Input: Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome.

Pelizaeus-Merzbacher disease


Input: The proteolipid protein gene (PLP) is normally present at chromosome Xq22.


Input: Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD).

Pelizaeus-Merzbacher disease

PMD


Input: Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22.

PMD


Input: In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene.


Input: The results of FISH analysis showed an additional copy of PLP in Xp22.


Input: 1, although no chromosomal rearrangements could be detected by standard karyotype analysis.


Input: Another three affected males from the family had similar findings.


Input: In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome.

PMD


Input: In the inv (X) carried by several affected family members, FISH showed PLP signals at Xp11.


Input: 4 and Xq22.


Input: A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern.


Input: The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.

genetic disorders


Input: The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations.


Input: The BRCA1 Exon 13 Duplication Screening Group.


Input: Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U.


Input: S S. families of European ancestry and in one Portuguese family.


Input: Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication.


Input: To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3, 580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases.

breast and/or ovarian cancer


Input: A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2).


Input: Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin.


Input: Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction-based assay described in this report.


Input: Genotype-phenotype correlations in families with deletions in the von Hippel-Lindau (VHL) gene.

von Hippel-Lindau

VHL


Input: Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome characterized by predisposition for bilateral and multi-centric hemangioblastoma in the retina and central nervous system, pheochromocytoma, renal cell carcinoma, and cysts in the kidney, pancreas, and epididymis.

Von Hippel-Lindau (VHL) disease

hereditary tumor syndrome

bilateral and multi-centric hemangioblastoma

pheochromocytoma

renal cell carcinoma

cysts in the kidney, pancreas, and epididymis


Input: We describe five families for which direct sequencing of the coding region of the VHL gene had failed to identify the family-specific mutation.

VHL


Input: Further molecular analysis revealed deletions involving the VHL gene in each of these families.

VHL


Input: In four families, partial deletions of one or more exons were detected by Southern blot analysis.


Input: In the fifth family, FISH analysis demonstrated the deletion of the entire VHL gene.

VHL


Input: Our results show that (quantitative) Southern blot analysis is a sensitive method for detecting germline deletions of the VHL gene and should be implemented in routine DNA diagnosis for VHL disease.

VHL

VHL disease


Input: Our data support the previously established observation that families with a germline deletion have a low risk for pheochromocytoma.

pheochromocytoma


Input: Further unraveling of genotype-phenotype correlations in VHL disease has revealed that families with a full or partial deletion of the VHL gene exhibit a phenotype with a preponderance of central nervous system hemangioblastoma..

VHL disease

VHL

central nervous system hemangioblastoma


Input: Age of the intronic GAA triplet repeat expansion mutation in Friedreich ataxia.

Friedreich ataxia


Input: Friedreich ataxia (FRDA), the most frequently inherited ataxia, is due in the vast majority of cases to a large expansion of an intronic GAA repeat.

Friedreich ataxia

FRDA

inherited ataxia


Input: Using linkage disequilibrium analysis based on haplotype data of seven polymorphic markers close to the frataxin gene, the age of FRDA founding mutational event (s) is estimated to be at least 682 +/-203 generations (95% confidence interval 564-801 g), a dating which is consistent with little or no negative selection and provides further evidence for an ancient spread of a pre-mutation (at-risk alleles) in western Europe..

FRDA


Input: Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.

ataxia-telangiectasia

Nijmegen breakage syndrome


Input: Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes.

Ataxia-telangiectasia

A-T

Nijmegen breakage syndrome

NBS

recessive genetic disorders

cancer


Input: The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain.

A-T


Input: The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mrel1.

Nijmegen breakage syndrome


Input: Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM.


Input: Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation.


Input: We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage.


Input: This response includes S-phase checkpoint activation, formation of the NBS1/Mrel1/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation.

hypersensitivity to ionizing radiation


Input: Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes..

genetic diseases


Input: Homozygosity mapping in a family with microcephaly, mental retardation, and short stature to a Cohen syndrome region on 8q21. 3-8q22. 1: redefining a clinical entity.

microcephaly

mental retardation

short stature

Cohen syndrome


Input: A syndrome of microcephaly, progressive postnatal growth deficiency, and mental retardation was observed in two brothers and their cousin from a multiply consanguineous kindred of Lebanese descent.

microcephaly

postnatal growth deficiency

mental retardation


Input: Hypotonia, chorioretinal dystrophy, and myopia were also identified.

Hypotonia

chorioretinal dystrophy

myopia


Input: The severity of the condition varied among the closely related patients.


Input: Because of absence of a distinctive facial appearance, the degree of mental retardation, and short stature, the initially considered clinical diagnosis of Cohen syndrome was withdrawn and a novel genetic entity was assumed.

mental retardation

short stature

Cohen syndrome


Input: Homozygosity mapping in this family assigned the gene to a 26.


Input: 8-cM region on the chromosome band 8q21.


Input: 1, between the microsatellites at D8S270 and D8S514.


Input: The maximum two-point LOD score was found for marker at D8S267 (Zmax = 3.. 237 at Omax = 0. 00).


Input: Intriguingly enough, the identified gene region overlaps the refined gene region for Cohen syndrome (COH1) [Kolehmainen et al., 1997 Euro J Hum Genet 5 206-213].

Cohen syndrome


Input: This fact encourages the hypothesis that the described kindred segregates for a variant of Cohen syndrome and suggests a redefinition of its phenotype

Cohen syndrome


Input: Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis.

ankylosing spondylitis


Input: Ankylosing spondylitis (AS) is a common and highly familial rheumatic disorder.

Ankylosing spondylitis

AS

rheumatic disorder


Input: The sibling recurrence risk ratio for the disease is 63 and heritability assessed in twins > 90%.


Input: Although MHC genes, including HLA-B27, contribute only 20-50% of the genetic risk for the disease, no non-MHC gene has yet been convincingly demonstrated to influence either susceptibility to the disease or its phenotypic expression.


Input: Previous linkage and association studies have suggested the presence of a susceptibility gene for AS close to, or within, the cytochrome P450 2D6 gene (CYP2D6, debrisoquine hydroxylase) located at chromosome 22q13. 1.

AS


Input: We performed a linkage study of chromosome 22 in 200 families with AS affected sibling-pairs.

AS


Input: Association of alleles of the CYP2D6 gene was examined by both case-control and within-family means.


Input: For case-control studies, 617 unrelated individuals with AS (361 probands from sibling-pair and parent-case trio families and 256 unrelated non-familial sporadic cases) and 402 healthy ethnically matched controls were employed.

AS


Input: For within-family association studies, 361 families including 161 parent-case trios and 200 affected sibling-pair families were employed.


Input: Homozygosity for poor metabolizer alleles was found to be associated with AS.

AS


Input: Heterozygosity for the most frequent poor metabolizer allele (CYP2D6 * 4) was not associated with increased susceptibility to AS.

AS


Input: Significant within-family association of CYP2D6 * 4 alleles and AS was demonstrated.

AS


Input: Weak linkage was also demonstrated between CYP2D6 and AS.

AS


Input: We postulate that altered metabolism of a natural toxin or antigen by the CYP2D6 gene may increase susceptibility to AS.

AS


Input: Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4).

PDS

Pendred syndrome

non-syndromic hearing loss


Input: The PDS gene encodes a transmembrane protein, known as pendrin, which functions as a transporter of iodide and chloride.

PDS


Input: Mutations in this gene are responsible for Pendred syndrome and autosomal recessive non-syndromic hearing loss at the DFNB4 locus on chromosome 7q31.

Pendred syndrome

autosomal recessive non-syndromic hearing loss


Input: A screen of 20 individuals from the midwestern USA with non-syndromic hearing loss and dilated vestibular aqueducts identified three people (15%) with PDS mutations.

non-syndromic hearing loss

PDS


Input: To determine whether PDS mutations in individuals with Pendred syndrome differ functionally from PDS mutations in individuals with non-syndromic hearing loss, we compared three common Pendred syndrome allele variants (L236P, T416P and E384G), with three PDS mutations reported only in individuals with non-syndromic hearing loss (V480D, V653A and I490L/G497S).

PDS

Pendred syndrome

PDS

non-syndromic hearing loss

Pendred syndrome

PDS

non-syndromic hearing loss


Input: The mutations associated with Pendred syndrome have complete loss of pendrin-induced chloride and iodide transport, while alleles unique to people with DFNB4 are able to transport both iodide and chloride, albeit at a much lower level than wild-type pendrin.

Pendred syndrome


Input: We hypothesize that this residual level of anion transport is sufficient to eliminate or postpone the onset of goiter in individuals with DFNB4.

goiter


Input: We propose a model for pendrin function in the thyroid in which pendrin transports iodide across the apical membrane of the thyrocyte into the colloid space..


Input: The human factor IX gene as germline mutagen test: samples from Mainland China have the putatively endogenous pattern of mutation.


Input: Germline mutations are the major source of genetic variation that allows a species to evolve over time but at the cost of Mendelian disease and genetic predisposition to multifactorial diseases.

Mendelian disease

multifactorial diseases


Input: Previous analyses have revealed that the pattern of germline mutations in the factor IX gene (F9) is similar among a variety of ethnically and geographically diverse populations and compatible with the ancient pattern that has shaped the mammalian genome.


Input: Here, we compare the pattern of germline mutation in a population of hemophilia B patients from Mainland China (n = 66) to that in U.

hemophilia B


Input: S.


Input: Caucasians, Blacks, and Mexican Hispanics and stratify by disease severity and ethnicity.


Input: The similar pattern of germline mutation in all ethnic groups studied to date provides additional data compatible with the inference that endogenous processes predominate in germline mutations.


Input: Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.


Input: Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced lymphocyte apoptosis in human autoimmune lymphoproliferative syndrome.

autoimmune lymphoproliferative syndrome


Input: This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand-independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain.


Input: Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein.


Input: These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease..


Input: Determination of carrier status for the Wiskott-Aldrich syndrome by flow cytometric analysis of Wiskott-Aldrich syndrome protein expression in peripheral blood mononuclear cells.

Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome


Input: The Wiskott-Aldrich syndrome (WAS) is caused by defects in the WAS protein (WASP) gene on the X chromosome.

Wiskott-Aldrich syndrome

WAS

WAS


Input: Previous study disclosed that flow cytometric analysis of intracellular WASP expression (FCM-WASP analysis) in lymphocytes was useful for the diagnosis of WAS patients.

WASP


Input: Lymphocytes from all WAS patients showed WASPdim instead of WASPbright.

