new point mutations in this study increases the available information regarding the spectrum of genetic abnormalities and clinical manifestations of XLRS.

genetic abnormalities

XLRS


Input: However, the limited data failed to reveal a correlation between mutation and disease phenotype.


Input: CLINICAL RELEVANCE Identification of mutations in the XLRS1 gene and expanded information on clinical manifestations will facilitate early diagnosis, appropriate early therapy, and genetic counseling regarding the prognosis of XLRS..


Input: Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system.


Input: Ataxia-telangiectasia is a hereditary multisystemic disease resulting from mutations of ataxia telangiectasia, mutated (ATM) and is characterized by neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing radiation.

Ataxia-telangiectasia

hereditary multisystemic disease

ataxia telangiectasia

neurodegeneration

cancer

immune defects

hypersensitivity to ionizing radiation


Input: The molecular details of ATM function in the nervous system are unclear, although the neurological lesion in ataxia-telangiectasia becomes apparent early in life, suggesting a developmental origin.

neurological lesion

ataxia-telangiectasia


Input: The central nervous system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage.


Input: Here, we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (IR).


Input: Although many of the same regions of the CNS in both Bax-/-and Atm-/-mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IR-induced apoptosis in the CNS.


Input: Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm-and Bax-independent branches.


Input: Further, Atm-and Bax-dependent apoptosis in the CNS also required caspase-3 activation.


Input: These data implicate Bax and caspase-3 as death effectors in neurodegenerative pathways..


Input: Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C.

Haim-Munk syndrome

Papillon-Lefevre syndrome


Input: Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefevre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction.

palmoplantar keratoderma (PPK) conditions

Papillon-Lefevre syndrome

PLS

Haim-Munk syndrome

HMS


Input: Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers.

PLS

HMS

PPK

periodontitis

HMS

arachnodactyly

acro-osteolysis

atrophic changes of the nails

radiographic deformity of the fingers


Input: While PLS cases have been identified throughout the world, HMS has only been described among descendants of a religious isolate originally from Cochin, India.

PLS

HMS


Input: Parental consanguinity is a characteristic of many cases of both conditions.


Input: Although autosomal recessive transmission of PLS is evident, a more " complex " autosomal recessive pattern of inheritance with phenotypic influences from a closely linked modifying locus has been hypothesised for HMS.

PLS

HMS


Input: Recently, mutations of the cathepsin C gene have been identified as the underlying genetic defect in PLS.

genetic defect

PLS


Input: To determine if a cathepsin C mutation is also responsible for HMS, we sequenced the gene in affected and unaffected subjects from the Cochin isolate in which both the PLS and HMS phenotypes appear.

HMS

PLS

HMS


Input: Here we report identification of a mutation of cathepsin C (exon 6, 2127A--> G) that changes a highly conserved amino acid in the cathepsin C peptide.


Input: This mutation segregates with HMS in four nuclear families.

HMS


Input: Additionally, the existence of a shared common haplotype for genetic loci flanking the cathepsin C gene suggests that affected subjects descended from the Cochin isolate are homozygous for a mutation inherited " identical by descent " from a common ancestor.


Input: This finding supports simple autosomal recessive inheritance for HMS in these families.

HMS


Input: We also report a mutation of the same exon 6 CTSC codon (2126C--> T) in a Turkish family with classical PLS.

PLS


Input: These findings provide evidence that PLS and HMS are allelic variants of cathepsin C gene mutations..

PLS

HMS


Input: ATM-heterozygous germline mutations contribute to breast cancer-susceptibility.

breast cancer


Input: Approximately 0.


Input: 5%-1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene.


Input: Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900).

autosomal recessive disorder ataxia-telangiectasia

A-T


Input: The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others.

breast cancer


Input: In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer.

breast cancer


Input: We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis.


Input: A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer.

sporadic breast cancer


Input: The 82 patients included in this study had developed breast cancer at age < 45 and had survived >/= 5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed.

breast cancer


Input: Among these patients we identified seven (8. 5%) ATM germline mutations, of which five are distinct.


Input: One splice-site mutation (IVS10-6T--> G) was detected three times in our series.


Input: Four heterozygous carriers were patients with bilateral breast cancer.


Input: Our results indicate that the mutations identified in this study are " A-T disease-causing " mutations that might be associated with an increased risk of breast cancer in heterozygotes.


Input: We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival.


Input: The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.


Input: Human mutations in glucose 6-phosphate dehydrogenase reflect evolutionary history.


Input: Glucose 6-phosphate dehydrogenase (G6PD) is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions.


Input: Inherited G6PD deficiency is associated with either episodic hemolytic anemia (triggered by fava beans or other agents) or life-long hemolytic anemia.

G6PD deficiency

episodic hemolytic anemia

life-long hemolytic anemia


Input: We show here that an evolutionary analysis is a key to understanding the biology of a housekeeping gene.


Input: From the alignment of the amino acid (aa) sequence of 52 glucose 6-phosphate dehydrogenase (G6PD) species from 42 different organisms, we found a striking correlation between the aa replacements that cause G6PD deficiency in humans and the sequence conservation of G6PD two-thirds of such replacements are in highly and moderately conserved (50-99%) aa; relatively few are in fully conserved aa (where they might be lethal) or in poorly conserved aa, where presumably they simply would not cause G6PD deficiency.

G6PD deficiency

G6PD deficiency


Input: This is consistent with the notion that all human mutants have residual enzyme activity and that null mutations are lethal at some stage of development.


Input: Comparing the distribution of mutations in a human housekeeping gene with evolutionary conservation is a useful tool for pinpointing amino acid residues important for the stability or the function of the corresponding protein.


Input: In view of the current explosive increase in full genome sequencing projects, this tool will become rapidly available for numerous other genes..


Input: Constitutive and regulated modes of splicing produce six major myotonic dystrophy protein kinase (DMPK) isoforms with distinct properties.

myotonic dystrophy


Input: Myotonic dystrophy (DM) is the most prevalent inherited neuromuscular disease in adults.

Myotonic dystrophy

DM

inherited neuromuscular disease


Input: The genetic defect is a CTG triplet repeat expansion in the 3-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene, consisting of 15 exons.

genetic defect

myotonic dystrophy


Input: Using a transgenic DMPK-overexpressor mouse model, we demonstrate here that the endogenous mouse DMPK gene and the human DMPK transgene produce six major alternatively spliced mRNAs which have almost identical cell type-dependent distribution frequencies and expression patterns.


Input: Use of a cryptic 5 splice site in exon 8, which results in absence or presence of 15 nucleotides specifying a VSGGG peptide motif, and/or use of a cryptic 3 splice site in exon 14, which leads to a frameshift in the mRNA reading frame, occur as independent stochastic events in all tissues examined.


Input: In contrast, the excision of exons 13/14 that causes a frameshift and creates a C-terminally truncated protein is clearly cell type dependent and occurs predominantly in smooth muscle.


Input: We generated all six full-length mouse cDNAs that result from combinations of these three major splicing events and show that their transfection into cells in culture leads to production of four different approximately 74 kDa full-length (heart-, skeletal muscle-or brain-specific) and two C-terminally truncated approximately 68 kDa (smooth muscle-specific) isoforms.


Input: Information on DMPK mRNA and protein isoform expression patterns will be useful for recognizing differential effects of (CTG) (n) expansion in DM manifestation..

DMPK


Input: Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S.

venous thrombosis

deficiencies of protein S


Input: Protein S deficiency is a recognized risk factor for venous thrombosis.

Protein S deficiency

venous thrombosis


Input: Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results.

thrombophilic conditions


Input: We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level.


Input: Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives.

protein S deficiency

PROS1 gene defect


Input: To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients relatives.


Input: In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1 gene defect (sensitivity 97. 7%, specificity 100%).

PROS1 gene defect


Input: First-degree relatives with a PROS1 gene defect had a 5.

