Input: Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer.

familial breast cancer

familial breast/ovarian cancer


Input: The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown.

cancer


Input: We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays.

ovarian or breast cancer


Input: Variant SSCP bands were subcloned and sequenced.


Input: Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals.


Input: Six frameshift and two missense mutations were detected in 10 different families.


Input: A frameshift mutation was detected in a male proband affected with both breast and prostate cancer.

breast and prostate cancer


Input: A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy.

intra-abdominal carcinomatosis


Input: Mutations were detected throughout the gene, and only one was detected in more than a single family.


Input: These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations.

inherited breast and ovarian cancer


Input: These results suggests that development of a screening test for BRCA1 mutations will be technically challenging.


Input: The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations..

male breast cancer


Input: Natural selection of hemi-and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria.

G6PD deficiency

malaria


Input: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy of humans, affects over 400 million people.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

enzymopathy


Input: The geographical correlation of its distribution with the historical endemicity of malaria suggests that this disorder has risen in frequency through natural selection by malaria.

malaria

malaria


Input: However, attempts to confirm that G6PD deficiency is protective in case-control studies of malaria have yielded conflicting results.

G6PD deficiency

malaria


Input: Hence, for this X-linked disorder, it is unclear whether both male hemizygotes and female heterozygotes are protected or, as frequently suggested, only females.

X-linked disorder


Input: Furthermore, how much protection may be afforded is unknown.


Input: Here we report that, in two large case-control studies of over 2, 000 African children, the common African form of G6PD deficiency (G6PD A-) is associated with a 46-58% reduction in risk of severe malaria for both female heterozygotes and male hemizygotes.

G6PD deficiency

G6PD A-

malaria


Input: A mathematical model incorporating the measured selective advantage against malaria suggests that a counterbalancing selective disadvantage, associated with this enzyme deficiency, has retarded its rise in frequency in malaria-endemic regions.

malaria

enzyme deficiency

malaria


Input: Although G6PD deficiency is now regarded as a generally benign disorder, in earlier environmental conditions it could have been significantly disadvantageous..

G6PD deficiency


Input: The alveolar rhabdomyosarcoma PAX3/FKHR fusion protein is a transcriptional activator.

alveolar rhabdomyosarcoma


Input: Chimeric transcription factors, created by gene fusions as the result of chromosomal translocations, have been implicated in the pathogenesis of several pathologically disparate solid tumors.

solid tumors


Input: The PAX3/FKHR fusion gene, formed by a t (2; 13) (q35; q14) in alveolar rhabdomyosarcoma, encodes a hybrid protein that contains both PAX3 DNA binding domains, the paired box and homeodomain, linked to the bisected DNA binding domain of FKHR, a member of the forkhead family of transcription factors.

alveolar rhabdomyosarcoma


Input: Here we report that PAX3 and PAX3/FKHR display similar, but not identical transactivation activities when tested with model Pax recognition sequences.


Input: No functional role could be ascribed solely to the residual FKHR binding domain present in the fusion protein, but FKHR was found to contribute a strong carboxyl terminal activation domain replacing the one located in the unrearranged PAX3 gene.


Input: We show that the native PAX3/FKHR protein present in tumor cells with this translocation has transcriptional characteristics similar to the in vitro expressed protein.

tumor


Input: The ability of the PAX3/FKHR hybrid protein to bind DNA in a sequence specific manner and to transactivate the expression of artificial reporter genes suggests that its aberrant expression could subvert the transcriptional programs that normally control the growth, differentiation, and survival of primitive myogenic precursors in vivo..


Input: A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma.

melanoma


Input: A mutated cyclin-dependent kinase 4 (CDK4) was identified as a tumor-specific antigen recognized by HLA-A2.

tumor


Input: 1-restricted autologous cytolytic T lymphocytes (CTLs) in a human melanoma.

melanoma


Input: The mutated CDK4 allele was present in autologous cultured melanoma cells and metastasis tissue, but not in the patients lymphocytes.

melanoma


Input: The mutation, an arginine-to-cysteine exchange at residue 24, was part of the CDK4 peptide recognized by CTLs and prevented binding of the CDK4 inhibitor p16INK4a, but not of p21 or of p27KIP1.


Input: The same mutation was found in one additional melanoma among 28 melanomas analyzed.

melanoma

melanomas


Input: These results suggest that mutation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16INK4a..

tumor

tumor


Input: Rapid detection of BRCA1 mutations by the protein truncation test.


Input: More than 75% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA1, result in truncated proteins.

hereditary breast and ovarian cancer


Input: We have used the protein truncation test (PTT) to screen for mutations in exon 11, which encodes 61% of BRCA1.


Input: In 45 patients from breast and/or ovarian cancer families we found six novel mutations two single nucleotide insertions, three small deletions (1-5 bp) and a nonsense mutation identified two unrelated families.

breast and/or ovarian cancer


Input: Furthermore, we were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA.


Input: Combined with PTT, we detected aberrantly spliced products affecting exons 5 and 6 in one of two BRCA1-linked families examined.


Input: The protein truncation test promises to become a valuable technique in detecting BRCA1 mutations..


Input: Cloning of human very-long-chain acyl-coenzyme A dehydrogenase and molecular characterization of its deficiency in two patients.


Input: Two overlapping cDNA clones (1, 991 bp and 736 bp, respectively) encoding the precursor of human mitochondrial very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) were cloned and sequenced.


Input: The cDNA inserts of these clones together encompass a region of 2, 177 bases, encoding the entire protein of 655 amino acids, including a 40-amino acid leader peptide and a 615-amino acid mature polypeptide.


Input: PCR-amplified VLCAD cDNAs were sequenced in cultured fibroblasts from two VLCAD-deficient patients.

VLCAD-deficient


Input: In both patients, a 105-bp deletion encompassing bases 1078-1182 in VLCAD cDNA was identified.


Input: The deletion seems to occur due to exon skipping during processing of VLCAD pre-mRNA.


Input: This is the first demonstration of a mutation causing VLCAD deficiency.

VLCAD deficiency


Input: Quantitative cDNA expression of normal human VLCAD was performed in the patients fibroblasts, using vaccinia viral system, which demonstrated that the deficiency of the normal VLCAD protein causes impaired long-chain fatty acid beta-oxidation activity in the patients fibroblasts.

deficiency of the normal VLCAD protein


Input: In patient fibroblasts, raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts, which may offer important information for the rational design of future somatic gene therapy for VLCAD deficiency..

VLCAD deficiency


Input: Brain disease and molecular analysis in myotonic dystrophy.

Brain disease

myotonic dystrophy


Input: Abnormal amplification of a CTG repeat on chromosome 19 is the molecular basis of myotonic dystrophy (DM).

myotonic dystrophy

DM


Input: Expansion of the repeat has been correlated with severity of several clinical features of the disease.


Input: We performed extensive cognitive testing, cerebral magnetic resonance imaging (MRI) and a molecular analysis in 28 cases of DM to determine the relationship between the molecular defect and brain disease.

DM

brain disease


Input: Performance in two or more cognitive tests was pathological in 10 cases.