WAS


Input: Here we report that FCM-WASP analysis in monocytes could be a useful tool for the WAS carrier diagnosis.

WASP


Input: Monocytes from all nine WAS carriers showed varied population of WASPdim together with WASPbright.

WAS


Input: None of control individuals possessed the WASPdim population.


Input: In contrast, lymphocytes from all the carriers except two lacked the WASPdim population.


Input: The difference of the WASPdim population in monocytes and lymphocytes observed in WAS carriers suggests that WASP plays a more critical role in the development of lymphocytes than in that of monocytes.

WASPdim


Input: The present studies suggest that a skewed X-chromosomal inactivation pattern observed in WAS carrier peripheral blood cells is not fixed at the hemopoietic stem cell level but progresses after the lineage commitment..

WAS


Input: Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy.

retinal degeneration


Input: The gene Prph2 encodes a photoreceptor-specific membrane glycoprotein, peripherin-2 (also known as peripherin/rds), which is inserted into the rims of photoreceptor outer segment discs in a complex with rom-1 (ref. 2).


Input: The complex is necessary for the stabilization of the discs, which are renewed constantly throughout life, and which contain the visual pigments necessary for photon capture.


Input: Mutations in Prph2 have been shown to result in a variety of photoreceptor dystrophies, including autosomal dominant retinitis pigmentosa and macular dystrophy.

photoreceptor dystrophies

autosomal dominant retinitis pigmentosa

macular dystrophy


Input: A common feature of these diseases is the loss of photoreceptor function, also seen in the retinal degeneration slow (rds or Prph2 Rd2/Rd2) mouse, which is homozygous for a null mutation in Prph2.

retinal degeneration


Input: It is characterized by a complete failure to develop photoreceptor discs and outer segments, downregulation of rhodopsin and apoptotic loss of photoreceptor cells.


Input: The electroretinograms (ERGs) of Prph2Rd2/Rd2 mice have greatly diminished a-wave and b-wave amplitudes, which decline to virtually undetectable concentrations by two months.


Input: Subretinal injection of recombinant adeno-associated virus (AAV) encoding a Prph2 transgene results in stable generation of outer segment structures and formation of new stacks of discs containing both perpherin-2 and rhodopsin, which in many cases are morphologically similar to normal outer segments.


Input: Moreover, the re-establishment of the structural integrity of the photoreceptor layer also results in electrophysiological correction.


Input: These studies demonstrate for the first time that a complex ultrastructural cell defect can be corrected both morphologically and functionally by in vivo gene transfer..


Input: Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.

congenital afibrinogenemia


Input: Congenital afibrinogenemia is a rare, autosomal, recessive disorder characterized by the complete absence of detectable fibrinogen.

Congenital afibrinogenemia

autosomal, recessive disorder


Input: We previously identified the first causative mutations in a nonconsanguineous Swiss family; the 4 affected persons have homozygous deletions of approximately 11 kb of the fibrinogen alpha (FGA) gene.


Input: Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism.


Input: We subsequently showed that all the deletions were identical to the base pair and probably resulted from a nonhomologous recombination mediated by 7-bp direct repeats.


Input: In this study, we have collected data on 13 additional unrelated patients to identify the causative mutations and to determine the prevalence of the 11-kb deletion.


Input: A common recurrent mutation, at the donor splice site of FGA intron 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles.


Input: One patient was heterozygous for the previously identified deletion.


Input: Three more frameshift mutations, 2 nonsense mutations, and a second splice site mutation were also identified.


Input: Consequently, 86% of afibrinogenemia alleles analyzed to date have truncating mutations of FGA, though mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia..

afibrinogenemia

congenital afibrinogenemia


Input: Myotonic dystrophy: the role of the CUG triplet repeats in splicing of a novel DMPK exon and altered cytoplasmic DMPK mRNA isoform ratios.

Myotonic dystrophy


Input: The mechanism by which (CTG) n expansion in the 3 UTR of the DMPK gene causes myotonic dystrophy (DM) is unknown.

myotonic dystrophy

DM


Input: We identified four RNA splicing factors--hnRNP C, U2AF (U2 auxiliary factor), PTB (polypyrimidine tract binding protein), and PSF (PTB associated splicing factor)--that bind to two short regions 3 of the (CUG) n, and found a novel 3 DMPK exon resulting in an mRNA lacking the repeats.


Input: We propose that the (CUG) n is an essential cis acting element for this splicing event.


Input: In contrast to (CUG) n containing mRNAs, the novel isoform is not retained in the nucleus in DM cells, resulting in imbalances in relative levels of cytoplasmic DMPK mRNA isoforms and a new dominant effect of the mutation on DMPK..

DM


Input: Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype.

Prader-willi syndrome


Input: Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13.

Prader-Willi syndrome

PWS


Input: Affected individuals exhibit neonatal hypotonia, developmental delay and childhood-onset obesity.

neonatal hypotonia

developmental delay

childhood-onset obesity


Input: Necdin, a protein implicated in the terminal differentiation of neurons, is the only PWS candidate gene to reduce viability when disrupted in a mouse model.

PWS


Input: In this study, we have characterized MAGEL2 (also known as NDNL1), a gene with 51% amino acid sequence similarity to necdin and located 41 kb distal to NDN in the PWS deletion region.

PWS


Input: MAGEL2 is expressed predominantly in brain, the primary tissue affected in PWS and in several fetal tissues as shown by northern blot analysis.

PWS


Input: MAGEL2 is imprinted with monoallelic expression in control brain, and paternal-only expression in the central nervous system as demonstrated by its lack of expression in brain from a PWS-affected individual.

PWS


Input: The orthologous mouse gene (Magel2) is located within 150 kb of NDN, is imprinted with paternal-only expression and is expressed predominantly in late developmental stages and adult brain as shown by northern blotting, RT-PCR and whole-mount RNA in situ hybridization.


Input: Magel2 distribution partially overlaps that of NDN, with strong expression being detected in the central nervous system in mid-gestation mouse embryos by in situ hybridization.


Input: We hypothesize that, although loss of necdin expression may be important in the neonatal presentation of PWS, loss of MAGEL2 may be critical to abnormalities in brain development and dysmorphic features in individuals with PWS..

PWS

abnormalities in brain development

dysmorphic features

PWS


Input: Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells.

X-linked retinoschisis


Input: X-linked retinoschisis is characterized by microcystic-like changes of the macular region and schisis within the inner retinal layers, leading to visual deterioration in males.

X-linked retinoschisis

visual deterioration


Input: Many missense and protein-truncating mutations of the causative gene RS1 have now been identified and are thought to be inactivating.


Input: RS1 encodes a 224 amino acid protein, retinoschisin, which contains a discoidin domain but is of unknown function.


Input: We have generated a polyclonal antibody against a peptide from a unique region within retinoschisin, which detects a protein of approximately 28 kDa in retinal samples reduced with dithiothreitol, but multimers sized > 40 kDa under non-reducing conditions.


Input: A screen of human tissues with this antibody reveals retinoschisin to be retina specific and the antibody detects a protein of similar size in bovine and murine retinae.


Input: We investigated the expression pattern in the retina of both RS1 mRNA (using in situ hybridization with riboprobes) and retinoschisin (using immunohistochemistry).


Input: The antisense riboprobe detected RS1 mRNA only in the photoreceptor layer but the protein product of the gene was present both in the photoreceptors and within the inner portions of the retina.


Input: Furthermore, differentiated retinoblastoma cells (Weri-Rb1 cells) were found to express RS1 mRNA and to release retinoschisin.

retinoblastoma


Input: These results suggest that retinoschisin is released by photo-receptors and has functions within the inner retinal layers.


Input: Thus, X-linked retinoschisis is caused by abnormalities in a putative secreted photoreceptor protein and is the first example of a secreted photo-receptor protein associated with a retinal dystrophy..

X-linked retinoschisis

retinal dystrophy


Input: Study of the voltage-gated sodium channel beta 1 subunit gene (SCN1B) in the benign familial infantile convulsions syndrome (BFIC).

benign familial infantile convulsions syndrome

BFIC


Input: Benign familial infantile convulsions (BFIC) is a rare autosomal dominant epilepsy syndrome.

Benign familial infantile convulsions

BFIC

autosomal dominant epilepsy syndrome


Input: This syndrome has been recently described in Italian and French pedigrees.


Input: Patients present with partial, then generalized seizures, with onset at age three months.


Input: The seizures usually spontaneously cease after one year without treatment, leaving no neurological abnormalities.

neurological abnormalities


Input: We have mapped BFIC to chromosome 19q in five Italian pedigrees.

BFIC


Input: The sodium channel beta1 subunit gene (SCN1B) maps to this candidate region and has been shown to be involved in one Australian pedigree with generalized epilepsy and febrile seizures " plus " (GEFS +).

generalized epilepsy and febrile seizures " plus "


Input: In this family, a missense mutation in SCN1B cosegregates with the GEFS + phenotype.


Input: BFIC and GEFS + have clinical features in common, therefore SCN1B is a candidate gene for BFIC.

BFIC

BFIC


Input: We studied SCN1B exons 1, 2, 3, 4, and 5, using four SSCP methods in 10 Caucasian BFIC probands of Western Europe.

BFIC


Input: We found no exon variants.


Input: One variant was identified in intron 5 (IVS5-10C > G), which did not segregate with BFIC and was observed in 9.

BFIC


Input: 2% controls.


Input: A second variant in intron 5 was identified (IVS5 + 30G > A).


Input: It was rare, as not observed in controls, but not segregating with the BFIC phenotype.

BFIC


Input: Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis.

APC

attenuated familial adenomatous polyposis


Input: Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in familial adenomatous polyposis (FAP).

adenomatous polyposis coli (APC) tumor

familial adenomatous polyposis

FAP


Input: Patients with FAP typically develop hundreds to thousands of benign colorectal tumors and early-onset colorectal cancer.

FAP

benign colorectal tumors

colorectal cancer


Input: A subset of germline APC mutations results in an attenuated FAP (AFAP) phenotype, in which patients develop fewer tumors and develop them at an older age.

APC

attenuated FAP

AFAP

tumors


Input: Although a genotype-phenotype correlation between the locations of APC germline mutations and the development of AFAP has been well documented, the mechanism for AFAP has not been well defined.

APC

AFAP

AFAP


Input: We investigated the mechanism for AFAP in patients carrying a mutant APC allele (APC (AS9)) that has a mutation in the alternatively spliced region of exon 9.