PROS1 gene defect


Input: 0-fold higher risk of thrombosis (95% confidence interval, 1. 5-16. 8) than those with a normal PROS1 gene and no other recognized thrombophilic defect.

thrombosis

thrombophilic defect


Input: Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous.

trauma

thrombosis


Input: Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations.

defects in the PROS1 gene


Input: We conclude that persons with PROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.

PROS1 gene defects

protein S deficiency

thrombosis


Input: (Blood. 2000; 95 1935-1941).


Input: Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?

Autoimmune lymphoproliferative syndrome

ALPS


Input: Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis.

Autoimmune lymphoproliferative syndrome

ALPS


Input: This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes.

ALPS


Input: Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely.


Input: Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain.


Input: The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous.


Input: The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype.

ALPS


Input: The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive..

ALPS


Input: Identification of novel imprinted transcripts in the Prader-Willi syndrome and Angelman syndrome deletion region: further evidence for regional imprinting control.

Prader-Willi syndrome

Angelman syndrome


Input: Deletions and other abnormalities of human chromosome 15q11-q13 are associated with two developmental disorders, Prader-Willi syndrome (PWS) and Angelman syndrome (AS).

Prader-Willi syndrome

PWS

Angelman syndrome

AS


Input: Loss of expression of imprinted, paternally expressed genes has been implicated in PWS.

PWS


Input: However, the number of imprinted genes that contribute to PWS, and the range over which the imprinting signal acts to silence one copy of the gene in a parent-of-origin-specific manner, are unknown.

PWS


Input: To identify additional imprinted genes that could contribute to the PWS phenotype and to understand the regional control of imprinting in 15q11-q13, we have constructed an imprinted transcript map of the PWS-AS deletion interval.

PWS


Input: The imprinting status of 22 expressed sequence tags derived from the radiation-hybrid human transcript maps or physical maps was determined in a reverse transcriptase-PCR assay and correlated with the position of the transcripts on the physical map.


Input: Seven new paternally expressed transcripts localize to an approximately 1.


Input: 5-Mb domain surrounding the SNRPN-associated imprinting center, which already includes four imprinted, paternally expressed genes.


Input: All other tested new transcripts in the deletion region were expressed from both alleles.


Input: A domain of exclusive paternal expression surrounding the imprinting center suggests strong regional control of the imprinting process.


Input: This study provides the means for further investigation of additional genes that cause or modify the phenotypes associated with rearrangements of 15q11-q13.


Input: Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics.

hereditary prostate cancer

hereditary prostate cancer

Prostate Cancer


Input: A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25.

prostate cancer


Input: Subsequent reports in additional collections of families have yielded conflicting results.


Input: In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36.

hereditary prostate cancer


Input: The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom.

hereditary prostate cancer

Prostate Cancer


Input: Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1.


Input: 40 (P =. 01) at D1S212.


Input: The estimated proportion of families (alpha) linked to the locus was.


Input: 06 (1-LOD support interval. 01-. 12).


Input: This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity.


Input: Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families.


Input: In the subset of 491 such families, the peak HLOD was 2.


Input: In the subset of 491 such families, the peak HLOD was 2.


Input: 56 (P =. 0006) and alpha =.


Input: 11 (1-LOD support interval. 04-. 19), compared with HLODs of 0 in the remaining 281 families.


Input: Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (< 65 years, alpha =. 19, with 1-LOD support interval. 06-. 34) and the number of affected family members (five or more family members, alpha =. 15, with 1-LOD support interval. 04-. 28).


Input: The highest value of alpha was observed for the 48 families that met all three criteria (peak HLOD = 2. 25, P =. 001, alpha =. 29, with 1-LOD support interval. 08-. 53).


Input: These results support the finding of a prostate cancer-susceptibility gene linked to 1q24-25, albeit in a defined subset of prostate cancer families.

prostate cancer

prostate cancer


Input: Although HPC1 accounts for only a small proportion of all families affected by hereditary prostate cancer, it appears to play a more prominent role in the subset of families with several members affected at an early age and with male-to-male disease transmission.

hereditary prostate cancer


Input: A recurrent expansion of a maternal allele with 36 CAG repeats causes Huntington disease in two sisters.

Huntington disease


Input: Large intergenerational repeat expansions of the CAG trinucleotide repeat in the HD gene have been well documented for the male germline.

HD


Input: We describe a recurrent large expansion of a maternal allele with 36 CAG repeats (to 66 and 57 repeats, respectively, in two daughters) associated with onset of Huntington disease (HD) in the second and third decade in a family without history of HD.

Huntington disease

HD

HD


Input: Our findings give evidence of a gonadal mosaicism in the unaffected mother.


Input: We hypothesize that large expansions also occur in the female germline and that a negative selection of oocytes with long repeats might explain the different instability behavior of the male and the female germlines..


Input: Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice.


Input: Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia-telangiectasia (A-T), which is caused by mutations in the ATM gene.

Motor incoordination

immune deficiencies

cancer

hereditary disease ataxia-telangiectasia

A-T


Input: Through gene targeting, we have generated a line of Atm mutant mice, Atm (y/y) mice.


Input: In contrast to other Atm mutant mice, Atm (y/y) mice show a lower incidence of thymic lymphoma and survive beyond a few months of age.

thymic lymphoma


Input: Atm (y/y) mice exhibit deficits in motor learning indicative of cerebellar dysfunction.

cerebellar dysfunction


Input: Even though we found no gross cerebellar degeneration in older Atm (y/y) animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages.

cerebellar degeneration


Input: These findings establish that some neuropathological abnormalities seen in A-T patients also are present in Atm mutant mice.

neuropathological abnormalities

A-T


Input: In addition, we report a previously unrecognized effect of Atm deficiency on development or maintenance of CD4 (+) 8 (+) thymocytes.

Atm deficiency


Input: We discuss these findings in the context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T..

A-T


Input: Novel mutations of the ATP7B gene in Japanese patients with Wilson disease.

Wilson disease


Input: Wilson disease (WD) is an autosomal recessive disorder characterized by copper accumulation in the liver, brain, kidneys, and corneas, and culminating in copper toxication in these organs.

Wilson disease

WD

autosomal recessive disorder


Input: In this study, we analyzed mutations of the responsible gene, ATP7B, in four Japanese patients with WD.

WD


Input: By direct sequencing, we identified five mutations, of which two were novel, and 16 polymorphisms, of which 6 were novel.


Input: The mutations 2871delC and 2513delA shift the reading frame so that truncated abnormal protein is expected.


Input: In contrast to these mutations found in patients with hepatic-type of early onset, the mutations A874V, R778L, and 3892delGTC were either missense mutations or in frame 1-amino acid deletion, and occurred in the patients with hepato-neurologic type of late onset.


Input: The mutations 2871delC and R778L have been previously reported in a relatively large number of Japanese patients.


Input: In particular, R778L is known to be more prevalent in Asian countries than in other countries of the world.


Input: Our data are compatible with the hypothesis that the mutations tend to occur in a population-specific manner.


Input: Therefore, the accumulation of the types of mutations in Japanese patients with WD will facilitate the fast and effective genetic diagnosis of WD in Japanese patients..

WD

WD


Input: Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein.

Wiskott-Aldrich syndrome


Input: The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through activation of Wiskott-Aldrich syndrome protein (WASP) family members.

Wiskott-Aldrich syndrome


Input: Activation relieves an autoinhibitory contact between the GTPase-binding domain and the carboxy-terminal region of WASP proteins.


Input: Here we report the autoinhibited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic co-solvents.


Input: In the autoinhibited complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating complex.


Input: Binding of Cdc42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core and release of the C terminus, enabling its interaction with the actin regulatory machinery.


Input: These data show that intrinsically unstructured peptides such as the GTPase-binding domain of WASP can be induced into distinct structural and functional states depending on context..


Input: hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response.


Input: Mutations in the BRCA1 (ref. 1) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer.

tumour

inherited breast and ovarian cancers

breast cancer


Input: Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair and cell-cycle checkpoint.


Input: BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage.


Input: It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related.


Input: In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family.