Input: Fourteen patients had subcortical white matter lesions on MRI, 14 had cerebral atrophy.

white matter lesions

cerebral atrophy


Input: Amplification of the CTG repeat showed a strong correlation with cognitive test deficits when exceeding a length of over 1000 trinucleotides.


Input: MRI lesions were associated with impaired psychometric performance, but MRI and molecular findings were only weakly related.


Input: Disease duration influenced the appearance and amount of white matter lesions on MRI.

white matter lesions


Input: Quantification of CTG repeat size may allow an early estimate on the probability of brain involvement in DM; cognitive dysfunction is associated with white matter lesions and cerebral atrophy later on in the course..

DM

cognitive dysfunction

white matter lesions

cerebral atrophy


Input: Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes.

X-linked adrenoleukodystrophy


Input: Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein.

peroxisomal disorder

X-linked adrenoleukodystrophy

X-ALD


Input: We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expression of X-ALD and in their female relatives; these clinical expressions were cerebral childhood ALD, adrenomyeloneuropathy (AMN), and " Addison disease only " (ADO) phenotype.

X-ALD

ALD

adrenomyeloneuropathy

AMN

Addison disease only

ADO


Input: In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5 portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation.

ALD

X-ALD

ALD


Input: In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed.

AMN


Input: Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison.

ADO


Input: The disruptive nature of two mutations (i. e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD.

ALD

AMN

X-ALD


Input: Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis

X-ALD


Input: Duchenne muscular dystrophy and myotonic dystrophy in the same patient.

Duchenne muscular dystrophy

myotonic dystrophy


Input: We report on the first patient identified with myotonic dystrophy and Duchenne muscular dystrophy (DMD).

myotonic dystrophy

Duchenne muscular dystrophy

DMD


Input: The family of the propositus had a strong history of myotonic dystrophy, and there was an intrafamilial pathological expansion of the responsible CTG repeat between the mildly affected mother (160 repeats; normal 27 repeats) and her more severely affected son (650 repeats), and his sister (650 repeats).

myotonic dystrophy


Input: The propositus was an isolated case of Duchenne muscular dystrophy with marked dystrophin deficiency in muscle biopsy.

Duchenne muscular dystrophy

dystrophin deficiency


Input: The patient was still ambulatory post age 16.


Input: Myotonic dystrophy could interfere to some extent with the progression of Duchenne dystrophy.

Myotonic dystrophy

Duchenne dystrophy


Input: However, other interpretations are possible.


Input: Twelve percent of dystrophin revertant fibers as observed by immunohistochemistry could be sufficient to ameliorate typical DMD clinical severity, or the patient may present a somatic mosaic.

DMD


Input: The pathophysiological interactions of these two unlinked disorders are discussed at the clinical and histopathological levels..


Input: Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer.

familial breast cancer


Input: We searched for criteria that could indicate breast cancer families with a high prior probability of being caused by the breast/ovarian cancer susceptibility locus BRCA1 on chromosome 17.

breast cancer

breast/ovarian cancer


Input: To this end, we performed a linkage study with 59 consecutively collected Dutch breast cancer families, including 16 with at least one case of ovarian cancer.

breast cancer

ovarian cancer


Input: We used an intake cut-off of at least three first-degree relatives with breast and/or ovarian cancer at any age.

breast and/or ovarian cancer


Input: Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years.

breast cancer


Input: An unexpectedly low proportion of the breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population.

breast-ovarian cancer


Input: Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing..

breast and/or ovarian cancer


Input: Linkage analysis of 26 Canadian breast and breast-ovarian cancer families.

breast and breast-ovarian cancer


Input: We have examined 26 Canadian families with hereditary breast or ovarian cancer for linkage to markers flanking the BRCA1 gene on chromosome 17q12-q21.

hereditary breast or ovarian cancer


Input: Of the 15 families that contain cases of ovarian cancer, 94% were estimated to be linked to BRCA1.

ovarian cancer


Input: In contrast, there was no overall evidence of linkage in the group of 10 families with breast cancer without ovarian cancer.

breast cancer

ovarian cancer


Input: A genetic recombinant in a breast-ovarian cancer family indicates a placement of BRCA1 telomeric to D17S776, and helps to define the region of assignment of the cancer susceptibility gene.

breast-ovarian cancer

cancer


Input: Other cancers of interest that appeared in the BRCA1-linked families included primary peritoneal cancer, cancer of the fallopian tube, and malignant melanoma..

cancers

primary peritoneal cancer

cancer of the fallopian tube

malignant melanoma


Input: Structural analysis of the 5' region of mouse and human Huntington disease genes reveals conservation of putative promoter region and di-and trinucleotide polymorphisms.

Huntington disease


Input: We have previously cloned and characterized the murine homologue of the Huntington disease (HD) gene and shown that it maps to mouse chromosome 5 within a region of conserved synteny with human chromosome 4p16.

Huntington disease

HD


Input: 3 3.


Input: Here we present a detailed comparison of the sequence of the putative promoter and the organization of the 5 genomic region of the murine (Hdh) and human HD genes encompassing the first five exons.

HD


Input: We show that in this region these two genes share identical exon boundaries, but have different-size introns.


Input: Two dinucleotide (CT) and one trinucleotide intronic polymorphism in Hdh and an intronic CA polymorphism in the HD gene were identified.

HD


Input: Comparison of 940-bp sequence 5 to the putative translation start site reveals a highly conserved region (78. 8% nucleotide identity) between Hdh and the HD gene from nucleotide-56 to-206 (of Hdh).

HD


Input: Neither Hdh nor the HD gene have typical TATA or CCAAT elements, but both show one putative AP2 binding site and numerous potential Sp1 binding sites.

HD


Input: The high sequence identity between Hdh and the HD gene for approximately 200 bp 5 to the putative translation start site indicates that these sequences may play a role in regulating expression of the Huntington disease gene

HD

Huntington disease


Input: The protein deficient in Lowe syndrome is a phosphatidylinositol-4, 5-bisphosphate 5-phosphatase.

Lowe syndrome


Input: Lowe syndrome, also known as oculocerebrorenal syndrome, is caused by mutations in the X chromosome-encoded OCRL gene.

Lowe syndrome

oculocerebrorenal syndrome


Input: The OCRL protein is 51% identical to inositol polyphosphate 5-phosphatase II (5-phosphatase II) from human platelets over a span of 744 aa, suggesting that OCRL may be a similar enzyme.


Input: We engineered a construct of the OCRL cDNA that encodes amino acids homologous to the platelet 5-phosphatase for expression in baculovirus-infected Sf9 insect cells.


Input: This cDNA encodes aa 264-968 of the OCRL protein.


Input: The recombinant protein was found to catalyze the reactions also carried out by platelet 5-phosphatase II.


Input: Thus OCRL converts inositol 1, 4, 5-trisphosphate to inositol 1, 4-bisphosphate, and it converts inositol 1, 3, 4, 5-tetrakisphosphate to inositol 1, 3, 4-trisphosphate.


Input: Most important, the enzyme converts phosphatidylinositol 4, 5-bisphosphate to phosphatidylinositol 4-phosphate.