AFAP

APC


Input: APC (AS9) was found to down-regulate beta-catenin-regulated transcription, the major tumor-suppressor function of APC, as did the wild-type APC.

tumor


Input: Mutation analysis showed that both APC (AS9) and the wild-type APC alleles were somatically mutated in most colorectal tumors from these patients.

APC

colorectal tumors


Input: Functional analysis showed that 4666insA, a common somatic mutation in APC (AS9) in these tumors, did not inactivate the wild-type APC.

tumors


Input: Our results indicate that carriers of APC (AS9) develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is necessary for colorectal tumorigenesis.

colorectal tumors

FAP

APC


Input: However, these patients develop colorectal tumors more frequently than does the general population because APC (AS9) is inactivated by mutations that do not inactivate the wild-type APC..

colorectal tumors


Input: Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia.

Friedreich ataxia


Input: Frataxin deficiency is the primary cause of Friedreich ataxia (FRDA), an autosomal recessive cardiodegenerative and neurodegenerative disease.

Frataxin deficiency

Friedreich ataxia

FRDA

autosomal recessive cardiodegenerative and neurodegenerative disease


Input: Frataxin is a nuclear-encoded mitochondrial protein that is widely conserved among eukaryotes.


Input: Genetic inactivation of the yeast frataxin homologue (Yfh1p) results in mitochondrial iron accumulation and hypersensitivity to oxidative stress.

mitochondrial iron accumulation

hypersensitivity to oxidative stress


Input: Increased iron deposition and evidence of oxidative damage have also been observed in cardiac tissue and cultured fibroblasts from patients with FRDA.

FRDA


Input: These findings indicate that frataxin is essential for mitochondrial iron homeostasis and protection from iron-induced formation of free radicals.


Input: The functional mechanism of frataxin, however, is still unknown.


Input: We have expressed the mature form of Yfh1p (mYfh1p) in Escherichia coli and have analyzed its function in vitro.


Input: Isolated mYfh1p is a soluble monomer (13, 783 Da) that contains no iron and shows no significant tendency to self-associate.


Input: Aerobic addition of ferrous iron to mYfh1p results in assembly of regular spherical multimers with a molecular mass of approximately 1.


Input: 1 MDa (megadaltons) and a diameter of 13 +/-2 nm.


Input: Each multimer consists of approximately 60 subunits and can sequester > 3, 000 atoms of iron.


Input: Titration of mYfh1p with increasing iron concentrations supports a stepwise mechanism of multimer assembly.


Input: Sequential addition of an iron chelator and a reducing agent results in quantitative iron release with concomitant disassembly of the multimer, indicating that mYfh1p sequesters iron in an available form.


Input: In yeast mitochondria, native mYfh1p exists as monomer and a higher-order species with a molecular weight > 600, 000.


Input: After addition of (55) Fe to the medium, immunoprecipitates of this species contain > 16 atoms of (55) Fe per molecule of mYfh1p.


Input: We propose that iron-dependent self-assembly of recombinant mYfh1p reflects a physiological role for frataxin in mitochondrial iron sequestration and bioavailability..


Input: A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome).

faciogenital dysplasia

Aarskog-Scott syndrome


Input: Aarskog-Scott Syndrome (AAS) is an X-linked disorder characterised by short stature and multiple facial, limb and genital abnormalities.

Aarskog-Scott Syndrome

AAS

X-linked disorder

short stature

facial, limb and genital abnormalities


Input: A gene, FGD1, altered in a patient with AAS phenotype, has been identified and found to encode a protein with homology to Rho/Rac guanine nucleotide exchange factors (Rho/Rac GEF).

AAS


Input: However, since this original report on identification of a mutated FGD1 gene in an AAS patient, no additional mutations in the FGD1 gene have been described.

AAS


Input: We analysed 13 independent patients with clinical diagnosis of AAS.

AAS


Input: One patient presented a mutation that results in a nucleotide change in exon 10 of the FGD1 gene (G2559 > A) substituting a Gln for Arg in position 610.


Input: The mutation was found to segregate with the AAS phenotype in affected males and carrier females in the family of this patient.

AAS


Input: Interestingly, Arg-610 is located within one of the two pleckstrin homology (PH) domains of the FGD1 gene and it corresponds to a highly conserved residue which has been involved in InsP binding in PH domains of other proteins.


Input: The same residue is often mutated in the Brutons tyrosine kinase (Btk) gene in patients with an X-linked agammaglobulinemia.

X-linked agammaglobulinemia


Input: The Arg610Gln mutation represents the first case of a mutation in the PH domain of the FGD1 gene and additional evidence that mutations in PH domains can be associated to human diseases..


Input: Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity.


Input: Huntington disease (HD) is caused by expansion of a glutamine repeat in the amino-terminal region of huntingtin.

Huntington disease

HD


Input: Despite its widespread expression, mutant huntingtin induces selective neuronal loss in striatal neurons.


Input: Here we report that, in mutant mice expressing HD repeats, the production and aggregation of N-terminal huntingtin fragments preferentially occur in HD-affected neurons and their processes and axonal terminals.

HD

HD


Input: N-terminal fragments of mutant huntingtin form aggregates and induce neuritic degeneration in cultured striatal neurons.

neuritic degeneration


Input: N-terminal mutant huntingtin also binds to synaptic vesicles and inhibits their glutamate uptake in vitro.


Input: The specific processing and accumulation of toxic fragments of N-terminal huntingtin in HD-affected striatal neurons, especially in their neuronal processes and axonal terminals, may contribute to the selective neuropathology of HD..

HD

HD


Input: BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer.

breast cancer


Input: Germline mutations in the tumor suppressor gene, BRCA1, predispose individuals to breast and ovarian cancers.

tumor

breast and ovarian cancers


Input: Using a combination of affinity-and conventional chromatographic techniques, we have isolated a predominant form of a multiprotein BRCA1-containing complex from human cells displaying chromatin-remodeling activity.


Input: Mass spectrometric sequencing of components of this complex indicated that BRCA1 is associated with a SWI/SNF-related complex.


Input: We show that BRCA1 can directly interact with the BRG1 subunit of the SWI/SNF complex.


Input: Moreover, p53-mediated stimulation of transcription by BRCA1 was completely abrogated by either a dominant-negative mutant of BRG1 or the cancer-causing deletion in exon 11 of BRCA1.

cancer


Input: These findings reveal a direct function for BRCA1 in transcriptional control through modulation of chromatin structure..


Input: Asef, a link between the tumor suppressor APC and G-protein signaling.

tumor


Input: The adenomatous polyposis coli gene (APC) is mutated in familial adenomatous polyposis and in sporadic colorectal tumors.

adenomatous polyposis coli

familial adenomatous polyposis

colorectal tumors


Input: Here the APC gene product is shown to bind through its armadillo repeat domain to a Rac-specific guanine nucleotide exchange factor (GEF), termed Asef.

APC


Input: Endogenous APC colocalized with Asef in mouse colon epithelial cells and neuronal cells.


Input: Furthermore, APC enhanced the GEF activity of Asef and stimulated Asef-mediated cell flattening, membrane ruffling, and lamellipodia formation in MDCK cells.


Input: These results suggest that the APC-Asef complex may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function..


Input: Function of an axonal chemoattractant modulated by metalloprotease activity.


Input: The axonal chemoattractant netrin-1 guides spinal commissural axons by activating its receptor DCC (Deleted in Colorectal Cancer).

Colorectal Cancer


Input: We have found that chemical inhibitors of metalloproteases potentiate netrin-mediated axon outgrowth in vitro.


Input: We have also found that DCC is a substrate for metalloprotease-dependent ectodomain shedding, and that the inhibitors block proteolytic processing of DCC and cause an increase in DCC protein levels on axons within spinal cord explants.


Input: Thus, potentiation of netrin activity by inhibitors may result from stabilization of DCC on the axons, and proteolytic activity may regulate axon migration by controlling the number of functional extracellular axon guidance receptors..


Input: Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat.

Myotonic dystrophy


Input: Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3 untranslated region of the DMPK gene.

Myotonic dystrophy

DM

muscular dystrophy


Input: The mutant DMPK messenger RNA (mRNA) contains an expanded CUG repeat and is retained in the nucleus.


Input: We have expressed an untranslated CUG repeat in an unrelated mRNA in transgenic mice.


Input: Mice that expressed expanded CUG repeats developed myotonia and myopathy, whereas mice expressing a nonexpanded repeat did not.

myotonia

myopathy


Input: Thus, transcripts with expanded CUG repeats are sufficient to generate a DM phenotype.

DM


Input: This result supports a role for RNA gain of function in disease pathogenesis..


Input: Genomic rearrangements of the APC tumor-suppressor gene in familial adenomatous polyposis.

APC tumor

familial adenomatous polyposis


Input: Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in the hereditary colorectal cancer syndrome familial adenomatous polyposis (FAP).

adenomatous polyposis coli (APC) tumor

hereditary colorectal cancer syndrome familial adenomatous polyposis

FAP


Input: Almost all APC mutations that have been identified are single-nucleotide alterations, small insertions, or small deletions that would truncate the protein product of the gene.

APC


Input: No well-characterized intragenic rearrangement of APC has been described, and the prevalence of this type of mutation in FAP patients is not clear.

FAP


Input: We screened 49 potential FAP families and identified 26 different germline APC mutations in 30 families.

FAP

APC


Input: Four of these mutations were genomic rearrangements resulting from homologous and nonhomologous recombinations mediated by Alu elements.


Input: Two of these four rearrangements were complex, involving deletion and insertion of nucleotides.


Input: Of these four rearrangements, one resulted in the deletion of exons 11 and 12 and two others resulted in either complete or partial deletion of exon 14.


Input: The fourth rearrangement grossly altered the sequence within intron 14.


Input: Although this rearrangement did not affect any coding sequence of APC at the genomic DNA level, it caused inappropriate splicing of exon 14.


Input: These rearrangements were initially revealed by analyzing cDNAs and could not have been identified by using mutation detection methods that screened each exon individually.


Input: The identification of a rearrangement that did not alter any coding exons yet affected the splicing further underscores the importance of using cDNA for mutation analysis.


Input: The identification of four genomic rearrangements among 30 mutations suggests that genomic rearrangements are frequent germline APC mutations..

APC


Input: Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM.

FHM


Input: Mutations in the brain specific P/Q type Ca2 + channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, viz. episodic ataxia type 2 (EA-2), familial hemiplegic migraine (FHM) and spinocerebellar ataxia 6 (SCA6).

episodic ataxia type 2

familial hemiplegic migraine

FHM

spinocerebellar ataxia 6


Input: For individuals with EA-2, the mutations described thus far are presumed to result in a truncated protein product.