Input: Here we report that the human Cds1 kinase (hCds1/Chk2) regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1.


Input: We show that hCds1 and BRCA1 interact and co-localize within discrete nuclear foci but separate after gamma irradiation.


Input: Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1.


Input: This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937..


Input: Characterization of the rat spinocerebellar ataxia type 3 gene.


Input: Machado-Joseph disease (MJD) belongs to a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive cerebellar ataxia.

Machado-Joseph disease

MJD

neurodegenerative disorders

progressive cerebellar ataxia


Input: The disease-causing mutation has recently been identified as an unstable and expanded (CAG) n trinucleotide repeat in a novel gene of unknown function.


Input: In Caucasians, repeat expansions in the MJD1 gene have also been found in patients with the clinically distinct autosomal dominant spinocerebellar ataxia type 3 (SCA3).

spinocerebellar ataxia type 3


Input: In order to gain insight into the biology of the MJD1/SCA3 gene we cloned the rat homologue and studied its expression.


Input: The rat and human ataxin-3 genes are highly homologous with an overall sequence identity of approximately 88%.


Input: However, the C-terminal end of the putative protein differs strongly from the published human sequence.


Input: The (CAG) n block in the rat cDNA consists of just three interrupted units suggesting that a long polyglutamine stretch is not essential for the normal function of the ataxin-3 protein in rodents.


Input: The expression pattern of the SCA3 gene in various rat and human tissues was investigated by Northern blot analyses.


Input: The mature transcript is approximately 6 kb in length.


Input: In rat testis, a smaller transcript of 1.


Input: 3 kb was identified.


Input: Transcription of rsca3 was detected in most rat tissues including brain.


Input: Analyzing the expression level of the SCA3 gene in several human brain sections revealed no significant higher mRNA level in regions predominantly affected in MJD.

MJD


Input: Thus additional molecules and/or regulatory events are necessary to explain the exclusive degeneration of certain brain areas.

degeneration of certain brain areas


Input: Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is localized at the inner nuclear membrane.

Emerin, deficiency

Emery-Dreifuss muscular dystrophy


Input: X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscle disorder characterized by the clinical triad of progressive wasting of humero-peroneal muscles, early contractures of the elbows, Achilles tendons and postcervical muscles, and cardiac conduction block with a high risk of sudden death.

X-linked recessive Emery-Dreifuss muscular dystrophy

EDMD

inherited muscle disorder

wasting of humero-peroneal muscles

contractures of the elbows, Achilles tendons and postcervical muscles

cardiac conduction block

sudden death


Input: The gene for EDMD on Xq28 encodes a novel protein named emerin that localizes at the nuclear membrane of skeletal, cardiac and smooth muscles and some other non-muscle tissues.

EDMD


Input: To investigate a possible physiological role for emerin, we examined the ultrastructural localization of the protein in human skeletal muscle and HeLa cells, using ultrathin cryosections.


Input: We found that the immune-labeled colloidal gold particles were localized on the nucleoplasmic surface of the inner nuclear membrane, but not on the nuclear pore.


Input: Emerin stayed on the cytoplasmic surface of the nuclear lamina, even after detergent treatment that solubilizes membrane lipids and washes out membrane proteins.


Input: These results suggest that emerin anchors at the inner nuclear membrane through the hydrophobic stretch, and protrudes from the hydrophilic region to the nucleoplasm where it interacts with the nuclear lamina.


Input: We speculate that emerin contributes to maintain the nuclear structure and stability, as well as nuclear functions, particularly in muscle tissues that have severe stress with rigorous contraction-relaxation movements and calcium flux..


Input: Locus heterogeneity in Friedreich ataxia.

Friedreich ataxia


Input: Friedreich ataxia (FRDA) is the most common form of autosomal recessive ataxia.

Friedreich ataxia

FRDA

autosomal recessive ataxia


Input: The disease locus was assigned to chromosome 9 and the disease gene, STM7/X25, has been isolated.


Input: To date most data suggest locus homogeneity in FRDA.

FRDA


Input: We now provide strong evidence of a second FRDA locus.

FRDA


Input: Studying two siblings with FRDA from two families we did not detect a mutation in STM7/X25.

FRDA


Input: Haplotype analysis of the STM7/X25 region of chromosome 9 demonstrated that the relevant portion of chromosome 9 differs in the patients.


Input: Although the patients studied had typical FRDA, one sibpair had the uncommon symptom of retained tendon reflexes.

FRDA


Input: In order to investigate whether retained tendon reflexes are characteristic of FRDA caused by the second locus, FRDA2, we studied an unrelated FRDA patient with retained tendon reflexes.

FRDA


Input: The observation of typical mutations in STM7/X25 (GAA expansions) in this patient demonstrates that the two genetically different forms of FRDA cannot be distinguished clinically..

FRDA


Input: Glycerol as a correlate of impaired glucose tolerance: dissection of a complex system by use of a simple genetic trait.

impaired glucose tolerance


Input: Glycerol kinase (GK) represents the primary entry of glycerol into glucose and triglyceride metabolism.


Input: Impaired glucose tolerance (IGT) and hypertriglyceridemia are associated with an increased risk of diabetes mellitus and cardiovascular disease.

Impaired glucose tolerance

IGT

hypertriglyceridemia

diabetes mellitus

cardiovascular disease


Input: The relationship between glycerol and the risk of IGT, however, is poorly understood.

IGT


Input: We therefore undertook the study of fasting plasma glycerol levels in a cohort of 1, 056 unrelated men and women of French-Canadian descent.


Input: Family screening in the initial cohort identified 18 men from five families with severe hyperglycerolemia (values above 2. 0 mmol/liter) and demonstrated an X-linked pattern of inheritance.

hyperglycerolemia


Input: Linkage analysis of the data from 12 microsatellite markers surrounding the Xp21.


Input: 3 GK gene resulted in a peak LOD score of 3.


Input: 46, centered around marker DXS8039.


Input: In addition, since all of the families originated in a population with a proven founder effect-the Saguenay Lac-St.


Input: -Jean region of Quebec-a common disease haplotype was sought.


Input: Indeed, a six-marker haplotype extending over a region of 5.


Input: 5 cM was observed in all families.


Input: Resequencing of the GK gene in family members led to the discovery of a N288D missense mutation in exon 10, which resulted in the substitution of a highly conserved asparagine residue by a negatively charged aspartic acid.


Input: Clinical and molecular genetics of primary dystonias.

primary dystonias


Input: Primary dystonias are movement disorders with dystonia as a major symptom.

Primary dystonias

movement disorders

dystonia


Input: They are frequently inherited as Mendelian traits.


Input: There are at least eight clinically distinct autosomal dominant and two X-linked recessive forms.


Input: In addition, pedigree analyses suggest the occurrence of an autosomal recessive variant.


Input: The clinical classification is increasingly being replaced by a genetic one.


Input: To date gene loci have been identified in at least six autosomal dominant forms, i. e., in idiopathic torsion dystonia (9q34), focal dystonia (18p), adult-onset idiopathic torsion dystonia of mixed type (8p21-q22), dopa-responsive dystonia (14q22. 1-q22. 2), and paroxysmal dystonic choreoathetosis (2q25-q33; 1p21-p13. 3).

idiopathic torsion dystonia

focal dystonia

idiopathic torsion dystonia

dopa-responsive dystonia

paroxysmal dystonic choreoathetosis


Input: Gene loci in the X-linked recessive forms have been assigned to Xq13.


Input: 1 in the X-linked dystonia parkinsonism syndrome and to Xq22 in X-linked sensorineural deafness, dystonia, and mental retardation.

X-linked dystonia parkinsonism syndrome

X-linked sensorineural deafness

dystonia

mental retardation


Input: The disease genes have been identified in two autosomal dominant forms and in one X-linked recessive form.