Input: The relative ability of OCRL to catalyze the three reactions is different from that of 5-phosphatase II and from that of another 5-phosphatase isoenzyme from platelets, 5-phosphatase I.


Input: The recombinant OCRL protein hydrolyzes the phospholipid substrate 10-to 30-fold better than 5-phosphatase II, and 5-phosphatase I does not cleave the lipid at all.


Input: We also show that OCRL functions as a phosphatidylinositol 4, 5-bisphosphate 5-phosphatase in OCRL-expressing Sf9 cells.


Input: These results suggest that OCRL is mainly a lipid phosphatase that may control cellular levels of a critical metabolite, phosphatidylinositol 4, 5-bisphosphate.


Input: Deficiency of this enzyme apparently causes the protean manifestations of Lowe syndrome..

Lowe syndrome


Input: New founder haplotypes at the myotonic dystrophy locus in southern Africa.

myotonic dystrophy


Input: The association between normal alleles at the CTG repeat and two nearby polymorphisms in the myotonin protein kinase gene, the Alu insertion/deletion polymorphism and the myotonic dystrophy kinase (DMK) (G/T) intron 9/HinfI polymorphism, has been analyzed in South African Negroids, a population in which myotonic dystrophy (DM) has not been described.

myotonic dystrophy

myotonic dystrophy

DM


Input: South African Negroids have a CTG allelic distribution that is significantly different from that in Caucasoids and Japanese the CTG repeat lengths of > or = 19 are very rare.


Input: The striking linkage disequilibrium between specific alleles at the Alu polymorphism (Alu (ins) and Alu (del)), the HinfI polymorphism (HinfI-1 and HinfI-2), and the CTG repeat polymorphism seen in Caucasoid (Europeans and Canadians) populations was also found in the South African Negroid population.


Input: Numerous haplotypes, not previously described in Europeans, were, however, found.


Input: It thus seems likely that only a small number of these " African " chromosomes were present in the progenitors of all non-African peoples.


Input: These data provide support for the " out of Africa " model for the origin of modern humans and suggest that the rare ancestral DM mutation event may have occurred after the migration from Africa, hence the absence of DM in sub-Saharan Negroid peoples..

DM

DM


Input: Discordant clinical outcome in myotonic dystrophy relatives showing (CTG) n > 700 repeats.

myotonic dystrophy


Input: A myotonic dystrophy (DM) family is described in which discordant DM phenotypes were found in the children of two affected sisters with similar CTG expansion and clinical manifestations.

myotonic dystrophy

DM

DM


Input: In this family, congenital as well as early severe childhood and later childhood onset DM coexist.

DM


Input: This observation strengthens the limited ability of lymphocytes CTG repeat number analysis in predicting genotype-phenotype correlations in DM patients..

DM


Input: Purification of human very-long-chain acyl-coenzyme A dehydrogenase and characterization of its deficiency in seven patients.


Input: Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) was purified from human liver.


Input: The molecular masses of the native enzyme and the subunit were estimated to be 154 and 70 kD, respectively.


Input: The enzyme was found to catalyze the major part of mitochondrial palmitoylcoenzyme A dehydrogenation in liver, heart, skeletal muscle, and skin fibroblasts (89-97, 86-99, 96-99, and 78-87%, respectively).


Input: Skin fibroblasts from 26 patients suspected of having a disorder of mitochondrial beta-oxidation were analyzed for VLCAD protein using immunoblotting, and 7 of them contained undetectable or trace levels of the enzyme.


Input: The seven deficient fibroblast lines were characterized by measuring acyl-coenzyme A dehydrogenation activities, overall palmitic acid oxidation, and VLCAD protein synthesis using pulse-chase, further confirming the diagnosis of VLCAD deficiency.

VLCAD deficiency


Input: These results suggested the heterogenous nature of the mutations causing the deficiency in the seven patients.


Input: Clinically, all patients with VLCAD deficiency exhibited cardiac disease.

VLCAD deficiency

cardiac disease


Input: At least four of them presented with hypertrophic cardiomyopathy.

hypertrophic cardiomyopathy


Input: This frequency (> 57%) was much higher than that observed in patients with other disorders of mitochondrial long-chain fatty acid oxidation that may be accompanied by cardiac disease in infants..

cardiac disease


Input: Hereditary deficiency of the fifth component of complement in man.

Hereditary deficiency of the fifth component of complement


Input: II.


Input: Biological properties of C5-deficient human serum.


Input: The first known human kindred with hereditary deficiency of the fifth component of complement (C5) was documented in the accompanying report.

hereditary deficiency of the fifth component of complement


Input: This study examines several biological properties of C5-deficient (C5D) human serum, particularly sera obtained from two C5D homozygotes.


Input: The proband, who has inactive systemic lupus erythematosus is completely lacking C5, while her healthy half-sister has 1-2% of normal levels.

systemic lupus erythematosus


Input: Both sera were severely impaired in their ability to generate chemotactic activity for normal human neutrophils upon incubation with aggregated human gamma-globulin or Escherichia coli endotoxin.


Input: This function was fully restored in the siblings serum, and substantially improved in the probands serum, by addition of highly purified human C5 to normal serum concentrations.


Input: Sera from eight family members who were apparently heterozygous for C5 deficiency gave normal chemotactic scores.

C5 deficiency


Input: The ability of C5D serum to opsonize Saccharomyces cerevisiae (bakers yeast) or Candida albicans for ingestion by normal neutrophils was completely normal.


Input: In addition, C5D serum was capable of promoting normal phagocytosis and intracellular killing of Staphylococcus aureus.


Input: The probands serum was incapable of mediating lysis of erythrocytes from a patient with paroxysmal nocturnal hemoglobinuria in both the sucrose hemolysia and acid hemolysis tests, and also lacked bactericidal activity against sensitized or unsensitized Salmonella typhi.

paroxysmal nocturnal hemoglobinuria


Input: The siblings serum, containing only 1-2% of normal C5, effectively lysed S. typhi, but only at eightfold lower serum dilutions as compared to normals.


Input: These findings underscore the critical role of C5 in the generation of chemotactic activity and in cytolytic reactions, as opposed to a nonobligatory or minimal role in opsonization, at least for the organisms under study..


Input: Human peroxisomal targeting signal-1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders.

peroxisomal disorders


Input: Two peroxisomal targeting signals, PTS1 and PTS2, are involved in the import of proteins into the peroxisome matrix.


Input: Human patients with fatal generalized peroxisomal deficiency disorders fall into at least nine genetic complementation groups.

peroxisomal deficiency disorders


Input: Cells from many of these patients are deficient in the import of PTS1-containing proteins, but the causes of the protein-import defect in these patients are unknown.


Input: We have cloned and sequenced the human cDNA homologue (PTS1R) of the Pichia pastoris PAS8 gene, the PTS1 receptor (McCollum, D., E. Monosov, and S. Subramani. 1993. J. Cell Biol. 121 761-774).


Input: The PTS1R mRNA is expressed in all human tissues examined.


Input: Antibodies to the human PTS1R recognize this protein in human, monkey, rat, and hamster cells.