Input: Several different missense mutations have been identified in patients with FHM.

FHM


Input: At least two of these mutations have been identified on two different chromosome 19p13 haplotypes and thus represent recurrent mutations.


Input: In the present study, we have screened several individuals for mutations in all 47 exons in the CACNA1A gene by single-strand conformation analysis.


Input: We have characterised a novel missense mutation, G5260A, in exon 32 in a family segregating for EA-2.


Input: The consequence of this mutation is an amino acid substitution at a highly conserved position within the CACNA1A gene.


Input: This represents the first point mutation not resulting in a proposed truncated protein.


Input: Furthermore, this mutation has been detected in a family member with mild clinical signs including only migraine.

migraine


Input: Additionally, a second previously identified recurrent muta tion, C2272T, in exon 16 has been discovered in a patient with FHM..

FHM


Input: Analbuminemia in a neonate.

Analbuminemia


Input: A small-for-gestational-age infant, found to have analbuminemia in the neonatal period, is reported and the twelve cases recorded in the world literature are reviewed.

analbuminemia


Input: Patients lacking this serum protein are essentially asymptomatic, apart from minimal ankle edema and ease of fatigue.

ankle edema

ease of fatigue


Input: Apparent compensatory mechanisms which come into play when serum albumin is low include prolonged half-life of albumin and transferrin, an increase in serum globulins, beta lipoprotein, and glycoproteins, arterial hypotension with reduced capillary hydrostatic pressure, and the ability to respond with rapid sodium and chloride diuresis in response to small volume changes.

arterial hypotension


Input: Examination of plasma amino acids, an investigation not previously reported, revealed an extremely low plasma tryptophan level, a finding which may be important in view of the role of tryptophan in albumin synthesis..


Input: Histidinemia.

Histidinemia


Input: Classical and atypical form in siblings.


Input: Two brothers, 6 and 13 years old, had histidinemia.

histidinemia


Input: On the basis of clinical and biochemical observations, the younger boy was considered to have a classical type of the disease, while the older boy had an atypical form characterized by partial impairment of the skin histidase activity and a moderately prolonged half-life of blood histidine.


Input: The mother is a heterozygous carrier, while the father and sister seem to be normal..


Input: Carrier detection of pyruvate carboxylase deficiency in fibroblasts and lymphocytes.

pyruvate carboxylase deficiency


Input: Pyruvate carboxylase (E. C. 6. 4. 1. 1) activity was determined in the circulating peripheral lymphocytes and cultured skin fibroblasts from the family of a patient with hepatic, cerebral, renal cortical, leukocyte, and fibroblast pyruvate carboxylase deficiency (PC Portland deficiency).

pyruvate carboxylase deficiency

PC Portland deficiency


Input: Lymphocyte activities were mother, 33--39%; father, 11--29%; brother, 82--103%; and sister, 38--48% of the lowest normal.


Input: Fibroblasts from the patients mother and father had 42 and 34%, respectively, of the activity of the lowest normal.


Input: These data demonstrate that the disease is inherited in an autosomal recessive manner and that lymphocytes and fibroblasts can be used to detect carriers.


Input: Neither pyruvate carboxylase nor mitochondrial PEPCK activity in lymphocytes was increased by a 21-hr fast.


Input: Glucose-6-phosphate dehydrogenase variants from Italian subjects associated with severe neonatal jaundice.

severe neonatal jaundice


Input: Screening for the G6PD deficiency was carried out at the Maternity Division of the Galliera Hospital in Genoa, Italy.

G6PD deficiency


Input: Two groups of subjects with hyperbilirubinaemia of non-immunological origin were examined (a) 302 newborn babies of Sardinian extraction (on cord blood) and (b) 201 newborn babies of south Italian ancestry (on peripheral blood).

hyperbilirubinaemia


Input: Among 503 subjects, 43 showed an enzyme deficiency; in 39 the defect was of the Mediterranean type.


Input: In one case, previously described, the enzyme was of the A-type.


Input: In the remaining cases three different variants were identified.


Input: In the present work these three cases, each with severe neonatal jaundice, are reported.

severe neonatal jaundice


Input: Their parents originated from Calabria, from Sardinia and from Sicily.


Input: The abnormal enzymes are respectively designated as GdDcbrousse-like, GdGallura and GdAgrigento..


Input: Cytogenetic investigations in families with ataxia-telangiectasia.

ataxia-telangiectasia


Input: Chromosomal studies were performed on peripheral blood lymphocytes and cultured skin fibroblasts from five Israeli-Moroccan families with ataxia-telangiectasia.

ataxia-telangiectasia


Input: A total of 24 individuals, including seven propositi, was investigated.


Input: Among the probands, significantly elevated rates of chromosome damage were observed in both blood and skin.


Input: Skin fibroblasts of affected individuals showed several orders of magnitude more chromosome breakage than lymphocytes.


Input: Increased rates of chromosome damage were also observed in the fibroblasts of some phenotypically normal family members (obligate heterozygotes and sibs) when compared to normal controls.


Input: An apparent abnormal clone of cells, possessing a large acrocentric marker chromosome (14q +), was observed in varying proportions among cells of all the propositi (2-5% of lymphocytes; 1-9% of fibroblasts)..


Input: Prenatal diagnosis of Wolman disease.

Wolman disease


Input: Two pregnancies at risk for Wolman disease were monitored by assay and electrophoresis of acid lipase in cultured amniotic-fluid cells.

Wolman disease


Input: Cells from patient 1 had 5% of control levels of acid lipase, using 14C-triolein as substrate; however, when artificial substrates (esters of 4-methylumbelliferone and p-nitrophenol) were used to measure acid lipase, these cells had 30% of control levels.


Input: Electrophoresis of cell extracts revealed the absence of the A form of acid lipase, consistent with the diagnosis of Wolman disease.

Wolman disease


Input: Analysis of fetal tissues following prostaglandin termination of this pregnancy confirmed the diagnosis.


Input: Assay of fetal-skin fibroblasts with 14C-triolein, as well as with artificial substrates, showed marked deficiency of acid lipase activity.


Input: Electrophoresis of fetal-tissue extracts also demonstrated the absence of the A form of acid lipase.


Input: Amniotic-fluid cells from patient 2 showed normal levels of acid lipase with all substrates tested; the electrophoretic pattern of acid lipase was normal.


Input: The results suggest that the prenatal diagnosis of Wolman disease be made using the radioassay of acid lipase and/or electrophoresis..

Wolman disease


Input: Malignant neoplasms in the families of patients with ataxia-telangiectasia.

Malignant neoplasms

ataxia-telangiectasia


Input: Ataxia-telangiectasia (A-T) is an autosomal recessive syndrome associated with a greatly increased incidence of malignant neoplasms in homozygous affected individuals.

Ataxia-telangiectasia

A-T

autosomal recessive syndrome

malignant neoplasms


Input: Heterozygotes for the gene for A-T are thought to comprise about 1% of the general population and, therefore, it is important to know whether this gene also predisposes the heterozygous carrier to cancers.

A-T

cancers


Input: Heterozygous carriers of this gene are common among the close relatives of patients with A-T, although individual carriers cannot be identified by any clinical criterion or laboratory test.

A-T


Input: For this reason, we compared the incidence of death from malignant neoplasms in 2 families of patients with A-T to that expected in a random sample of the general population.

malignant neoplasms

A-T


Input: There were 59 deaths from malignant neoplasms in relatives dying before age 75, compared to 42.

malignant neoplasms


Input: 6 expected (p less than 0. 02).


Input: For A-T heterozygotes younger than age 45, the risk of dying from a malignant neoplasm was estimated to be greater than 5 times the risk for the general population.

A-T

malignant neoplasm


Input: A-T heterozygotes may comprise more than 5% of all persons dying from a cancer before age 45.

A-T

cancer


Input: The incidence of ovarian, gastric, and biliary system carcinomas and of leukemia and lymphoma was increased in these A-T families.

ovarian, gastric, and biliary system carcinomas

leukemia

lymphoma

A-T


Input: Other neoplasms that may be associated with this gene in heterozygotes include pancreatic, basal cell, colonic, breast, and cervical carcinomas.

neoplasms

pancreatic, basal cell, colonic, breast, and cervical carcinomas


Input: Striking prevalence of ankylosing spondylitis in " healthy " w27 positive males and females.

ankylosing spondylitis


Input: Ankylosing spondylitis is diagnosed once or twice in each 1000 males and one tenth as frequently in females, but the true prevalence is unknown.

Ankylosing spondylitis


Input: Indentification of genetic marker, HL-A W27, for susceptible persons has provided a tool facilitating epidemiologic studies and allowing identification of " control " populations without the marker.


Input: Evaluation by postal questionnaires, and pelvic radiography of 78 HL-A 27W-positive blood donors selected from a group of apparently healthy subjects revealed 14 who satisfied the criteria for definite ankylosing spondylitis.

ankylosing spondylitis


Input: The prevalence was similar in both sexes.


Input: One hundred and twenty-six W27-negative controls matched for race, sex, and age failed to yield a single case.


Input: For a person of either sex with HL-A W27, there appears to be about a 20 per cent chance that ankylosing spondylitis will develop, suggesting a prevalence of 10 to 15 per thousand.

ankylosing spondylitis


Input: Hitherto accepted figures may underestimate the frequency by a factor of 10 to 20..


Input: Analbuminemia in an American Indian girl.

Analbuminemia


Input: Analbuminemia was fortuitously detected in a nonedematous 12-year-old American Indian girl with atopic dermatitis, mild bronchial asthma, a mild seizure disorder, and hyperlipoproteinemia with a corneal arcus.

Analbuminemia

atopic dermatitis

bronchial asthma

seizure disorder

hyperlipoproteinemia

corneal arcus


Input: Immunologic methods revealed trace amounts (17 mg/100 ml) of apparently normal serum albumin.


Input: The patients parents were remotely related.


Input: The pedigree and clinical findings were compatible with autosomal recessive transmission of analbuminemia.

analbuminemia


Input: Heterozygotes had subnormal levels of serum albumin.


Input: The Gc-locus is closely linked to the structural albumin locus.