Input: Mutations in a gene coding for an ATP-binding protein were detected in idiopathic torsion dystonia (DYT1), and the GTP cyclohydrolase 1 gene is mutated in dopa-responsive dystonia (DYT5).

idiopathic torsion dystonia

dopa-responsive dystonia


Input: In sensorineural deafness, dystonia, and mental retardation, mutations were found in the gene DDP coding for a polypeptide of unknown function.

sensorineural deafness

dystonia

mental retardation


Input: This article reviews the clinical and molecular genetics of primary dystonias, critically discusses present findings, and proposes referring to the known forms, most of which can be distinguished by genetic criteria, as dystonias 1-12.

primary dystonias

dystonias 1-12


Input: Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described.

X-linked adrenoleukodystrophy


Input: X-linked Adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease.

X-linked Adrenoleukodystrophy

X-ALD

peroxisomal disease


Input: It mainly involves the nervous system white matter, adrenal cortex and testes.


Input: Several distinct clinical phenotypes are known.


Input: The principal biochemical abnormality is the accumulation of saturated very-long-chain fatty acids (VLCFAs > C22 0, mainly C26 0), which is due to impaired capacity for beta-oxidation in peroxisomes.


Input: Diagnosis is usually based on the VLCFA levels in plasma or cultured skin fibroblasts in both patients and carriers.


Input: In 0.


Input: 1% of affected males, however, the plasma C26 0 level is borderline normal, and 15% of obligate female carriers have normal results.


Input: Effective mutation detection in these families is therefore fundamental to unambiguously determine the genetic status of each individual at risk.


Input: Of particular concern are female members of kindreds segregating X-ALD mutations, because normal VLCFA levels do not guarantee lack of carrier status.

X-ALD


Input: We describe a fast method for detection of X-ALD mutations.

X-ALD


Input: The method is based on SSCP analysis of nested PCR fragments followed by sequence-determination reactions.


Input: Using this methodology we have found X-ALD mutations in 30 kindreds, including 15 not previously reported.

X-ALD


Input: beta-galactosidase gene mutations affecting the lysosomal enzyme and the elastin-binding protein in GM1-gangliosidosis patients with cardiac involvement.

cardiac involvement


Input: GM1-gangliosidosis is a lysosomal storage disorder caused by deficiency of acid beta-galactosidase (GLB1).

lysosomal storage disorder

deficiency of acid beta-galactosidase


Input: We report five new beta-galactosidase gene mutations in nine Italian patients and one fetus, segregating in seven unrelated families.


Input: Six of the eight patients with the infantile, severe form of the disease presented cardiac involvement, a feature rarely associated with GM1-gangliosidosis.

cardiac involvement


Input: Molecular analysis of the patients RNA and DNA identified two new RNA splicing defects, three new and three previously described amino acid substitutions.


Input: Interestingly, all patients with cardiac involvement were homozygous for one of these mutations R59H, Y591C, Y591N, or IVS14-2A > G.

cardiac involvement


Input: In contrast, all other patients were compound heterozygous for one of the following mutations R201H, R482H, G579D, IVS8 + 2T > C.


Input: Although we could not directly correlate the presence of cardiac abnormalities with specific genetic lesions, the mutations identified in patients with cardiomyopathy fell in the GLB1 cDNA region common to the lysosomal enzyme and the Hbeta-Gal-related protein, also known as the elastin binding protein (EBP).

cardiac abnormalities

genetic lesions

cardiomyopathy


Input: Consequently, both molecules are affected by the mutations, and they may contribute differently to the occurrence of specific clinical manifestations..


Input: In vivo modulation of Hmgic reduces obesity.

obesity


Input: The HMGI family of proteins consists of three members, HMGIC, HMGI and HMGI (Y), that function as architectural factors and are essential components of the enhancesome.


Input: HMGIC is predominantly expressed in proliferating, undifferentiated mesenchymal cells and is not detected in adult tissues.


Input: It is disrupted and misexpressed in a number of mesenchymal tumour cell types, including fat-cell tumours (lipomas).

mesenchymal tumour

fat-cell tumours

lipomas


Input: In addition Hmgic-/-mice have a deficiency in fat tissue.


Input: To study its role in adipogenesis and obesity, we examined Hmgic expression in the adipose tissue of adult, obese mice.

obesity

obese


Input: Mice with a partial or complete deficiency of Hmgic resisted diet-induced obesity.

partial or complete deficiency of Hmgic

obesity


Input: Disruption of Hmgic caused a reduction in the obesity induced by leptin deficiency (Lepob/Lepob) in a gene-dose-dependent manner.

obesity

leptin deficiency


Input: Our studies implicate a role for HMGIC in fat-cell proliferation, indicating that it may be an adipose-specific target for the treatment of obesity..

obesity


Input: Molecular analysis of the genotype-phenotype relationship in factor X deficiency.

factor X deficiency


Input: Factor X deficiency is a rare haemorrhagic condition, normally inherited as an autosomal recessive trait, in which a variable clinical presentation correlates poorly with laboratory phenotype.

Factor X deficiency

haemorrhagic condition


Input: The factor X (F10) genes of 14 unrelated individuals with factor X deficiency (12 familial and two sporadic cases) were sequenced yielding a total of 13 novel mutations.

factor X deficiency


Input: Family studies were performed in order to distinguish the contributions of individual mutant F10 alleles to the clinical and laboratory phenotypes.


Input: Missense mutations were studied by means of molecular modelling, whereas single basepair substitutions in splice sites and the 5 flanking region were examined by in vitro splicing assay and luciferase reporter gene assay respectively.


Input: The deletion allele of a novel hexanucleotide insertion/deletion polymorphism in the F10 gene promoter region was shown by reporter gene assay, to reduce promoter activity by approximately 20%.


Input: One family manifesting an autosomal dominant pattern of inheritance possessed three clinically affected members who were heterozygous for a splice-site mutation that was predicted to lead to the production of a truncated protein product.


Input: A model which accounts for the dominant negative effect of this lesion is presented.


Input: Variation in the antigen level of heterozygous relatives of probands was found to be significantly higher between families than within families, consistent with the view that the nature of the F10 lesion (s) segregating in a given family is a prime determinant of the laboratory phenotype.


Input: By contrast, no such relationship could be discerned between laboratory phenotype and polymorphism genotype..


Input: Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas.

lipomas


Input: Chromosomal translocations in human lipomas frequently create fusion transcripts encoding high mobility group (HMG) I-C DNA-binding domains and C-terminal sequences from different presumed transcription factors, suggesting a potential role for HMG I-C in the development of lipomas.

lipomas

lipomas


Input: To evaluate the role of the HMG I-C component, the three DNA-binding domains of HMG I-C have now been expressed in transgenic mice.


Input: Despite the ubiquitous expression of the truncated HMG I-C protein, the transgenic mice develop a selective abundance of fat tissue early in life, show marked adipose tissue inflammation, and have an abnormally high incidence of lipomas.

adipose tissue inflammation

lipomas


Input: These findings demonstrate that the DNA-binding domains of HMG I-C, in the absence of a C-terminal fusion partner, are sufficient to perturb adipogenesis and predispose to lipomas.

lipomas


Input: We provide data supporting the central utility of this animal model as a tool to understand the molecular mechanisms underlying the development of one of the most common kind of human benign tumors..

benign tumors


Input: ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway.


Input: The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation.

rare diseases ataxia-telangiectasia

AT

Nijmegen breakage syndrome

NBS

phenotypic abnormalities

chromosomal instability


Input: The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs, whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks.


Input: Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1.

AT

NBS


Input: Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation.

NBS


Input: However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation.


Input: A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells.

NBS


Input: These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases..


Input: Understanding the molecular basis of fragile X syndrome.

fragile X syndrome


Input: Fragile X syndrome, a common form of inherited mental retardation, is mainly caused by massive expansion of CGG triplet repeats located in the 5-untranslated region of the fragile X mental retardation-1 (FMR1) gene.

Fragile X syndrome

inherited mental retardation

fragile X mental retardation


Input: In patients with fragile X syndrome, the expanded CGG triplet repeats are hypermethylated and the expression of the FMR1 gene is repressed, which leads to the absence of FMR1 protein (FMRP) and subsequent mental retardation.

fragile X syndrome

mental retardation


Input: FMRP is an RNA-binding protein that shuttles between the nucleus and cytoplasm.