Input: The protein is localized mainly in the cytosol but is also found to be associated with peroxisomes.


Input: Part of the peroxisomal PTS1R protein is tightly bound to the peroxisomal membrane.


Input: Antibodies to PTS1R inhibit peroxisomal protein-import of PTS1-containing proteins in a permeabilized CHO cell system.


Input: In vitro-translated PTS1R protein specifically binds a serine-lysine-leucine-peptide.


Input: A PAS8-PTS1R fusion protein complements the P. pastoris pas8 mutant.


Input: The PTS1R cDNA also complements the PTS1 protein-import defect in skin fibroblasts from patients--belonging to complementation group two--diagnosed as having neonatal adrenoleukodystrophy or Zellweger syndrome.

PTS1 protein-import defect

neonatal adrenoleukodystrophy

Zellweger syndrome


Input: The PTS1R gene has been localized to a chromosomal location where no other peroxisomal disorder genes are known to map.

peroxisomal disorder


Input: Our findings represent the only case in which the molecular basis of the protein-import deficiency in human peroxisomal disorders is understood.

protein-import deficiency

peroxisomal disorders


Input: Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma.

hereditary and non hereditary retinoblastoma


Input: Germline mutations in the RB1 gene confer hereditary predisposition to retinoblastoma.

retinoblastoma


Input: We have performed a mutation survey of the RB1 gene in 232 patients with hereditary or non hereditary retinoblastoma.

hereditary or non hereditary retinoblastoma


Input: We systematically explored all 27 exons and flanking sequences as well as the promotor.


Input: All types of point mutations are represented and are found unequally distributed along the RB1 gene sequence.


Input: In the population we studied, exons 3, 8, 18 and 19 are preferentially altered.


Input: The range of frequency of detection of germline mutations is about 20%, indicating that other mechanisms of inactivation of RB1 should be involved.


Input: The spectrum of mutations presented here should help to improve the clinical management of retinoblastoma and to understand the molecular mechanisms leading to tumorigenesis..

retinoblastoma


Input: Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype.

Aniridia


Input: Current evidence suggests that aniridia (absence of iris) is caused by loss of function of one copy of the PAX6 gene, which maps to 11p13.

aniridia

absence of iris


Input: We present the further characterisation of two aniridia pedigrees in which the disease segregates with chromosomal rearrangements which involve 11p13 but do not disrupt the PAX6 gene.

aniridia


Input: We have isolated three human YAC clones which encompass the PAX6 locus and we have used these to show that in both cases the chromosomal breakpoint is at least 85 kb distal of the 3 end of PAX6.


Input: In addition, the open reading frame of PAX6 is apparently free of mutations.


Input: We propose that the PAX6 gene on the rearranged chromosome 11 is in an inappropriate chromatin environment for normal expression and therefore that a position effect is the underlying mechanism of disease in these families..


Input: Somatic mutations in the BRCA1 gene in sporadic ovarian tumours.

sporadic ovarian tumours


Input: The BRCA1 gene on chromosome 17q21 is responsible for an autosomal dominant syndrome of increased susceptibility to breast and ovarian cancer but no somatic mutations in tumours have yet been described.

autosomal dominant syndrome

breast and ovarian cancer

tumours


Input: To study the potential role of BRCA1 in sporadic carcinogenesis, we analysed the genomic DNA of tumour and normal fractions of 47 ovarian cancers for mutations in BRCA1 using the single-strand conformation polymorphism technique.

tumour

ovarian cancers


Input: We now describe somatic mutations in the DNA of four tumours which also had loss of heterozygosity (LOH) at a BRCA1 intragenic marker.

tumours


Input: Our data support a tumour suppressor mechanism for BRCA1; somatic mutations and LOH may result in inactivation of BRCA1 in at least a small number of ovarian cancers..

tumour

ovarian cancers


Input: Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression.

sporadic breast cancer


Input: We have characterized expression of the familial breast and ovarian cancer gene, BRCA1, in cases of non-hereditary (sporadic) breast cancer and analyzed the effect of antisense inhibition of BRCA1 on the proliferative rate of mammary epithelial cells.

familial breast and ovarian cancer

non-hereditary (sporadic) breast cancer


Input: BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer.

carcinoma in situ

invasive cancer


Input: Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells, but had no effect on non-mammary epithelial cells.


Input: These studies suggest that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth whose function is compromised in breast cancer either by direct mutation or alterations in gene expression..

breast cancer


Input: Additional case of female monozygotic twins discordant for the clinical manifestations of Duchenne muscular dystrophy due to opposite X-chromosome inactivation.

Duchenne muscular dystrophy


Input: A pair of female monozygotic (MZ) twins, heterozygous carriers for a deletion in the DMD gene and discordant for the clinical manifestations of Duchenne muscular dystrophy, were analyzed by molecular studies, in situ hybridization, and methylation pattern of X chromosomes to search for opposite X inactivation as an explanation of their clinical discordance.

DMD

Duchenne muscular dystrophy


Input: Results in lymphocytes and skin fibroblast cell lines suggest a partial mirror inactivation with the normal X chromosome preferentially active in the unaffected twin, and the maternal deleted X chromosome preferentially active in the affected twin.


Input: A review shows that MZ female twins discordant for X-linked diseases are not uncommon.

X-linked diseases


Input: Twinning and X inactivation may be interrelated and could explain the female twins discordant for X-linked traits..


Input: X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes.

X-linked adrenoleukodystrophy

ALD

ALD


Input: Fragments of the adrenoleukodystrophy (ALD) cDNA from a patient with adolescent ALD were amplified by polymerase chain reaction and subcloned.

adrenoleukodystrophy

ALD

adolescent ALD


Input: Bidirectional sequencing of the entire coding ALD gene disclosed a cytosine to guanine transversion at nucleotide 1451 in exon five, resulting in substitution of proline 484 by arginine.

ALD


Input: Five of nine siblings of the patient, comprising two cerebral ALD, one adrenomyeloneuropathy, one Addison only as well as the symptomatic mother (all accumulating very long chain fatty acids) carried this mutation, which was not found in the unaffected persons, in five unrelated ALD patients, and in twenty controls.

cerebral ALD

adrenomyeloneuropathy

Addison only

ALD


Input: We propose that this missense mutation generated the disease per se as well as the metabolic defect; the different phenotypes, however, must have originated by means of additional pathogenetic factors..


Input: Novel mutation at the initiation codon in the Norrie disease gene in two Japanese families.

Norrie disease


Input: We have identified a new mutation of Norrie disease (ND) gene in two Japanese males from unrelated families; they showed typical ocular features of ND but no mental retardation or hearing impairment.

Norrie disease

ND

ND

mental retardation

hearing impairment


Input: A mutation was found in both patients at the initiation codon of exon 2 of the ND gene (ATG to GTG), with otherwise normal nucleotide sequences.

ND


Input: Their mothers had the normal and mutant types of the gene, which was expected for heterozygotes of the disease.


Input: The mutation of the initiation codon would cause the failure of ND gene expression or a defect in translation thereby truncating the amino terminus of ND protein.