Input: Gc-protein levels were normal in the patient and together with normal chromosomal banding studies make it unlikely that a chromosomal deletion caused analbuminemia.

analbuminemia


Input: Gc-types in the family were compatible with, but did not prove, linkage of analbuminemia to the Gc-locus.

analbuminemia


Input: These findings suggest a " thalassemia "-like mutation for this disorder..

thalassemia


Input: Deletion of the KIT and PDGFRA genes in a patient with piebaldism.

piebaldism


Input: We have previously shown that human piebaldism results from mutations of the KIT gene, which encodes the receptor for the mast/stem cell growth factor and is located in chromosome segment 4q12.

piebaldism


Input: Using DNA of a patient with piebaldism, mental retardation, and multiple congenital anomalies associated with a 46, XY, del (4) (q12q21. 1) karyotype, we carried out quantitative Southern blot hybridization analyses of the KIT gene and the adjacent PDGFRA (platelet-derived growth factor receptor alpha subunit) genes.

piebaldism

mental retardation

multiple congenital anomalies


Input: The patient was hemizygous for both the KIT and PDGFRA genes, indicating that both of these genes are included within the deleted region.


Input: Therefore, deletion of the KIT and PDGFRA genes may account for the piebald phenotype in this patient.

piebald


Input: A germ line mutation within the coding sequence for the putative 5-phosphoribosyl-1-pyrophosphate binding site of hypoxanthine-guanine phosphoribosyltransferase (HPRT) in a Lesch-Nyhan patient: missense mutations within a functionally important region probably cause disease.

Lesch-Nyhan


Input: Lesch-Nyhan syndrome caused by a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) is the result of a heterogeneous group of germ line mutations.

Lesch-Nyhan syndrome

complete deficiency of hypoxanthine guanine phosphoribosyltransferase


Input: Identification of each mutant gene provides valuable information as to the type of mutation that occurs spontaneously.


Input: We report here a newly identified HPRT mutation in a Japanese patient with Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome


Input: This gene, designated HPRT Tokyo, had a single nucleotide change from G to A, as identified by sequencing cDNA amplified by the polymerase chain reaction.


Input: Allele specific oligonucleotide hybridization analysis using amplified genomic DNA showed that the mutant gene was transmitted from the maternal germ line.


Input: This mutation would lead to an amino acid substitution of Asp for Gly at the amino acid position 140 located within the putative 5-phosphoribosyl-1-pyrophosphate (PRPP) binding region.


Input: Missense mutations in human HPRT deficient patients thus far reported tend to accumulate in this functionally active region.

HPRT deficient


Input: However, a comparison of the data suggested that both missense and synonymous mutations can occur at any coding sequence of the human germ line HPRT gene, but that a limited percentage of all the missense mutations cause disease.


Input: The probability that a mutation will cause disease tends to be higher when the missense mutation is within a functionally important sequence..


Input: Characterisation of a new rare fragile site easily confused with the fragile X.

fragile X


Input: A new fragile site (FRAXE) in Xq28 is described.


Input: It appears to be a typical folate sensitive fragile site.


Input: The fragile site is not associated with mental retardation, it does not give abnormal results when subjected to Southern analysis with probe pfxa3 which detects the unstable DNA sequence characteristic of fragile X syndrome.

mental retardation

fragile X syndrome


Input: In situ hybridization mapping locates the fragile site between 150 kb and 600 kb distal to FRAXA.


Input: The distinction between the two fragile sites is important clinically since cytogenetic detection of FRAXE, without molecular analysis, could result in misdiagnosis of fragile X syndrome..

fragile X syndrome


Input: The Norrie disease gene maps to a 150 kb region on chromosome Xp11. 3.

Norrie disease


Input: Norrie disease is a human X-linked recessive disorder of unknown etiology characterized by congenital blindness, sensory neural deafness and mental retardation.

Norrie disease

X-linked recessive disorder

congenital blindness

sensory neural deafness

mental retardation


Input: This disease gene was previously linked to the DXS7 (L1. 28) locus and the MAO genes in band Xp11.


Input: 3 3.


Input: We report here fine physical mapping of the obligate region containing the Norrie disease gene (NDP) defined by a recombination and by the smallest submicroscopic chromosomal deletion associated with Norrie disease identified to date.

Norrie disease

Norrie disease


Input: Analysis, using in addition two overlapping YAC clones from this region, allowed orientation of the MAOA and MAOB genes in a 5-3-3-5 configuration.


Input: A recombination event between a (GT) n polymorphism in intron 2 of the MAOB gene and the NDP locus, in a family previously reported to have a recombination between DXS7 and NDP, delineates a flanking marker telomeric to this disease gene.


Input: An anonymous DNA probe, dc12, present in one of the YACs and in a patient with a submicroscopic deletion which includes MAOA and MAOB but not L1.


Input: 28, serves as a flanking marker centromeric to the disease gene.


Input: An Alu-PCR fragment from the right arm of the MAO YAC (YMAO. AluR) is not deleted in this patient and also delineates the centromeric extent of the obligate disease region.


Input: The apparent order of these loci is telomere.


Input: DXS7-MAOA-MAOB-NDP-dc12-YMAO DXS7-MAOA-MAOB-NDP-dc12-YMAO.


Input: AluR. centromere.


Input: Together these data define the obligate region containing the NDP gene to a chromosomal segment less than 150 kb.


Input: Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.

phenylketonuria

hyperphenylalaninemias


Input: Mutations in the human phenylalanine hydroxylase gene producing phenylketonuria or hyperphenylalaninemia have now been identified in many patients from various ethnic groups.

phenylketonuria

hyperphenylalaninemia


Input: These mutations all exhibit a high degree of association with specific restriction fragment-length polymorphism haplotypes at the PAH locus.


Input: About 50 of these mutations are single-base substitutions, including six nonsense mutations and eight splicing mutations, with the remainder being missense mutations.


Input: One splicing mutation results in a 3 amino acid in-frame insertion.


Input: Two or 3 large deletions, 2 single codon deletions, and 2 single base deletions have been found.


Input: Twelve of the missense mutations apparently result from the methylation and subsequent deamination of highly mutagenic CpG dinucleotides.


Input: Recurrent mutation has been observed at several of these sites, producing associations with different haplotypes in different populations.


Input: About half of all missense mutations have been examined by in vitro expression analysis, and a significant correlation has been observed between residual PAH activity and disease phenotype.


Input: Since continuing advances in molecular methodologies have dramatically accelerated the rate in which new mutations are being identified and characterized, this register of mutations will be updated periodically..


Input: A glycine250--> aspartate substitution in the alpha-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a Lebanese-Canadian family.

Tay-Sachs disease


Input: The mutation causing juvenile Tay-Sachs disease (TSD) in two sibs of Lebanese-Maronite origin is described.

Tay-Sachs disease

TSD


Input: An mRNA-containing extract of cultured fibroblasts obtained from one of the probands was used as a template to amplify the coding sequence of the hexosaminidase A (Hex A) alpha-subunit.


Input: Sequencing of amplified cDNA fragments revealed a single alteration, guanine to adenine at nt 749 creating a G250D mutation.


Input: The mutation introduces a new recognition site for the restriction enzyme Eco RV, permitting identification of heterozygotes for this allele following PCR amplification and Eco RV digestion of exon 7 sequences from genomic DNA templates.


Input: In order to test the effect of this substitution, an in vitro mutagenized cDNA construct was introduced into a mammalian expression vector and transfected into monkey Cos-1 cells separately or along with a beta-cDNA expression vector.


Input: When the mutant alpha-cDNA was the only gene introduced into COS cells no enzymatic activity above endogenous COS cell activity was detected.


Input: Cotransfection of normal alpha-cDNA and beta-cDNA followed by immunoprecipitation of human Hex A resulted in 20-fold increase in the ratio between positive and negative (mock transfection) control values.


Input: This allowed the detection of some residual activity (12% of the positive control) when the mutant alpha-cDNA replaced its wild-type counterpart.


Input: The predicted protein environment in which the mutation occurs is compared to that of the adult-onset Tay-Sachs disease mutation caused by a Gly269--> Ser substitution in exon 7.

Tay-Sachs disease


Input: (ABSTRACT TRUNCATED AT 250 WORDS).


Input: Novel Tay-Sachs disease mutations from China.

Tay-Sachs disease


Input: We describe three HEXA mutations associated with infantile Tay-Sachs disease (TSD) in three unrelated nonconsanguineous Chinese families.

Tay-Sachs disease

TSD


Input: Novel mutations were found in two of these families.


Input: The third is a previously reported mutation (G--> A transition at nt 1444) (Nakano et al., 1988).


Input: Direct sequencing of PCR products identified a novel insertion of an A after nt 547 in family 1.


Input: This change generates an early termination codon 6 bp downstream from the insertion site.


Input: Allele-specific oligonucleotide hybridization confirmed homozygosity in the proband.


Input: Single strand conformational polymorphism analysis and direct sequencing of amplified exon 13 revealed a T--> C transition at nt 1453 with the corresponding amino acid substitution W485R in the second family.


Input: This mutation creates an Fnu4HI restriction site.


Input: The proband is homozygous for this allele.


Input: When the site-specific mutagenized alpha cDNA carrying the T--> C transition at nt 1453 was expressed in COS 1 cells hexosaminidase S activity was not detectable above background.


Input: A G--> A transition at nt 1444 (exon 13) corresponding to the E482K substitution was found in the third family.


Input: This mutation occurs at a CpG dinucleotide.


Input: It has been reported in an Italian TSD proband and causes defective intracellular transport of the alpha-subunit from the rough endoplasmic reticulum to the Golgi apparatus.

TSD


Input: Two missense mutations causing mild hyperphenylalaninemia associated with DNA haplotype 12.

hyperphenylalaninemia


Input: The genetic defects responsible for most phenylketonuria (PKU) and hyperphenylalaninemia (HPA) cases are located in the phenylalanine hydroxylase (PAH) gene.

genetic defects

phenylketonuria

PKU

hyperphenylalaninemia

HPA


Input: Approximately 50-60 mutations have been reported in Caucasians and are reflected in a wide range of clinical severities.


Input: Most mutations are linked to specific haplotypes, as defined by eight polymorphic restriction sites in the PAH gene.


Input: We hypothesized that there is at least one mild mutation linked to haplotype 12 in the Swedish PKU/HPA population, since 7 of 8 patients carrying haplotype 12 had mild HPA.

PKU

HPA

HPA


Input: Sequence analysis revealed a C-to-G transversion at the second base of codon 322, resulting in a substitution of glycine for alanine, in four mutant haplotype 12 genes, and a G-to-A transition at the second base of codon 408, resulting in a substitution of glutamine for arginine, in another three mutant haplotype 12 genes.


Input: These mutations segregated with mutant haplotype 12 alleles in nuclear families but were not present on normal or other mutant alleles.