Input: This protein has been implicated in protein translation as it is found associated with polyribosomes and the rough endoplasmic reticulum.


Input: We discuss here the recent progress made towards understanding the molecular mechanism of CGG repeat expansion and physiological function (s) of FMRP.


Input: These studies will not only help to illuminate the molecular basis of the general class of human diseases with trinucleotide repeat expansion but also provide an avenue to understand aspects of human cognition and intelligence..


Input: Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development.

Haploinsufficiency of the transcription factors FOXC1 and FOXC2


Input: Anterior segment developmental disorders, including Axenfeld-Rieger anomaly (ARA), variably associate with harmfully elevated intraocular pressure (IOP), which causes glaucoma.

Anterior segment developmental disorders

Axenfeld-Rieger anomaly

ARA

glaucoma


Input: Clinically observed dysgenesis does not correlate with IOP, however, and the etiology of glaucoma development is not understood.

glaucoma


Input: The forkhead transcription factor genes Foxc1 (formerly Mf1) and Foxc2 (formerly Mfh1) are expressed in the mesenchyme from which the ocular drainage structures derive.


Input: Mutations in the human homolog of Foxc1, FKHL7, cause dominant anterior segment defects and glaucoma in various families.

anterior segment defects

glaucoma


Input: We show that Foxc1 (+/-) mice have anterior segment abnormalities similar to those reported in human patients.

anterior segment abnormalities


Input: These abnormalities include small or absent Schlemms canal, aberrantly developed trabecular meshwork, iris hypoplasia, severely eccentric pupils and displaced Schwalbes line.

iris hypoplasia


Input: The penetrance of clinically obvious abnormalities varies with genetic background.


Input: In some affected eyes, collagen bundles were half normal diameter, or collagen and elastic tissue were very sparse.


Input: Thus, abnormalities in extracellular matrix synthesis or organization may contribute to development of the ocular phenotypes.


Input: Despite the abnormalities in ocular drainage structures in Foxc1 (+/-) mice, IOP was normal in almost all mice analyzed, on all genetic backgrounds and at all ages.


Input: Similar abnormalities were found in Foxc2 (+/-) mice, but no disease-associated mutations were identified in the human homolog FKHL14 in 32 ARA patients.

ARA


Input: Foxc1 (+/-) and Foxc2 (+/-) mice are useful models for studying anterior segment development and its anomalies, and may allow identification of genes that interact with Foxc1 and Foxc2 (or FKHL7 and FKHL14) to produce a phenotype with elevated IOP and glaucoma..

glaucoma


Input: (Over) correction of FMR1 deficiency with YAC transgenics: behavioral and physical features.

FMR1 deficiency


Input: Fragile X syndrome is a common cause of mental retardation involving loss of expression of the FMR1 gene.

Fragile X syndrome

mental retardation


Input: The role of FMR1 remains undetermined but the protein appears to be involved in RNA metabolism.


Input: Fmr1 knockout mice exhibit a phenotype with some similarities to humans, such as macroorchidism and behavioral abnormalities.

macroorchidism


Input: As a step toward understanding the function of FMR1 and the determination of the potential for therapeutic approaches to fragile X syndrome, yeast artificial chromosome (YAC) transgenic mice were generated in order to determine whether the Fmr1 knockout mouse phenotype could be rescued.

fragile X syndrome


Input: Several transgenic lines were generated that carried the entire FMR1 locus with extensive amounts of flanking sequence.


Input: We observed that the YAC transgene supported production of the human protein (FMRP) which was present at levels 10 to 15 times that of endogenous protein and was expressed in a cell-and tissue-specific manner.


Input: Macro-orchidism was absent in knockout mice carrying the YAC transgene indicating functional rescue by the human protein.


Input: Given the complex behavioral phenotype in fragile X patients and the mild phenotype previously reported for the Fmr1 knockout mouse, we performed a more thorough evaluation of the Fmr1 knockout phenotype using additional behavioral assays that had not previously been reported for this animal model.

fragile X


Input: The mouse displayed reduced anxiety-related responses with increased exploratory behavior.

anxiety


Input: FMR1 YAC transgenic mice overexpressing the human protein did produce opposing behavioral responses and additional abnormal behaviors were also observed.


Input: These findings have significant implications for gene therapy for fragile X syndrome since overexpression of the gene may harbor its own phenotype..

fragile X syndrome


Input: Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability.

DM


Input: Myotonic dystrophy (DM) is caused by a CTG repeat expansion in the 3UTR of the DM protein kinase (DMPK) gene.

Myotonic dystrophy

DM

DM


Input: A very high level of instability is observed through successive generations and the size of the repeat is generally correlated with the severity of the disease and with age at onset.


Input: Furthermore, tissues from DM patients exhibit somatic mosaicism that increases with age.

DM


Input: We generated transgenic mice carrying large human genomic sequences with 20, 55 or > 300 CTG, cloned from patients from the same affected DM family.

DM


Input: Using large human flanking sequences and a large amplification, we demonstrate that the intergenerational CTG repeat instability is reproduced in mice, with a strong bias towards expansions and with the same sex-and size-dependent characteristics as in humans.


Input: Moreover, a high level of instability, increasing with age, can be observed in tissues and in sperm.


Input: Although we did not observe dramatic expansions (or big jumps over several hundred CTG repeats) as in congenital forms of DM, our model carrying > 300 CTG is the first to show instability so close to the human DM situation.

DM

DM


Input: Our three models carrying different sizes of CTG repeat provide insight on the different factors modulating the CTG repeat instability..


Input: Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation.

Friedreich ataxia

embryonic lethality


Input: Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is caused in almost all cases by homozygous intronic expansions resulting in the loss of frataxin, a mitochondrial protein conserved through evolution, and involved in mitochondrial iron homeostasis.

Friedreich ataxia

FRDA

autosomal recessive ataxia


Input: Yeast knockout models, and histological and biochemical data from patient heart biopsies or autopsies indicate that the frataxin defect causes a specific iron-sulfur protein deficiency and mitochondrial iron accumulation leading to the pathological changes.

iron-sulfur protein deficiency


Input: Affected human tissues are rarely available to further examine this hypothesis.


Input: To study the mechanism of the disease, we generated a mouse model by deletion of exon 4 leading to inactivation of the Frda gene product.

Frda


Input: We show that homozygous deletions cause embryonic lethality a few days after implantation, demonstrating an important role for frataxin during early development.

embryonic lethality


Input: These results suggest that the milder phenotype in humans is due to residual frataxin expression associated with the expansion mutations.


Input: Surprisingly, in the frataxin knockout mouse, no iron accumulation was observed during embryonic resorption, suggesting that cell death could be due to a mechanism independent of iron accumulation..


Input: Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations.

Gaucher disease


Input: Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA).

Gaucher disease

GD

lysosomal storage disorder


Input: Type 1 disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish (AJ) descent.


Input: Of the causative GBA mutations, N370S is particularly frequent in the AJ population, (q approximately. 03), whereas the 84GG insertion (q approximately. 003) occurs exclusively in the Ashkenazim.


Input: To investigate the genetic history of these mutations in the AJ population, short tandem repeat (STR) markers were used to map a 9.


Input: 3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 AJ 84GG chromosomes.


Input: A highly conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to both populations.


Input: Of note, the presence of different divergent haplotypes suggested the occurrence of de novo, recurrent N370S mutations.


Input: In contrast, a different conserved haplotype at these markers was identified on the 84GG chromosomes, which was unique to the AJ population.


Input: On the basis of the linkage disequilibrium (LD) delta values, the non-Jewish European N370S chromosomes had greater haplotype diversity and less LD at the markers flanking the conserved haplotype than did the AJ N370S chromosomes.


Input: This finding is consistent with the presence of the N370S mutation in the non-Jewish European population prior to the founding of the AJ population.