ND

ND


Input: In view of the rarity and marked heterogeneity of mutations in the ND gene, the present apparently unrelated Japanese families who have lived in the same area for over two centuries presumably share the origin of the mutation..

ND


Input: Anticipation resulting in elimination of the myotonic dystrophy gene: a follow up study of one extended family.

myotonic dystrophy


Input: We have re-examined an extended myotonic dystrophy (DM) family, previously described in 1955, in order to study the long term effects of anticipation in DM and in particular the implications for families affected by this disease.

myotonic dystrophy

DM

DM


Input: This follow up study provides data on 35 gene carriers and 46 asymptomatic at risk family members in five generations.


Input: Clinical anticipation, defined as the cascade of mild, adult, childhood, or congenital disease in subsequent generations, appeared to be a relentless process, occurring in all affected branches of the family.

congenital disease


Input: The cascade was found to proceed asynchronously in the different branches, mainly because of an unequal number of generations with mild disease.


Input: The transition from the mild to the adult type was associated with transmission through a male parent.


Input: Stable transmission of the asymptomatic/mild phenotype showed a female transmission bias.


Input: We further examined the extent and causes of gene loss in this pedigree.


Input: Gene loss in the patient group was complete, owing to infertility of the male patients with adult onset disease and the fact that mentally retarded patients did not procreate.

infertility

mentally retarded


Input: Out of the 46 at risk subjects in the two youngest generations, only one was found to have a full mutation.


Input: This is the only subject who may transmit the gene to the sixth generation.


Input: No protomutation carriers were found in the fourth and fifth generations.


Input: Therefore it is highly probable that the DM gene will be eliminated from this pedigree within one generation.

DM


Input: The high population frequency of DM can at present not be explained by the contribution of asymptomatic cases in the younger generations of known families, but is probably caused by the events in the ancestral generations..

DM


Input: The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24. 3-q32. 2.

spinal cerebellar ataxia


Input: SCA3, the gene for spinal cerebellar ataxia 3, was recently mapped to a 15-cM interval between D14S67 and D14S81 on chromosome 14q, by linkage analysis in two families of French ancestry.

spinal cerebellar ataxia


Input: The SCA3 candidate region has now been refined by linkage analysis with four new microsatellite markers (D14S256, D14S291, D14S280, and AFM343vf1) in the same two families, in which 19 additional individuals were genotyped, and in a third French family.


Input: Combined two-point linkage analyses show that the new markers, D14S280 and AFM343vf1, are tightly linked to the SCA3 locus, with maximal lod scores, at recombination fraction, (theta) =.


Input: 00, of 7.


Input: 05 and 13.


Input: 70, respectively.


Input: Combined multipoint and recombinant haplotype analyses localize the SCA3 locus to a 3-cM interval flanked by D14S291 and D14S81.


Input: The same allele for D14S280 segregates with the disease locus in the three kindreds.


Input: This allele is frequent in the French population, however, and linkage disequilibrium is not clearly established.


Input: The SCA3 locus remains within the 29-cM region on 14q24.


Input: 2 containing the gene for the Machado-Joseph disease, which is clinically related to the phenotype determined by SCA3, but it cannot yet be concluded that both diseases result from alterations of the same gene

Machado-Joseph disease


Input: An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families.

breast-ovarian cancer


Input: Breast Cancer Linkage Consortium.

Breast Cancer


Input: The breast-ovary cancer-family syndrome is a dominant predisposition to cancer of the breast and ovaries which has been mapped to chromosome region 17q12-q21.

breast-ovary cancer-family syndrome

cancer of the breast and ovaries


Input: The majority, but not all, of breast-ovary cancer families show linkage to this susceptibility locus, designated BRCA1.

breast-ovary cancer


Input: We report here the results of a linkage analysis of 145 families with both breast and ovarian cancer.

breast and ovarian cancer


Input: These families contain either a total of three or more cases of early-onset (before age 60 years) breast cancer or ovarian cancer.

breast cancer

ovarian cancer


Input: All families contained at least one case of ovarian cancer.

ovarian cancer


Input: Overall, an estimated 76% of the 145 families are linked to the BRCA1 locus.


Input: None of the 13 families with cases of male breast cancer appear to be linked, but it is estimated that 92% (95% confidence interval 76%-100%) of families with no male breast cancer and with two or more ovarian cancers are linked to BRCA1.

male breast cancer

male breast cancer

ovarian cancers


Input: These data suggest that the breast-ovarian cancer-family syndrome is genetically heterogeneous.

breast-ovarian cancer-family syndrome


Input: However, the large majority of families with early-onset breast cancer and with two or more cases of ovarian cancer are likely to be due to BRCA1 mutations..

breast cancer

ovarian cancer


Input: Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase).

essential fructosuria


Input: Essential fructosuria is one of the oldest known inborn errors of metabolism.

Essential fructosuria

inborn errors of metabolism


Input: It is a benign condition which is believed to result from deficiency of hepatic fructokinase (ketohexokinase, KHK, E. C. 2. 7. 1. 3).

deficiency of hepatic fructokinase


Input: This enzyme catalyses the first step of metabolism of dietary fructose, conversion of fructose to fructose-1-phosphate.


Input: Despite the early recognition of this disorder, the primary structure of human KHK and the molecular basis of essential fructosuria have not been previously defined.

essential fructosuria


Input: In this report, the isolation and sequencing of full-length cDNA clones encoding human ketohexokinase are described.


Input: Alternative mRNA species and alternative KHK isozymes are produced by alternative polyadenylation and splicing of the KHK gene.


Input: The KHK proteins show a high level of sequence conservation relative to rat KHK.


Input: Direct evidence that mutation of the KHK structural gene is the cause of essential fructosuria was also obtained.

essential fructosuria


Input: In a well-characterized family, in which three of eight siblings have fructosuria, all affected individuals are compound heterozygotes for two mutations Gly40Arg and Ala43Thr.

fructosuria


Input: Both mutations result from G--> A transitions, and each alters the same conserved region of the KHK protein.


Input: Neither mutation was seen in a sample of 52 unrelated control individuals.


Input: An additional conservative amino acid change (Val49IIe) was present on the KHK allele bearing Ala43Thr


Input: Homozygous presence of the crossover (fusion gene) mutation identified in a type II Gaucher disease fetus: is this analogous to the Gaucher knock-out mouse model?

type II Gaucher disease


Input: Gaucher disease (GD) is an inherited deficiency of beta-glucocerebrosidase (EC 3. 1. 2. 45, gene symbol GBA).

Gaucher disease

GD

deficiency of beta-glucocerebrosidase


Input: In type I GD, the CNS is not involved (nonneuronopathic), whereas in type II GD (acute neuronopathic) CNS involvement is early and rapidly progressive, while in type III GD (subacute neuronopathic) CNS involvement occurs later and is slowly progressive.

type I GD

type II GD

type III GD


Input: The T6433C (L444P) substitution is prevalent in type GD II.

type GD II


Input: It may occur alone as a single base-pair mutation but often is found as part of a complex allele containing additional GBA nucleotide substitutions, G6468C (A456P) and G6482C (V460V), without (recNciI) or with (recTL) G5957C (D409H).