Input: Both mutations were tested in a eukaryotic expression system in which enzyme activities of different mutant PAH enzymes reflect the relative severities of the mutations, although these in vitro activities cannot be translated directly into in vivo hepatic activities.


Input: The A322G mutant PAH had about 75% and the R408Q mutant PAH about 55% of the wild-type PAH enzyme activity.


Input: These in vitro activities are the highest reported for mutant PAH enzymes produced in the same expression system.


Input: (ABSTRACT TRUNCATED AT 250 WORDS).


Input: In vitro and in vivo correlations for I65T and M1V mutations at the phenylalanine hydroxylase locus.


Input: Mutations at the phenylalanine hydroxylase (PAH) locus are the major cause of hyperphenylalaninemia.

hyperphenylalaninemia


Input: We have previously described four mutations (M1V, IVS12nt1, R408W, and S349P) at the PAH locus in French Canadians with ancestry in eastern Quebec.


Input: Here we report (1) identification of another mutation, on a haplotype 9 chromosome, which converts codon 65 from isoleucine (ATT) to threonine (ACT), (2) expression analysis of the I65T mutation in COS cells demonstrating 75% loss of both immunoreactive protein and enzyme activity, and (3) expression analysis of the most prevalent PKU allele (M1V) in eastern Quebec, showing nondetectable levels of PAH protein and activity, a finding compatible with a mutation in the translation initiation codon.

PKU


Input: Homozygosity for M1V and codominant inheritance of I65T/R408W were both associated with classical phenylketonuria..

classical phenylketonuria


Input: Molecular basis of hexosaminidase A deficiency and pseudodeficiency in the Berks County Pennsylvania Dutch.

hexosaminidase A deficiency


Input: Following the birth of two infants with Tay-Sachs disease (TSD), a non-Jewish, Pennsylvania Dutch kindred was screened for TSD carriers using the biochemical assay.

Tay-Sachs disease

TSD

TSD


Input: A high frequency of individuals who appeared to be TSD heterozygotes was detected (Kelly et al., 1975).

TSD


Input: Clinical and biochemical evidence suggested that the increased carrier frequency was due to at least two altered alleles for the hexosaminidase A alpha-subunit.


Input: We now report two mutant alleles in this Pennsylvania Dutch kindred, and one polymorphism.


Input: One allele, reported originally in a French TSD patient (Akli et al., 1991), is a GT--> AT transition at the donor splice-site of intron 9.

TSD


Input: The second, a C--> T transition at nucleotide 739 (Arg247Trp), has been shown by Triggs-Raine et al.


Input: (1992) to be a clinically benign " pseudodeficient " allele associated with reduced enzyme activity against artificial substrate.


Input: Finally, a polymorphism [G--> A (759)], which leaves valine at codon 253 unchanged, is described.


Input: A mutation common in non-Jewish Tay-Sachs disease: frequency and RNA studies.

Tay-Sachs disease


Input: Tay-Sachs disease (TSD) is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (Hex A).

Tay-Sachs disease

TSD

autosomal recessive genetic disorder


Input: We have discovered that a Tay-Sachs mutation, IVS-9 + 1 G--> A, first detected by Akli et al.

Tay-Sachs


Input: (Genomics 11 124-134, 1991), is a common disease allele in non-Jewish Caucasians (10/58 alleles examined).


Input: A PCR-based diagnostic test, which detects an NlaIII site generated by the mutation, revealed a frequency among enzyme-defined carriers of 9/64 (14%).


Input: Most of those carrying the allele trace their origins to the United Kingdom, Ireland, or Western Europe.


Input: It was not identified among 12 Black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers who did not carry any of the mutations common to this population.

TSD


Input: No normally spliced RNA was detected in PCR products generated from reverse transcription of RNA carrying the IVS-9 mutation.


Input: Instead, the low levels of mRNA from this allele were comprised of aberrant species resulting from the use of either of two cryptic donor sites, one truncating exon 9 and the other within IVS-9, spliced to exon 10.


Input: Numerous additional splice products were detected, most involving skipping of one or more surrounding exons.


Input: Together with a recently identified allele responsible for Hex A pseudodeficiency (Triggs-Raine et al. Am J Hum Genet, 1992), these two alleles accounted for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening tests in non-Jewish Caucasians..

TSD


Input: Aberrant splicing of the CHM gene is a significant cause of choroideremia.

CHM

choroideremia


Input: Choroideremia (CHM) is an X-linked progressive degeneration of the choroid and retina.

Choroideremia

CHM

X-linked progressive degeneration of the choroid and retina


Input: 12% of unrelated male patients carry deletions of the partially cloned CHM gene.

CHM


Input: In Finland, there are more than 120 living CHM patients belonging to eight apparently unrelated pedigrees.

CHM


Input: Molecular deletions involving the CHM gene have been detected in three families.

CHM


Input: We have screened the remaining five families for point mutations.


Input: In one large family a single nucleotide (T) insertion into the donor splice site of exon C leads to two aberrantly spliced mRNAs both producing a premature stop codon.


Input: The mutation can be assayed easily by amplification and digestion with Msel.


Input: Our findings provide additional evidence for the pathogenetic role of CHM mutations and provide a diagnostic tool for one fifth of the worlds known CHM patients..

CHM

CHM


Input: Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.

Wilms' tumour


Input: Denys-Drash syndrome is a rare human developmental disorder affecting the urogenital system and leading to renal failure, intersex disorders and Wilms tumour.

Denys-Drash syndrome

developmental disorder

renal failure

intersex disorders

Wilms tumour


Input: In this report, four individuals with this syndrome are described carrying germline point mutations in the Wilms tumour suppressor gene, WT1.

Wilms tumour


Input: Three of these mutations were in the zinc finger domains of WT1.


Input: The fourth occurred within intron 9, preventing splicing at one of the alternatively chosen splice donor sites of exon 9 when assayed in vitro.


Input: These results provide genetic evidence for distinct functional roles of the WT1 isoforms in urogenital development..


Input: Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs.

myotonic dystrophy


Input: The mutation underlying myotonic dystrophy (DM) has been identified as an expansion of a polymorphic CTG-repeat in a gene encoding protein kinase activity.

myotonic dystrophy

DM


Input: Brain and heart transcripts of the DM-kinase (DMR-B15) gene are subject to alternative RNA splicing in both human and mouse.


Input: The unstable [CTG] 5-30 motif is found uniquely in humans, although the flanking nucleotides are also present in mouse.


Input: Characterization of the DM region of both species reveals another active gene (DMR-N9) in close proximity to the kinase gene.

DM


Input: DMR-N9 transcripts, mainly expressed in brain and testis, possess a single, large open reading frame, but the function of its protein product is unknown.


Input: Clinical manifestation of DM may be caused by the expanded CTG-repeat compromising the (alternative) expression of DM-kinase or DMR-N9 proteins..

DM


Input: Fragile X syndrome without CCG amplification has an FMR1 deletion.

Fragile X syndrome


Input: We describe a patient with typical clinical features of the fragile X syndrome, but without cytogenetic expression of the fragile X or an amplified CCG trinucleotide repeat fragment.

fragile X syndrome

fragile X


Input: The patient has a previously uncharacterized submicroscopic deletion encompassing the CCG repeat, the entire FMR1 gene and about 2.


Input: 5 megabases of flanking sequences.


Input: This finding confirms that the fragile X phenotype can exist, without amplification of the CCG repeat or cytogenetic expression of the fragile X, and that fragile X syndrome is a genetically homogeneous disorder involving FMR1.

fragile X

fragile X

fragile X syndrome


Input: We also found random X-inactivation in the mother of the patient who was shown to be a carrier of this deletion.


Input: Cloning of the Huntington disease region in yeast artificial chromosomes.

Huntington disease


Input: The gene responsible for Huntington disease has been localized to a 2.

Huntington disease


Input: 5 million base pair (Mb) region between the loci D4S10 and D4S168 on the short arm of chromosome 4.


Input: As part of a strategy to clone the HD gene on the basis of its chromosomal location, we isolated genomic DNA from the HD region as a set of overlapping yeast artificial chromosome (YAC) clones.

HD

HD


Input: Twenty-eight YAC clones were identified by screening human YAC libraries with twelve PCR-based sequence-tagged sites (STSs) from the region.


Input: We assembled the YAC clones into overlapping sets by hybridizing them to a large number of DNA probes from the HD region, including the STSs.

HD


Input: In addition, we isolated the ends of the human DNA inserts of most of the YAC clones to assist in the construction of the contig.


Input: Although almost half of the YACs appear to contain chimeric inserts and several contain internal deletions or other rearrangements, we were able to obtain over 2.


Input: 2 Mb of the HD region in YACs, including one continuous segment of 2.

HD


Input: 0 Mb covering the region that most likely contains the HD gene.

HD


Input: Ten of the twenty eight YAC clones comprise a minimal set spanning the 2.


Input: 2 Mb.


Input: These clones provide reagents for the complete characterization of this region of the genome and for the eventual isolation of the HD gene.

HD


Input: Characterization of a YAC containing part or all of the Norrie disease locus.

Norrie disease


Input: It has been shown from pulsed-field gel electrophoresis (PFGE) that the monoamine oxidase genes A and B (MAOA & MAOB) and DXS7 loci are physically very close.


Input: We have therefore extended studies on their relationship through the characterisation of a 650 kb YAC isolated using L1.


Input: 28 (recognising the DXS7 locus) as a probe.


Input: Restriction mapping of the YAC indicates that it contains both MAOA and MAOB genes in addition to the DXS7 locus.


Input: The map derived from the YL1.


Input: 28-YAC is compatible both with the map from an independently derived YAC carrying MAOA and B genes and with the long range genomic map for the region.


Input: A series of subclones prepared from a phage library (lambda DASH II) of the YAC have been characterised and have been employed to determine the end point of the deletion of a Norrie disease (NDP) patient who has been shown to lack both DXS7 and MAO coding sequences.

Norrie disease

NDP


Input: The pattern of retention of subclones in the deletion patient place the end point of the deletion within 30-130 kb of the proximal end of the YAC.


Input: By combining the data with established recombination analysis, we provide evidence that all or part of the NDP lies in the interval of approximately 250kb within the YAC.


Input: Both mutations in G6PD A-are necessary to produce the G6PD deficient phenotype.

G6PD deficient


Input: The high prevalence of glucose 6-phosphate dehydrogenase (G6PD) deficiency in African populations is due almost entirely to the enzyme variant A-, which differs from the wild-type G6PD B by two amino acid replacements, 68 Val--> Met and 126 Asn--> Asp.

glucose 6-phosphate dehydrogenase (G6PD) deficiency


Input: The non-deficient polymorphic variant G6PD A contains only the mutation 126 Asn--> Asp.