Input: Coalescence analyses for the N370S and 84GG mutations estimated similar coalescence times, of 48 and 55. 5 generations ago, respectively.


Input: The results of these studies are consistent with a significant bottleneck occurring in the AJ population during the first millennium, when the population became established in Europe.


Input: HLA B27 and the genetics of ankylosing spondylitis.

ankylosing spondylitis


Input: One hundred and twenty-eight of 145 patients with ankylosing spondylitis (AS) were found to be HLA B27 positive.

ankylosing spondylitis

AS


Input: Five patients had evidence of a sero-negative peripheral arthritis resembling peripheral psoriatic arthritis and 3 of these were B27 negative.

peripheral arthritis

peripheral psoriatic arthritis


Input: One further B27 negative patients had a sister with ankylosing spondylitis and ulcerative colitis and a mother with ulcerative colitis.

ankylosing spondylitis

ulcerative colitis

ulcerative colitis


Input: There was evidence of a somewhat later age of onset of symptoms in B27 negative patients.


Input: These findings are interpreted as suggesting some degree of clinical and genetic heterogeneity in ankylosing spondylitis with genes for psoriasis and inflammatory bowel disease being important in some individuals, particularly those who are B27 negative.

ankylosing spondylitis

psoriasis

inflammatory bowel disease


Input: Twenty-five first-degree relatives with ankylosing spondylitis were all B27 positive.

ankylosing spondylitis


Input: The only instance of disassociation of B27 and spondylitis in a family was where the proband had ulcerative colitis as well as spondylitis.

spondylitis

ulcerative colitis

spondylitis


Input: Of 13 B27 positive fathers 3 could be diagnosed as having definite ankylosing spondylitis (23%).

ankylosing spondylitis


Input: These findings are thought to provide evidence against the concept that the gene for ankylosing spondylitis is not B27 but a closely linked gene and favour the occurrence of an environmental event affecting approximately one-fifth of B27 positive males to result in disease..

ankylosing spondylitis


Input: Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.

breast-ovarian cancer


Input: We have undertaken a hospital-based study, to identify possible BRCA1 and BRCA2 founder mutations in the Polish population.


Input: The study group consisted of 66 Polish families with cancer who have at least three related females affected with breast or ovarian cancer and who had cancer diagnosed, in at least one of the three affected females, at age < 50 years.

cancer

breast or ovarian cancer

cancer


Input: A total of 26 families had both breast and ovarian cancers, 4 families had ovarian cancers only, and 36 families had breast cancers only.

breast and ovarian cancers

ovarian cancers

breast cancers


Input: Genomic DNA was prepared from the peripheral blood leukocytes of at least one affected woman from each family.


Input: The entire coding region of BRCA1 and BRCA2 was screened for the presence of germline mutations, by use of SSCP followed by direct sequencing of observed variants.


Input: Mutations were found in 35 (53%) of the 66 families studied.


Input: All but one of the mutations were detected within the BRCA1 gene.


Input: BRCA1 abnormalities were identified in all four families with ovarian cancer only, in 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only.

BRCA1 abnormalities

ovarian cancer

breast and ovarian cancer

breast cancer


Input: The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome.

breast-ovarian cancer syndrome


Input: Seven distinct mutations were identified; five of these occurred in two or more families.


Input: In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations.


Input: Three BRCA1 abnormalities-5382insC, C61G, and 4153delA-accounted for 51%, 20%, and 11% of the identified mutations, respectively..

BRCA1 abnormalities


Input: Molecular basis of very long chain acyl-CoA dehydrogenase deficiency in three Israeli patients: identification of a complex mutant allele with P65L and K247Q mutations, the former being an exonic mutation causing exon 3 skipping.

very long chain acyl-CoA dehydrogenase deficiency


Input: Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a life-threatening disorder of mitochondrial fatty acid beta-oxidation.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency


Input: We identified four novel mutations in three unrelated patients.


Input: All patients had the severe childhood form of VLCAD deficiency with early onset and high mortality.

VLCAD deficiency


Input: Immunoblot analysis revealed that VLCAD protein was undetectable in patients 2 and 3, whereas normal-size VLCAD protein and an aberrant form of VLCAD (4kDa smaller) were detected in patient 1.


Input: As expected, null mutations were found in patients 2 and 3 patient 2 is homozygous for a frameshift mutation, del 4 bp at 798-801, and patient 3 is homozygous for a nonsense mutation 65C > A (S22X).


Input: Patient 1 was homozygous for a complex mutant allele containing two alterations, including a 194C > T transition (P65L) and 739A > C transversion (K247Q); in the case of P65L, the amino acid change does not reduce enzyme activity.


Input: However, the nucleotide change resulted in exon 3 skipping, whereas the latter K247Q mutation had a drastic effect on enzyme activity.


Input: We verified these events by in vivo splicing experiments and transient expression analysis of mutant cDNAs.


Input: The P65L mutation locates 11 bases upstream of a splice donor site of intron 3.


Input: This is an example of an exonic mutation which affects exon-splicing..


Input: Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting.

Prader-Willi syndrome


Input: The Prader-Willi syndrome (PWS) critical region on 15q11-q13 is subject to imprinting.

Prader-Willi syndrome

PWS


Input: PWS becomes apparent when genes on the paternally inherited chromosome are not expressed.

PWS


Input: Familial PWS is rare.

Familial PWS


Input: We report on a family in which a male and a female paternal first cousin both have PWS with cytogenetically normal karyotypes.

PWS


Input: Fluorescence in situ hybridization (FISH) analysis shows a submicroscopic deletion of SNRPN, but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3.


Input: The cousins fathers and two paternal aunts have the same deletion and are clinically normal.


Input: The grandmother of the cousins is deceased and not available for study, and their grandfather is not deleted for SNRPN.


Input: DNA methylation analysis of D15S63 is consistent with an abnormality of the imprinting center associated with PWS.

PWS


Input: " Grandmatrilineal " inheritance occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons.


Input: In this case, PWS does not become evident as long as the deletion is passed through the matrilineal line.

PWS


Input: This represents a unique inheritance pattern due to imprinting..


Input: Human glycine decarboxylase gene (GLDC) and its highly conserved processed pseudogene (psiGLDC): their structure and expression, and the identification of a large deletion in a family with nonketotic hyperglycinemia.

nonketotic hyperglycinemia


Input: Mutations in the glycine decarboxylase gene (GLDC) cause nonketotic hyperglycinemia (NKH), an in-born error of metabolism characterized by severe neurological disturbance.

nonketotic hyperglycinemia

NKH

in-born error of metabolism

neurological disturbance


Input: We have determined the structure of GLDC and of its pseudogene (psiGLDC) and studied their expression for a molecular analysis of NKH.

NKH


Input: The GLDC gene spans at least 135 kb and consists of 25 exons.


Input: All donor and acceptor sites adhere to the canonical GT-AG rule, except for the donor site of intron 21, where a variant form GC is used instead of GT.


Input: The transcription initiation site has been assigned to a residue 163 bp upstream from the translation initiation triplet by primer extension analysis.


Input: The psiGLDC gene has no intron and shares 97.


Input: 5% homology with the coding region of functional GLDC, suggesting that psiGLDC is a processed pseudogene that arose from the GLDC transcript about 4-8 million years ago.


Input: RNA blotting analysis has revealed that GLDC is expressed in human liver, kidney, brain, and placenta.


Input: We have also examined a patient with NKH with no detectable GLDC mRNA in his lymphoblasts.

NKH


Input: Exons 1-3 of the functional GLDC gene from this patient are not amplified by polymerase chain reaction (PCR), whereas those from control subjects are.


Input: These results suggest a large homozygous deletion (at least 30 kb) in the patient.


Input: Furthermore, we have devised a semi-quantitative PCR to estimate the number of GLDC alleles by using psiGLDC as an internal control and have confirmed the homozygosity and heterozygosity of the deletion in the patient and his parents, respectively.


Input: Structural information of GLDC and psiGLDC should facilitate the molecular analysis of NKH.