Input: This complex allele is presumed to have formed by recombination (crossover, fusion) of the structural gene with the pseudogene, which contains the mutated sequences.


Input: Two complex alleles have never been demonstrated to coexist in any individual.


Input: We devised a selective PCR method for the specific amplification of the normal and/or fusion gene.


Input: Using this procedure we demonstrated the fusion gene in homozygous form for the first time, in a Macedonian/Ashkenazi Jewish GD type II fetus.

GD type II


Input: Both parents were carriers of the recombination.


Input: This was confirmed by direct sequence analysis.


Input: A previous conceptus in this family was stillborn at 36 weeks, with features of severe type II GD.

stillborn

type II GD


Input: Neonates showing a severe clinical phenotype, analogous to the early neonatal lethal disease occurring in mice homozygous for a null allele produced by targeted disruption of GBA, have been described elsewhere, but the specific mutations in these cases have not yet been characterized.


Input: (ABSTRACT TRUNCATED AT 250 WORDS)


Input: Late infantile metachromatic leukodystrophy in Israel.

metachromatic leukodystrophy


Input: Metachromatic Leukodystrophy (MLD) is a neurodegenerative disease in which the lysosomal enzyme, Aryl sulfatase A (ARSA) is deficient.

Metachromatic Leukodystrophy

MLD

neurodegenerative disease


Input: The disease is inherited as an autosomal recessive trait and its frequency is estimated to be 1/40, 000 live births.


Input: The gene of ARSA has been cloned and up to now eight mutations causing MLD have been reported.

MLD


Input: Another mutation, PD, leads to the deficiency of the enzyme in vitro (pseudodeficiency) without any known clinical effect.


Input: The PD mutation is frequent in all populations.


Input: In Israel, late infantile MLD was found to be very frequent in a small Jewish isolate, the Habbanite Jews (1/75 live births).

MLD


Input: The molecular analysis demonstrated that in the Habbanite population, the mutation occurred on an allele with the PD mutation.


Input: The loss of ARSA activity is due to a point mutation C > T leading to a change of proline to leucine.


Input: MLD is also frequent among Moslem Arabs in Jerusalem.

MLD


Input: The mutation is a transition G > A destroying the splice donor site of exon 2.


Input: This mutation has been reported in patients with the late infantile MLD from different ethnic groups.

MLD


Input: The Christian Arabs in Israel also have a high incidence of the disease (1/10, 000 live births); the mutation in this population is still unknown.


Input: Knowledge of the different mutations causing MLD in these defined populations will allow a carrier screening program to be carried out and prevent the birth of additional affected children..

MLD


Input: A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia.

Kniest dysplasia


Input: Kniest dysplasia is a moderately severe chondrodysplasia phenotype that results from mutations in the gene for type II collagen, COL2A1.

Kniest dysplasia

chondrodysplasia


Input: Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss.

short trunk and extremities

mid-face hypoplasia

cleft palate

myopia

retinal detachment

hearing loss


Input: Recently, deletions of all or part of exon 12 have been identified in individuals with Kniest dysplasia, suggesting that mutations within this region of the protein may primarily result in the Kniest dysplasia phenotype.

Kniest dysplasia

Kniest dysplasia


Input: We used SSCP to analyze an amplified genomic DNA fragment containing exon 12 from seven individuals with Kniest dysplasia.

Kniest dysplasia


Input: An abnormality was identified in one patient.


Input: DNA sequence analysis demonstrated that the patient was heterozygous for a G to A transition that implied substitution of glycine103 of the triple helical domain by aspartate.


Input: The mutation was not observed in DNA from either of the clinically unaffected parents of the proband.


Input: Protein microsequencing demonstrated expression of the abnormal allele in cartilage.


Input: These data demonstrate that point mutations which result in single amino acid substitutions can produce Kniest dysplasia and further support the hypothesis that alteration of a domain, which includes the region encoded by exon 12, in the type II collagen protein leads to this disorder..

Kniest dysplasia


Input: CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32. 1.

Machado-Joseph disease


Input: We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32.


Input: 1, the genetic locus for Machado-Joseph disease (MJD).

Machado-Joseph disease

MJD


Input: In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68-79).

MJD


Input: Southern blot analyses and genomic cloning demonstrates the existence of related genes.


Input: These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD.

MJD


Input: Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.

breast and ovarian cancer


Input: We analysed 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene, using single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA.

breast and/or ovarian cancer


Input: A total of eight putative disease-causing alterations were identified four of these are frameshifts and two are nonsense mutations.


Input: In addition, we found two missense mutations, one of which changes the final cysteine of the BRCA1 zinc finger motif to glycine.


Input: These data are consistent with a tumour suppressor model, and support the notion that this candidate gene is in fact BRCA1.

tumour


Input: The heterogeneity of mutations, coupled with the large size of the gene, indicates that clinical application of BRCA1 mutation testing will be technically challenging..


Input: Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.

breast and ovarian cancer


Input: We provide genetic evidence supporting the identity of the candidate gene for BRCA1 through the characterization of germline mutations in 63 breast cancer patients and 10 ovarian cancer patients in ten families with cancer linked to chromosome 17q21.

breast cancer

ovarian cancer

cancer


Input: Nine different mutations were detected by screening BRCA1 DNA and RNA by single-strand conformation polymorphism analysis and direct sequencing.


Input: Seven mutations lead to protein truncations at sites throughout the gene.


Input: One missense mutation (which occurred independently in two families) leads to loss of a cysteine in the zinc binding domain.


Input: An intronic single basepair substitution destroys an acceptor site and activates a cryptic splice site, leading to a 59 basepair insertion and chain termination.


Input: The four families with both breast and ovarian cancer had chain termination mutations in the N-terminal half of the protein..

breast and ovarian cancer


Input: High resolution genetic analysis suggests one ancestral predisposing haplotype for the origin of the myotonic dystrophy mutation.

myotonic dystrophy


Input: The mutation causing myotonic dystrophy (DM) has been identified as an amplification of an unstable trinucleotide (CTG) n repeat in over 99% of the global DM population.

myotonic dystrophy

DM

DM


Input: It is in complete linkage disequilibrium with an Alu element polymorphism within the DM kinase gene, suggesting that DM is a consequence of one or few ancestral mutations.

DM

DM


Input: A recent analysis utilizing this polymorphism as well as a flanking dinucleotide marker, suggested that similar to Fragile X syndrome, DM exhibited a founder effect (Imbert et al., 1993 Nature Genet. 4, 72-76).

Fragile X syndrome

DM


Input: In contrast, the low reproductive fitness of individuals with congenital DM (the endpoint of genetic anticipation in myotonic dystrophy) suggests a higher rate of new mutations.

DM

myotonic dystrophy


Input: We present a high resolution genetic analysis of the DM locus using PCR based assays of nine polymorphisms, spanning a physical distance of 30 kb, within and immediately flanking the DM kinase gene.