Input: The frequencies of the G6PD A and of the G6PD A-genes in parts of Africa are both about 0.


Input: The 68 Val--> Met mutation has not been found in a B background.


Input: This could be because the 68 Val--> Met mutation happened to arise in an A gene in the first instance, or because the 68 Val--> Met mutation alone is not sufficient to cause G6PD deficiency.

G6PD deficiency


Input: We have approached this question by producing G6PD B, A, A-, and G6PD 68 Val--> Met in a bacterial expression system and analysing their biochemical properties.


Input: With each single mutation we found a slight decrease in both the specific activity and the yield of enzyme when compared to G6PD B.


Input: When both mutations were introduced together, there was a roughly additive effect on specific activity, but a much more drastic effect on enzyme yield (4% of normal).


Input: This synergistic effect was also demonstrated on thermal stability, especially at low NADP concentrations.


Input: Comparable results were produced when the replacement 119 Gln--> Glu was studied instead of 126 Asn--> Asp.


Input: We infer that the coexistence of the two mutations is responsible for enzyme deficiency in G6PD A-because they act synergistically in causing instability of the enzyme.

enzyme deficiency in G6PD


Input: Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region.

Prader-Willi syndrome


Input: Prader-Willi syndrome (PWS) is associated with paternally derived chromosomal deletions in region 15q11-13 or with maternal disomy for chromosome 15.

Prader-Willi syndrome

PWS

maternal disomy for chromosome 15


Input: Therefore, loss of the expressed paternal alleles of maternally imprinted genes must be responsible for the PWS phenotype.

PWS


Input: We have mapped the gene encoding the small nuclear RNA associated polypeptide SmN (SNRPN) to human chromosome 15q12 and a processed pseudogene SNRPNP1 to chromosome region 6pter-p21.


Input: Furthermore, SNRPN was mapped to the minimal deletion interval that is critical for PWS.

PWS


Input: The fact that the mouse Snrpn gene is maternally imprinted in brain suggests that loss of the paternally derived SNRPN allele may be involved in the PWS phenotype..

PWS


Input: The presence of two different infantile Tay-Sachs disease mutations in a Cajun population.

Tay-Sachs disease


Input: A study was undertaken to characterize the mutation (s) responsible for Tay-Sachs disease (TSD) in a Cajun population in southwest Louisiana and to identify the origins of these mutations.

Tay-Sachs disease

TSD


Input: Eleven of 12 infantile TSD alleles examined in six families had the beta-hexosaminidase A (Hex A) alpha-subunit exon 11 insertion mutation that is present in approximately 70% of Ashkenazi Jewish TSD heterozygotes.

TSD

TSD


Input: The mutation in the remaining allele was a single-base transition in the donor splice site of the alpha-subunit intron 9.


Input: To determine the origins of these two mutations in the Cajun population, the TSD carrier status was enzymatically determined for 90 members of four of the six families, and extensive pedigrees were constructed for all carriers.

TSD


Input: A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion.


Input: Pedigree data suggest that this mutation has been in the Cajun population since its founding over 2 centuries ago and that it may be widely distributed within the population.


Input: In contrast, the intron 9 mutation apparently was introduced within the last century and probably is limited to a few Louisiana families..


Input: Mutations in the candidate gene for Norrie disease.

Norrie disease


Input: Recently, we and others have isolated a candidate gene for X linked Norrie disease (ND) which was found to be deleted or disrupted in several patients.

X linked Norrie disease

ND


Input: As a prerequisite for the identification of point mutations in the ND gene we have established the exon-intron structure of this gene.

ND


Input: In 17 unrelated patients and 15 controls, PCR products derived from the promoter region, exons 1 and 2 as well as the coding part of exon 3 were analysed with the single strand conformation polymorphism (SSCP) technique.


Input: In 12 patients altered PCR fragments were detected which were studied in detail by direct sequencing.


Input: Eleven different mutations were found, and all but one are likely to give rise to significant structural changes in the predicted protein.


Input: These findings, and the absence of functionally relevant base changes in healthy controls, emphasize the causal role of this candidate gene in Norrie disease and pave the way for reliable diagnosis and carrier detection..

Norrie disease


Input: Detection of a nonsense mutation in the dystrophin gene by multiple SSCP.


Input: A combination of multiplex PCR with the single strand conformation polymorphism (SSCP) technique was employed to screen for point mutations in the human dystrophin gene.


Input: Co-amplification of 11 exons from genomic DNA of Duchenne and Becker muscular dystrophy (DMD/BMD) patients with no deletion or duplication was performed and the samples subjected to multiple SSCP analysis.

Duchenne and Becker muscular dystrophy

DMD

BMD


Input: We report the case of a nonsense mutation in a Duchenne patient identified by this approach.

Duchenne


Input: The mutation introduces a termination codon within exon 8 of the dystrophin gene.


Input: It is predicted to cause a very premature translational termination accounting for the severe phenotype observed.


Input: The patient inherited this mutation from his mother.


Input: In addition the analysis revealed 5 polymorphisms useful for internal control..


Input: Proliferation-related expression of p19/nm23 nucleoside diphosphate kinase.


Input: High level expression of the nm23-H1 gene, which encodes for a nucleoside diphosphate kinase, has been found to correlate with diminished metastasis in some tumors but not in others.

tumors


Input: We have previously identified the protein product of the nm23-H1 gene in two-dimensional electrophoretic gels and have designated it p19/nm23.


Input: In neuroblastoma, higher levels of p19/nm23, which are associated with amplification of the N-myc oncogene, large tumor mass, and metastasis, were observed in advanced stage tumors compared with limited stage disease.

neuroblastoma

tumor

tumors


Input: Because of the variable expression of nm23-H1 in different tumors, we have investigated the relationship between amounts of the protein and cell proliferation.

tumors


Input: The levels of p19/nm23 were compared between resting and mitotically stimulated normal human PBLs and in leukemia cells.

leukemia


Input: The amount of p19/nm23 increased in normal lymphocytes in response to mitotic stimulation and paralleled the increase in DNA synthesis.


Input: In leukemia cells obtained from patients with different subtypes of acute leukemia, p19/nm23 levels were also increased relative to resting normal lymphocytes.

leukemia

acute leukemia


Input: Treatment of mitotically stimulated lymphocytes with cyclosporin, which inhibits proliferation, blocked the increase in p19/nm23; treatment of the leukemia cell line HL-60 with dimethylsulfoxide, which induces terminal differentiation, resulted in diminished levels of p19/nm23.

leukemia


Input: Our data therefore provide evidence that nm23-H1 expression is related to cell proliferative activity..


Input: An intrachromosomal insertion causing 5q22 deletion and familial adenomatous polyposis coli in two generations.

familial adenomatous polyposis coli


Input: We report familial adenomatous polyposis coli (FAPC) with epidermoid cysts, osteomata, and areas of congenital hypertrophy of the retinal pigment epithelium (CHRPEs) in a male patient and his maternal aunt, both of whom suffered a mild to moderate degree of mental handicap.

familial adenomatous polyposis coli

FAPC

epidermoid cysts

osteomata

congenital hypertrophy of the retinal pigment epithelium

CHRPEs

mental handicap


Input: Both had an interstitial deletion of the long arm of chromosome 5 (del (5) (q22q23. 2)).


Input: Two other normal family members had the underlying direct insertion of chromosome 5 (dir ins (5) (q31. 3q22q23 3q22q23. 2)).


Input: Molecular genetic and fluorescent hybridisation studies have shown that loci D5S37 and D5S98 are outside the deletion whereas loci detected by probes EF5.


Input: 44 and YN5.


Input: 48 are lost.


Input: As expected, the molecular analyses indicate loss of one allele at the MCC and APC loci.

APC


Input: The APC gene is located within band 5q22.

APC


Input: Familial direct insertions should be considered as a cause of recurrent microdeletion syndromes.


Input: Chromosome mapping of the rod photoreceptor cGMP phosphodiesterase beta-subunit gene in mouse and human: tight linkage to the Huntington disease region (4p16. 3).

Huntington disease


Input: The retinal degeneration mouse (gene symbol, rd) is an animal model for certain forms of human hereditary retinopathies.

retinal degeneration

hereditary retinopathies


Input: Recent findings of a nonsense mutation in the rd mouse PDE beta-subunit gene (Pdeb) prompted us to investigate the chromosome locations of the mouse and human genes.


Input: We have utilized backcross analysis in mice to verify and define more precisely the location of the Pdeb locus 6.


Input: 1 +/-2.


Input: 3 cM distal of Mgsa on mouse chromosome 5.


Input: We have determined that the human gene (PDEB) maps to 4p16.


Input: 3, very close to the Huntington disease (HD) region.

Huntington disease

HD


Input: Analysis of the comparative map for mice and humans shows that the mouse homologue of the HD gene will reside on chromosome 5.

HD


Input: Linkage of the mouse Pdeb locus with other homologues in the human 4p16.


Input: 3 region is maintained but gene order is not, suggesting at least three possible sites for the corresponding mouse HD gene.

HD


Input: Coincident Kaposi sarcoma and T-cell lymphoma in a patient with the Wiskott-Aldrich syndrome.

Kaposi sarcoma

T-cell lymphoma

Wiskott-Aldrich syndrome


Input: A 24 year old male with a history of eczema, recurrent mild infections, and thrombocytopenia consistent with the Wiskott-Aldrich syndrome (WAS) presented with a mediastinal mass, generalized lymphadenopathy, splenomegaly, and severe thrombocytopenia.

eczema

thrombocytopenia

Wiskott-Aldrich syndrome

WAS

lymphadenopathy

splenomegaly

thrombocytopenia


Input: Studies of immune function including immunoglobulin levels and T-cell subsets were normal.


Input: Furthermore, his T lymphocytes proliferated normally in response to phytohemagglutinin, concanavalin A, and the combination of neuraminidase/galactose oxidase.


Input: However, their proliferative responses to anti-CD43 antibody and periodate were diminished, consistent with the clinical diagnosis of WAS.

WAS


Input: An initial inguinal lymph node biopsy surprisingly revealed Kaposi sarcoma.

Kaposi sarcoma


Input: However, following splenectomy to increase the platelet count, biopsy of the mediastinal mass revealed T-cell large cell lymphoma.