NKH


Input: De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch.


Input: Prader-Willi syndrome (PWS) is a neurogenetic disease characterized by infantile hypotonia, gonadal hypoplasia, obsessive behaviour and neonatal feeding difficulties followed by hyperphagia, leading to profound obesity.

Prader-Willi syndrome

PWS

neurogenetic disease

infantile hypotonia

gonadal hypoplasia

hyperphagia

obesity


Input: PWS is due to a lack of paternal genetic information at 15q11-q13 (ref. 2).

PWS


Input: Five imprinted, paternally expressed genes map to the PWS region, MKRN3 (ref. 3), NDN (ref. 4), NDNL1 (ref. 5), SNRPN (refs 6-8) and IPW (ref. 9), as well as two poorly characterized framents designated PAR-1 and PAR-5 (ref. 10).

PWS


Input: Imprinting of this region involves a bipartite imprinting centre (IC), which overlaps SNRPN (refs 10, 11).


Input: Deletion of the SNRPN promoter/exon 1 region (the PWS IC element) appears to impair the establishment of the paternal imprint in the male germ line and leads to PWS.

PWS

PWS


Input: Here we report a PWS family in which the father is mosaic for an IC deletion on his paternal chromosome.

PWS


Input: The deletion chromosome has acquired a maternal methylation imprint in his somatic cells.


Input: We have made identical findings in chimaeric mice generated from two independent embryonic stem (ES) cell lines harbouring a similar deletion.


Input: Our studies demonstrate that the PWS IC element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance..

PWS


Input: Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy.

deficient in Six5

cataracts

myotonic dystrophy


Input: Expansion of a CTG trinucleotide repeat in the 3 UTR of the gene DMPK at the DM1 locus on chromosome 19 causes myotonic dystrophy, a dominantly inherited disease characterized by skeletal muscle dystrophy and myotonia, cataracts and cardiac conduction defects.

myotonic dystrophy

dominantly inherited disease

muscle dystrophy

myotonia

cataracts

cardiac conduction defects


Input: Targeted deletion of Dm15, the mouse orthologue of human DMPK, produced mice with a mild myopathy and cardiac conduction abnormalities, but without other features of myotonic dystrophy, such as myotonia and cataracts.

myopathy

cardiac conduction abnormalities

myotonic dystrophy

myotonia

cataracts


Input: We, and others, have demonstrated that repeat expansion decreases expression of the adjacent gene SIX5 (refs 7, 8), which encodes a homeodomain transcription factor.


Input: To determine whether SIX5 deficiency contributes to the myotonic dystrophy phenotype, we disrupted mouse Six5 by replacing the first exon with a beta-galactosidase reporter.

SIX5 deficiency

myotonic dystrophy


Input: Six5-mutant mice showed reporter expression in multiple tissues, including the developing lens.


Input: Homozygous mutant mice had no apparent abnormalities of skeletal muscle function, but developed lenticular opacities at a higher rate than controls.

abnormalities of skeletal muscle function

lenticular opacities


Input: Our results suggest that SIX5 deficiency contributes to the cataract phenotype in myotonic dystrophy, and that myotonic dystrophy represents a multigenic disorder..

SIX5 deficiency

cataract

myotonic dystrophy

myotonic dystrophy

multigenic disorder


Input: Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts.

cataracts


Input: Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts.

Myotonic dystrophy

DM

autosomal dominant disorder

muscle wasting

myotonia

cardiac arrhythmia

hyperinsulinaemia

mental retardation

cataracts


Input: The genetic defect in DM is a CTG repeat expansion located in the 3 untranslated region of DMPK and 5 of a homeodomain-encoding gene, SIX5 (formerly DMAHP; refs 2-5).

genetic defect

DM


Input: There are three mechanisms by which CTG expansion can result in DM.

DM


Input: First, repeat expansion may alter the processing or transport of the mutant DMPK mRNA and consequently reduce DMPK levels.


Input: Second, CTG expansion may establish a region of heterochromatin 3 of the repeat sequence and decrease SIX5 transcription.


Input: Third, toxic effects of the repeat expansion may be intrinsic to the repeated elements at the level of DNA or RNA (refs 10, 11).


Input: Previous studies have demonstrated that a dose-dependent loss of Dm15 (the mouse DMPK homologue) in mice produces a partial DM phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders.

DMPK

cardiac conduction disorders


Input: To test the role of Six5 loss in DM, we have analysed a strain of mice in which Six5 was deleted.

DM


Input: Our results demonstrate that the rate and severity of cataract formation is inversely related to Six5 dosage and is temporally progressive.

cataract


Input: Six5 +/-and Six5-/-mice show increased steady-state levels of the Na +/K +-ATPase alpha-1 subunit and decreased Dm15 mRNA levels.


Input: Thus, altered ion homeostasis within the lens may contribute to cataract formation.

cataract


Input: As ocular cataracts are a characteristic feature of DM, these results demonstrate that decreased SIX5 transcription is important in the aetiology of DM.

cataracts

DM

DM


Input: Our data support the hypothesis that DM is a contiguous gene syndrome associated with the partial loss of both DMPK and SIX5..

DM


Input: ATM-dependent phosphorylation of nibrin in response to radiation exposure.


Input: Mutations in the gene ATM are responsible for the genetic disorder ataxia-telangiectasia (A-T), which is characterized by cerebellar dysfunction, radiosensitivity, chromosomal instability and cancer predisposition.

genetic disorder ataxia-telangiectasia

A-T

cerebellar dysfunction

cancer


Input: Both the A-T phenotype and the similarity of the ATM protein to other DNA-damage sensors suggests a role for ATM in biochemical pathways involved in the recognition, signalling and repair of DNA double-strand breaks (DSBs).

A-T


Input: There are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS).

cancer

A-T

Nijmegen breakage syndrome

NBS


Input: The protein defective in NBS, nibrin (encoded by NBS1), forms a complex with MRE11 and RAD50 (refs 1, 2).

NBS


Input: This complex localizes to DSBs within 30 minutes after cellular exposure to ionizing radiation (IR) and is observed in brightly staining nuclear foci after a longer period of time.


Input: The overlap between clinical and cellular phenotypes in A-T and NBS suggests that ATM and nibrin may function in the same biochemical pathway.

A-T

NBS


Input: Here we demonstrate that nibrin is phosphorylated within one hour of treatment of cells with IR.


Input: This response is abrogated in A-T cells that either do not express ATM protein or express near full-length mutant protein.

A-T


Input: We also show that ATM physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro.


Input: Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells.

NBS


Input: ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association as revealed by radiation-induced foci formation.


Input: Our data provide a biochemical explanation for the similarity in phenotype between A-T and NBS..

A-T

NBS


Input: Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.

BRCA-linked and sporadic ovarian cancer


Input: CONTEXT Most hereditary ovarian cancers are associated with germline mutations in BRCA1 or BRCA2.

hereditary ovarian cancers


Input: Attempts to define the clinical significance of BRCA mutation status in ovarian cancer have produced conflicting results, especially regarding survival.

ovarian cancer


Input: OBJECTIVE To determine whether hereditary ovarian cancers have distinct clinical and pathological features compared with sporadic (nonhereditary) ovarian cancers.

hereditary ovarian cancers

sporadic (nonhereditary) ovarian cancers


Input: DESIGN AND SETTING Retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at our institution, which is a comprehensive cancer center as designated by the National Cancer Institute, over a 12-year period (December 1986 to August 1998).

ovarian cancers

cancer

Cancer


Input: PATIENTS The study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group.


Input: From the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2.


Input: The remaining 101 cases from the same series not associated with a BRCA mutation and 2 additional groups (Gynecologic Oncology Group protocols 52 and 111) with ovarian cancer from clinical trials (for the survival analysis) were included for comparison.

ovarian cancer


Input: MAIN OUTCOME MEASURES Age at diagnosis, surgical stage, histologic cell type and grade, and surgical outcome; and response to chemotherapy and survival for advanced-stage (II and IV) cases.