DM

DM


Input: The persistent complete allelic association of the DM mutation with all these polymorphisms provides further support to previous observations and suggests more strongly that the DM mutation occurred on the background of a particular haplotype in which the (CTG) n repeat became inherently unstable and therefore predisposed to amplification.

DM

DM


Input: Genetic instability in human ovarian cancer cell lines.

ovarian cancer


Input: We have analyzed the stability of microsatellites in cell lines derived from human ovarian cancers and found that 5 out of 10 of the ovarian tumor cell lines are genetically unstable at the majority of the loci analyzed.

ovarian cancers

ovarian tumor


Input: In clones and subclones derived serially from one of these cell lines (2774; serous cystadenocarcinoma), a very high proportion of microsatellites distributed in many different regions of the genome change their size in a mercurial fashion.

serous cystadenocarcinoma


Input: We conclude that genomic instability in ovarian tumors is a dynamic and ongoing process whose high frequency may have been previously underestimated by PCR-based allelotyping of bulk tumor tissue.

ovarian tumors

tumor


Input: We have identified the source of the genetic instability in one ovarian tumor as a point mutation (R524P) in the human mismatch-repair gene MSH2 (Salmonella MutS homologue), which has recently been shown to be involved in hereditary nonpolyposis colorectal cancer.

ovarian tumor

hereditary nonpolyposis colorectal cancer


Input: Patient 2774 was a 38-year-old heterozygote, and her normal tissue carried both mutant and wild-type alleles of the human MSH2 gene.


Input: However the wild-type allele was lost at some point early during tumorigenesis so that DNA isolated either from the patients ovarian tumor or from the 2774 cell line carries only the mutant allele of the human MSH2 gene.

ovarian tumor


Input: The genetic instability observed in the tumor and cell line DNA, together with the germ-line mutation in a mismatch-repair gene, suggest that the MSH2 gene is involved in the onset and/or progression in a subset of ovarian cancer..

tumor

ovarian cancer


Input: BRCA1 mutations in primary breast and ovarian carcinomas.

breast and ovarian carcinomas


Input: Loss of heterozygosity data from familial tumors suggest that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor.

familial tumors

ovarian and early-onset breast cancer

tumor


Input: The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors.

sporadic breast and ovarian cancers

tumors


Input: The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus.

breast and ovarian tumors


Input: Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers.

ovarian carcinomas

cancers


Input: These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele..

breast and ovarian cancers


Input: PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects.

congenital cataracts

aniridia

anophthalmia

central nervous system defects


Input: The human eye malformation aniridia results from haploinsufficiency of PAX6, a paired box DNA-binding protein.

aniridia

haploinsufficiency of PAX6


Input: To study this dosage effect, we characterized two PAX6 mutations in a family segregating aniridia and a milder syndrome consisting of congenital cataracts and late onset corneal dystrophy.

aniridia

congenital cataracts

corneal dystrophy


Input: The nonsense mutations, at codons 103 and 353, truncate PAX6 within the N-terminal paired and C-terminal PST domains, respectively.


Input: The wild-type PST domain activates transcription autonomously and the mutant form has partial activity.


Input: A compound heterozygote had severe craniofacial and central nervous system defects and no eyes.

craniofacial and central nervous system defects

no eyes


Input: The pattern of malformations is similar to that in homozygous Sey mice and suggests a critical role for PAX6 in controlling the migration and differentiation of specific neuronal progenitor cells in the brain..


Input: A physical map and candidate genes in the BRCA1 region on chromosome 17q12-21.


Input: We have constructed a physical map of a 4 cM region on chromosome 17q12-21 that contains the hereditary breast and ovarian cancer gene BRCA1.

hereditary breast and ovarian cancer


Input: The map comprises a contig of 137 overlapping yeast artificial chromosomes and P1 clones, onto which we have placed 112 PCR markers.


Input: We have localized more than 20 genes on this map, ten of which had not been mapped to the region previously, and have isolated 30 cDNA clones representing partial sequences of as yet unidentified genes.


Input: Two genes that lie within a narrow region defined by meiotic breakpoints in BRCA1 patients have been sequenced in breast cancer patients without revealing any deleterious mutations.

breast cancer


Input: These new reagents should facilitate the identification of BRCA1..


Input: The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene.

Wilson disease


Input: The Long-Evans Cinnamon (LEC) rat shows similarity to Wilson disease in many clinical and biochemical features.

Wilson disease


Input: We have cloned cDNAs for the rat gene (Atp7b) homologous to the human Wilson disease gene (ATP7B) and have used them to identify a partial deletion in the Atp7b gene in the LEC rat.

Wilson disease


Input: The deletion removes at least 900 bp of the coding region at the 3 end, includes the crucial ATP binding domain and extends downstream of the gene.


Input: Our results provide convincing evidence for defining the LEC rat as an animal model for Wilson disease.

Wilson disease


Input: This model will be important for studying liver pathophysiology, for developing therapy for Wilson disease and for studying the pathway of copper transport and its possible interaction with other heavy metals..

Wilson disease


Input: Genomic organization of the adrenoleukodystrophy gene.

adrenoleukodystrophy


Input: Adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder, is a severe neurodegenerative disease associated with an impairment of very long chain fatty acids beta-oxidation.

Adrenoleukodystrophy

ALD

peroxisomal disorder

neurodegenerative disease

impairment of very long chain fatty acids beta-oxidation


Input: We have recently identified by positional cloning the gene responsible for ALD, located in Xq28.

ALD


Input: It encodes a new member of the " ABC " superfamily of membrane-associated transporters that shows, in particular, significant homology to the 70-kDa peroxisomal membrane protein (PMP70).


Input: We report here a detailed characterization of the ALD gene structure.

ALD


Input: It extends over 21 kb and consists of 10 exons.


Input: To facilitate the detection of mutations in ALD patients, we have determined the intronic sequences flanking the exons as well as the sequence of the 3 untranslated region and of the immediate 5 promoter region.

ALD


Input: Sequences present in distal exons cross-hybridize strongly to additional sequences in the human genome.


Input: The ALD gene has been positioned on a pulsed-field map between DXS15 and the L1CAM gene, about 650 kb upstream from the color pigment genes.

ALD


Input: The frequent occurrence of color vision anomalies observed in patients with adrenomyeloneuropathy (the adult onset form of ALD) thus does not represent a contiguous gene syndrome but a secondary manifestation of ALD..

adrenomyeloneuropathy

ALD

contiguous gene syndrome

ALD


Input: The murine homologues of the Huntington disease gene (Hdh) and the alpha-adducin gene (Add1) map to mouse chromosome 5 within a region of conserved synteny with human chromosome 4p16. 3.

Huntington disease


Input: Huntington disease (HD) is a severe autosomal dominant neurodegenerative disorder associated with a novel gene (IT15).

Huntington disease

HD

autosomal dominant neurodegenerative disorder


Input: Recently, we reported the cloning of Hdh, the murine homologue of IT15.


Input: Here, using an interspecific backcross, we have mapped both Hdh and the mouse homologue of human alpha-adducin (Add1), a membrane-associated cytoskeletal protein gene.