T-cell large cell lymphoma


Input: Studies of biopsied tissue for the presence of Epstein-Barr virus and cytomegalovirus were negative, as were studies of blood, including the polymerase chain reaction, for the presence of the human immunodeficiency virus (HIV).

Epstein-Barr virus

cytomegalovirus

human immunodeficiency virus

HIV


Input: This is the first report of Kaposi sarcoma arising in a patient with a congenital immunodeficiency syndrome.

Kaposi sarcoma

congenital immunodeficiency syndrome


Input: Although Kaposi sarcoma can arise in the face of the severe immunosuppression that follows allograft transplantation and in patients infected with HIV, we postulate that longevity in the face of mild immunosuppression was the major factor in the development of Kaposi sarcoma in this patient..

Kaposi sarcoma

HIV

Kaposi sarcoma


Input: The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer.

APC

familial adenomatous polyposis

gastric cancer


Input: Although gastric cancer is the most common cancer in the world, genetic changes during its carcinogenesis are not well understood.

gastric cancer

cancer


Input: Since some gastric cancers are considered to originate from the intestinal metaplasia, it is likely that the adenomatous polyposis coli (APC) gene, the mutation of which causes adenomatous polyps in the colon, is associated with carcinogenesis of gastric cancer.

gastric cancers

adenomatous polyposis coli

APC

adenomatous polyps in the colon

gastric cancer


Input: Based on this idea, DNAs isolated from gastric cancers were examined by means of a RNase protection analysis coupled with polymerase chain reaction followed by sequencing of the polymerase chain reaction products.

gastric cancers


Input: By screening nearly one-half of the coding region of the APC gene in 44 tumors, somatic mutations were detected in three tumors a missense mutation, a nonsense mutation, and a 5-base pair deletion resulting in a frame shift which causes truncation of the gene product.

APC

tumors

tumors


Input: These results suggest that the mutation of the APC gene also plays an important role during the carcinogenesis of at least some gastric cancers..

APC

gastric cancers


Input: A 71-kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues.

Duchenne muscular dystrophy


Input: The known Duchenne muscular dystrophy (DMD) gene products, the muscle-and brain-type dystrophin isoforms, are 427-kDa proteins translated from 14-kilobase (kb) mRNAs.

Duchenne muscular dystrophy

DMD


Input: Recently we described a 6.


Input: 5-kb mRNA that also is transcribed from the DMD gene.

DMD


Input: Cloning and in vitro transcription and translation of the entire coding region show that the 6.


Input: 5-kb mRNA encodes a 70.


Input: 8-kDa protein that is a major product of the DMD gene.

DMD


Input: It contains the C-terminal and the cysteine-rich domains of dystrophin, seven additional amino acids at the N terminus, and some modifications formed by alternative splicing in the C-terminal domain.


Input: It lacks the entire large domain of spectrin-like repeats and the actin-binding N-terminal domain of dystrophin.


Input: This protein is the major DMD gene product in brain and other nonmuscle tissues but is undetectable in skeletal muscle extracts.

DMD


Input: Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients.

APC

colorectal polyps

familial adenomatous polyposis


Input: Recently we have isolated the adenomatous polyposis coli (APC) gene which causes familial adenomatous polyposis (FAP), and its germ-line mutations in a substantial number of FAP patients have been identified.

adenomatous polyposis coli

APC

familial adenomatous polyposis

FAP

FAP


Input: On the basis of this information, we compared the location of germ-line mutations in the APC gene in 22 unrelated patients (12 of whom have been reported previously) with the number of colorectal polyps developed in FAP patients; 17 were sparse types and five were profuse types.

APC

colorectal polyps

FAP


Input: All but one of the mutations were considered to cause truncation of the gene product by frame-shift due to deletion (14 cases) or nonsense mutation (seven cases).


Input: The location of the germ-line mutations seems to correlate with the two clinical types; germ-line mutations in five FAP patients with profuse polyps were observed between codon 1250 and codon 1464, whereas mutations in 17 FAP patients with fewer polyps were observed in the other regions of the APC gene.

FAP

polyps

FAP

polyps

APC


Input: The result suggests that the number of colorectal polyps in FAP patients may be associated with a difference in the stability or biological function of the truncated APC protein..

colorectal polyps

FAP

APC


Input: Identification and rapid detection of three Tay-Sachs mutations in the Moroccan Jewish population.

Tay-Sachs


Input: Infantile Tay-Sachs disease (TSD) is caused by mutations in the HEXA gene that result in the complete absence of beta-hexosaminidase A activity.

Tay-Sachs disease

TSD


Input: It is well known that an elevated frequency of TSD mutations exists among Ashkenazi Jews.

TSD


Input: More recently it has become apparent that elevated carrier frequencies for TSD also occur in several other ethnic groups, including Moroccan Jews, a subgroup of Sephardic Jews.

TSD


Input: Elsewhere we reported an in-frame deletion of one of the two adjacent phenylalanine codons at position 304 or 305 (delta F304/305) in one HEXA allele of a Moroccan Jewish TSD patient and in three obligate carriers from six unrelated Moroccan Jewish families.

TSD


Input: We have now identified two additional mutations within exon 5 of the HEXA gene that account for the remaining TSD alleles in the patient and carriers.

TSD


Input: One of the mutations is a novel C-to-G transversion, resulting in a replacement of Tyr180 by a stop codon.


Input: The other mutation is a G-to-A transition resulting in an Arg170-to-Gln substitution.


Input: This mutation is at a CpG site in a Japanese infant with Tay-Sachs disease and was described elsewhere.

Tay-Sachs disease


Input: Analysis of nine obligate carriers from seven unrelated families showed that four harbor the delta F304/305 mutation, two the Arg170----Gln mutation, and one the Tyr180----Stop mutation.


Input: We also have developed rapid, nonradioactive assays for the detection of each mutation, which should be helpful for carrier screening..


Input: Molecular characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency by natural and amplification created restriction sites: five mutations account for most G6PD deficiency cases in Taiwan.

glucose-6-phosphate dehydrogenase (G6PD) deficiency

G6PD deficiency


Input: We have developed a rapid and simple method to diagnose the molecular defects of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Chinese in Taiwan.

glucose-6-phosphate dehydrogenase (G6PD) deficiency


Input: This method involves the selective amplification of a DNA fragment from human G6PD gene with specific oligonucleotide primers followed by digestion with restriction enzymes that recognize artificially created or naturally occurring restriction sites.


Input: Ninety-four Chinese males with G6PD deficiency were studied.

G6PD deficiency


Input: The results show that 50% (47 of 94) were G to T mutation at nucleotide (nt) 1376, 21.


Input: 3% (20 of 94) were G to A mutation at nt 1388, 7.


Input: 4% (7 of 94) were A to G mutation at nt 493, 7.


Input: 4% (7 of 94) were A to G mutation at nt 95, 4.


Input: 2% (4 of 94) were C to T mutation at nt 1024, 1.


Input: 1% (1 of 94) was G to T mutation at nt 392, and 1.


Input: 1% (1 of 94) was G to A mutation at nt 487.


Input: These results show that the former five mutations account for more than 90% of G6PD deficiency cases in Taiwan.

G6PD deficiency


Input: Aside from showing that G to T change at nt 1376 is the most common mutation, our research indicates that nt 493 mutation is a frequent mutation among Chinese in Taiwan.


Input: We compared G6PD activity among different mutations, without discovering significant differences between them.


Input: Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis.

APC


Input: Familial adenomatous polyposis (FAP) is a dominantly inherited condition predisposing to colorectal cancer.

Familial adenomatous polyposis

FAP

colorectal cancer


Input: The recent isolation of the responsible gene (adenomatous polyposis coli or APC) has facilitated the search for germ line mutations in affected individuals.

adenomatous polyposis coli

APC


Input: Previous authors have used the RNase protection assay and the single-strand conformation polymorphisms procedure to screen for mutations.


Input: In this study we used denaturing gradient gel electrophoresis (DGGE).


Input: DGGE analysis of 10 APC exons (4, 5, 7, 8, 9, 10, 12, 13, 14, and part of 15) in 33 unrelated Dutch FAP patients has led to the identification of eight novel germ line mutations resulting in stop codons or frameshifts.

APC

FAP


Input: The results reported here indicate that (1) familial adenomatous polyposis is caused by an extremely heterogeneous spectrum of point mutations; (2) all the mutations found in this study are chain terminating; and (3) DGGE represents a rapid and sensitive technique for the detection of mutations in the unusually large APC gene.

familial adenomatous polyposis

APC


Input: An extension of the DGGE analysis to the entire coding region in a sufficient number of clinically well-characterized, unrelated patients will facilitate the establishment of genotype-phenotype correlations.


Input: On the other hand, the occurrence of an extremely heterogeneous spectrum of mutations spread throughout the entire length of the large APC gene among the FAP patients indicates that this approach may not be useful as a rapid presymptomatic diagnostic procedure in a routine laboratory.

APC

FAP


Input: Nevertheless, the above DGGE approach has incidentally led to the identification of a common polymorphism in exon 13.


Input: Such intragenic polymorphisms offer a practical approach to a more rapid procedure for presymptomatic diagnosis of FAP by linkage analysis in informative families..

FAP


Input: Yeast artificial chromosomes for the molecular analysis of the familial polyposis APC gene region.

familial polyposis APC


Input: Two yeast artificial chromosomes (YACs) spanning a total distance of 1.


Input: 1 megabase pairs of DNA around the MCC (for mutated in colorectal carcinoma) and APC (for adenomatous polyposis coli) genes at 5q21 have been isolated and characterized.

colorectal carcinoma

APC

adenomatous polyposis coli


Input: Starting from the MCC gene, a strategy was undertaken to identify constitutional submicroscopic deletions in familial adenomatous polyposis patients that might considerably narrow down the position of the APC gene.

familial adenomatous polyposis

APC


Input: To this end, YACs identified by the MCC gene were screened across a chromosome 5-specific cosmid library to provide a source of DNA probes for genomic scanning.


Input: The cosmids isolated from these experiments were used to screen a panel of somatic cell hybrids containing chromosome 5 segregated from patients suspected to carry putative interstitial deletions.


Input: This screening approach led to the confirmation of a small heterozygous deletion in a polyposis patient that overlaps one of the two isolated YACs.

polyposis


Input: This YAC has been shown to contain the entire APC gene, in addition to a significant portion of DNA flanking the 5 end of the gene, and should therefore prove a valuable resource for functional studies by transfer to colorectal tumor-derived cell lines.

APC

colorectal tumor


Input: Inherited WT1 mutation in Denys-Drash syndrome.

Denys-Drash syndrome