Input: RESULTS Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1-vs BRCA2-linked patients (54 vs 62 years; P =. 04).

Hereditary cancers


Input: Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases.


Input: The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (P <. 001).


Input: Those with hereditary cancers had improved survival compared with the nonhereditary group (P =. 004).

hereditary cancers


Input: For stage III cancers, BRCA mutation status was an independent prognostic variable (P =. 03).

stage III cancers


Input: CONCLUSIONS Although BRCA-associated hereditary ovarian cancers in this population have surgical and pathological characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients survive longer than nonhereditary cancer patients.

BRCA-associated hereditary ovarian cancers

sporadic cancers

advanced-stage hereditary cancer

nonhereditary cancer


Input: Age penetrance is greater for BRCA1-linked than for BRCA2-linked cancers in this population.

BRCA1-linked than for BRCA2-linked cancers


Input: The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators.

familial Mediterranean fever


Input: Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever and neutrophil-mediated serosal inflammation.

Familial Mediterranean fever

FMF

recessive disorder

fever

neutrophil-mediated serosal inflammation


Input: We recently identified the gene causing FMF, designated MEFV, and found it to be expressed in mature neutrophils, suggesting that it functions as an inflammatory regulator.

FMF


Input: To facilitate our understanding of the normal function of MEFV, we extended our previous studies.


Input: MEFV messenger RNA was detected by reverse transcriptase-polymerase chain reaction in bone marrow leukocytes, with differential expression observed among cells by in situ hybridization.


Input: CD34 hematopoietic stem-cell cultures induced toward the granulocytic lineage expressed MEFV at the myelocyte stage, concurrently with lineage commitment.


Input: The prepromyelocytic cell line HL60 expressed MEFV only at granulocytic and monocytic differentiation.


Input: MEFV was also expressed in the monocytic cell lines U937 and THP-1.


Input: Among peripheral blood leukocytes, MEFV expression was detected in neutrophils, eosinophils, and to varying degrees, monocytes.


Input: Consistent with the tissue specificity of expression, complete sequencing and analysis of upstream regulatory regions of MEFV revealed homology to myeloid-specific promoters and to more broadly expressed inflammatory promoter elements.


Input: In vitro stimulation of monocytes with the proinflammatory agents interferon (IFN) gamma, tumor necrosis factor, and lipopolysaccharide induced MEFV expression, whereas the antiinflammatory cytokines interleukin (IL) 4, IL-10, and transforming growth factor beta inhibited such expression.

tumor


Input: Induction by IFN-gamma occurred rapidly and was resistant to cycloheximide.


Input: IFN-alpha also induced MEFV expression.


Input: In granulocytes, MEFV was up-regulated by IFN-gamma and the combination of IFN-alpha and colchicine.


Input: These results refine understanding of MEFV by placing the gene in the myelomonocytic-specific proinflammatory pathway and identifying it as an IFN-gamma immediate early gene..


Input: Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes.

mucopolysaccharidosis IVA


Input: Mucopolysaccharidosis IVA (MPS IVA; OMIM #253000), a lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), has variable clinical phenotypes.

Mucopolysaccharidosis IVA

MPS IVA

lysosomal storage disorder

deficiency of N-acetylgalactosamine-6-sulfate sulfatase


Input: To date we have identified 65 missense mutations in the GALNS gene from MPS IVA patients, but the correlation between genotype and phenotype has remained unclear.

MPS IVA


Input: We studied 17 missense mutations using biochemical approaches and 32 missense mutations, using structural analyses.


Input: Fifteen missense mutations and two newly engineered active site mutations (C79S, C79T) were characterized by transient expression analysis.


Input: Mutant proteins, except for C79S and C79T, were destabilized and detected as insoluble precursor forms while the C79S and C79T mutants were of a soluble mature size.


Input: Mutants found in the severe phenotype had no activity.


Input: Mutants found in the mild phenotype had a considerable residual activity (1. 3-13. 3% of wild-type GALNS activity).


Input: Sulfatases, including GALNS, are members of a highly conserved gene family sharing an extensive sequence homology.


Input: Thus, a tertiary structural model of human GALNS was constructed from the X-ray crystal structure of N-acetylgalacto-samine-4-sulfatase and arylsulfatase A, using homology modeling, and 32 missense mutations were investigated.


Input: Consequently, we propose that there are at least three different reasons for the severe phenotype (i) destruction of the hydrophobic core or modification of the packing; (ii) removal of a salt bridge to destabilize the entire conformation; (iii) modification of the active site.


Input: In contrast, mild mutations were mostly located on the surface of the GALNS protein.


Input: These studies shed further light on the genotype-phenotype correlation of MPS IVA and structure-function relationship in the sulfatase family.

MPS IVA


Input: Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.

ataxia-telangiectasia

A-T


Input: Mutations at the ataxia-telangiectasia (A-T) locus on chromosome band 11q22 cause a distinctive autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer, ischemic heart disease, and early mortality.

ataxia-telangiectasia

A-T

autosomal recessive syndrome

cancer

ischemic heart disease


Input: PCR amplification from genomic DNA and automated sequencing of the entire coding region (66 exons) and splice junctions detected 77 mutations (85%) in 90 A-T chromosomes.

A-T


Input: Heteroduplex analysis detected another 42 mutations at the A-T locus.

A-T


Input: Out of a total of 71 unique mutations, 50 were found only in a single family, and 51 had not been reported previously.


Input: Most (58/71, 82%) mutations were frameshift and nonsense mutations that are predicted to cause truncation of the A-T protein; the less common mutation types were missense (9/71, 13%), splicing (3/71, 4%) and one in-frame deletion, 2546 3 (1/71, 1%).

A-T


Input: The mean survival and height distribution of 134 A-T patients correlated significantly with the specific mutations present in the patients.

A-T


Input: Patients homozygous for a single truncating mutation, typically near the N-terminal end of the gene, or heterozygous for the in-frame deletion 2546 3, were shorter and had significantly shorter survival than those heterozygous for a splice site or missense mutation, or heterozygous for two truncating mutations.


Input: Alterations of the length or amino acid composition of the A-T gene product affect the A-T clinical phenotype in different ways.

A-T

A-T


Input: Mutation analysis at the A-T locus may help estimate the prognosis of A-T patients..

A-T

A-T


Input: Isolation, genomic organization, and expression analysis of the mouse and rat homologs of MEFV, the gene for familial mediterranean fever.

familial mediterranean fever


Input: Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis.

Familial Mediterranean fever

FMF

recessive disorder

fever

serositis

synovitis


Input: Recently the FMF gene (MEFV) was cloned; the protein product, pyrin/marenostrin, is thought to regulate inflammation in myeloid cells.

FMF


Input: In this manuscript we report the mouse and rat homologs of MEFV.


Input: The murine gene contains ten exons with a coding sequence of 2304 bp, while the rat homolog has nine exons with a coding sequence of 2253 bp.


Input: A considerable amino acid sequence homology was observed between the mouse and human (47. 6% identity and 65. 5% similarity) and between the mouse and rat genes (73. 5% identity and 82. 1% similarity).


Input: The predicted rodent proteins have several important domains and signals found in human pyrin, including a B-box zinc finger domain, Robbins-Dingwall nuclear localization signal, and coiled-coil domain.


Input: However, perhaps because of an ancient frame-shift mutation, neither the mouse nor the rat protein has an intact C-terminal B30.


Input: 2 domain, in which most FMF-associated mutations have been found in human MEFV.

FMF


Input: Nevertheless, like the human gene, mouse Mefv is expressed in peripheral blood granulocytes but not lymphocytes.


Input: Consistent with its expression in granulocytes, Mefv was detected at high levels in the primary follicles and marginal zones of the splenic white pulp.


Input: Mefv is localized on mouse Chromosome (Chr) 16, region A3-B1, extending a region of synteny with human Chr 16p13.


Input: Development of knockout and knockin mouse models may provide further insights into the functional evolution of this gene.