Input: Both of these genes map in the same position on mouse chromosome 5 in a region associated with ancestral chromosomal rearrangements and show no recombination with D5H4S43, D5H4S115, and D5H4S62, the murine homologues of D4S43, D4S115, and D4S62, respectively.


Input: Further mapping studies of humans, mice, and other mammalian species should reveal the nature of the rearrangements affecting this chromosomal segment during mammalian evolution..


Input: Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol.

cholesteryl ester transfer protein deficiency


Input: Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood.


Input: We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G (+ 1)-to-A mutation (Int14 A) in several families with very high HDL-C levels in Japan.

cholesteryl ester transfer protein (CETP) deficiency


Input: Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene.


Input: Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products a novel intron 14 splice donor site mutation caused by a T insertion at position + 3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G).


Input: The Int14 T mutation was only found in one family.


Input: However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively.


Input: Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively.


Input: These two mutations accounted for about 10% of the total variance of HDL-C in this population.


Input: The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele.


Input: In four D442G homozygotes, mean HDL-C levels (86 +/-26 mg/dl) were lower than in Int14 A homozygotes (158 +/-35 mg/dl), reflecting residual CETP activity in plasma.


Input: In 47 D442G heterozygotes, mean HDL-C levels were 91 +/-23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/-15 mg/dl).


Input: Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele.


Input: CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population..

CETP deficiency

genetic deficiency


Input: Treatment of cerebrotendinous xanthomatosis: effects of chenodeoxycholic acid, pravastatin, and combined use.

cerebrotendinous xanthomatosis


Input: Treatments by oral administration of chenodeoxycholic acid (CDCA) alone, 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitor (pravastatin) alone, and combination of the two drugs were attempted for 7 patients with cerebrotendinous xanthomatosis (CTX).

cerebrotendinous xanthomatosis

CTX


Input: CDCA treatment at a dose of 300 mg/day reduced serum cholestanol (67. 3% reduction), lathosterol (50. 8%), campesterol (61. 7%) and sitosterol (12. 7%).


Input: However, the sera of the patients changed to be " atherogenic "; total cholesterol, triglyceride and low-density lipoprotein (LDL)-cholesterol were increased, while high-density lipoprotein (HDL)-cholesterol was decreased.


Input: Contrarily, pravastatin at a dose of 10 mg/day improved the sera of the patients to be markedly " anti-atherogenic ", but the reductions of cholestanol (30. 4%), lathosterol (44. 0%), campesterol (22. 9%) and sitosterol (9. 6%) were inadequate.


Input: Combined treatment with CDCA and pravastatin showed good overlapping of the effects of each drug alone.


Input: The sera of the patients were apparently more " anti-atherogenic " than those after CDCA treatment.


Input: Serum cholestanol concentration was still 2.


Input: 7 times higher than in controls, but the serum lathosterol level was within the normal range, indicating that the enhancement of overall cholesterol synthesis in the patients was sufficiently suppressed.


Input: Plant sterol levels were also within the normal range.


Input: The combination of CDCA and pravastatin was a good treatment for CTX, based on the improvement of serum lipoprotein metabolism, the suppression of cholesterol synthesis, and reductions of cholestanol and plant sterol levels.

CTX


Input: In all of 7 patients, the progression of disease was arrested, but dramatic effects on clinical manifestations, xanthoma, and electrophysiological findings could not be found after the treatment of these drugs

xanthoma


Input: Mutation spectrum in the CHM gene of Danish and Swedish choroideremia patients.

CHM

choroideremia


Input: The recent isolation of the complete open reading frame of the choroideremia (CHM) gene and the characterization of the exon-intron boundaries has paved the way to mutation detection in patients with classical choroideremia.

choroideremia

CHM

choroideremia


Input: We have performed mutation screening in patients from 15 Danish and Swedish families by using Southern blot hybridization and the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) technique.


Input: Causative mutations in the CHM gene were detected in at least 12 families, indicating that a substantial part of the mutations can be identified by this approach.

CHM


Input: In four of these families deletions of different sizes were found.


Input: Thus, in one patient, the deletion resulted in the absence of only one exon, while in another the deletion comprised the entire CHM gene.

CHM


Input: Mapping of the deletion endpoints in these four patients and in another 11 male patients with sizeable deletions enabled us to construct a very detailed map of intervals 2 and 3 of Xq21.


Input: In the remaining 11 Danish and Swedish families at least 8 causative mutations were found by PCR-SSCP analysis and direct sequencing.


Input: Interestingly, all CHM gene mutations detected thus far in choroideremia patients give rise to the introduction of a premature stop codon..

CHM

choroideremia


Input: Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in The Netherlands: a survey of 30 kindreds.

adrenomyeloneuropathy

X-linked adrenoleukodystrophy


Input: X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal beta-oxidation associated with accumulation of saturated very long-chain fatty acids, which results in central and peripheral demyelination and in impaired function of adrenal cortex and testes.

X-linked adrenoleukodystrophy

X-ALD

inherited disorder

demyelination

impaired function of adrenal cortex and testes


Input: The phenotypic expression is highly variable, childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN) being the main variants.

childhood cerebral ALD

CCALD

adrenomyeloneuropathy

AMN


Input: We explored the 30 Dutch kindreds well known to the Dutch X-ALD/AMN Study Group and phenotyped 77 male patients 35 (46%) had AMN and 24 (31%) CCALD or adolescent cerebral ALD (AdolCALD).

X-ALD

AMN

AMN

CCALD

adolescent cerebral ALD

AdolCALD


Input: These percentages differ significantly from previous reports, in which 25 to 28% of the patients developed AMN and 53 to 57% CCALD or AdolCALD.

AMN

CCALD

AdolCALD


Input: Our findings indicate that--at least in the Netherlands--AMN may be the most frequent phenotype of X-ALD..

AMN

X-ALD


Input: Adrenoleukodystrophy gene encodes an 80 kDa membrane protein.

Adrenoleukodystrophy


Input: An antibody against the synthetic C-terminal peptides deduced from the cDNA of the gene responsible for X-linked adrenoleukodystrophy (ALD) was produced to characterize the product of the ALD gene.

X-linked adrenoleukodystrophy

ALD

ALD


Input: The antibody reacted with the 80 kDa band protein in control fibroblasts, while no bands were detected in the fibroblasts from a patient with ALD (#163), in which mRNA of the ALD gene was undetectable based on Northern blot analysis.

ALD

ALD


Input: The 293T cells transfected with the full-coding cDNA inserted in the expression vector produced a new 80 kDa protein, as detected by Western blot.


Input: In an immunocytological study, the staining was in a punctate pattern, in the normal fibroblasts.


Input: However, there was no punctate staining in the #163 cells.


Input: These data thus indicate that the ALD gene encodes an 80 kDa membrane protein..

ALD


Input: Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein.

McLeod syndrome


Input: McLeod syndrome is an X-linked multisystem disorder characterized by abnormalities in the neuromuscular and hematopoietic systems.

McLeod syndrome

X-linked multisystem disorder


Input: We have assembled a cosmid contig of 360 kb that encompasses the McLeod gene locus.

McLeod


Input: A 50 kb deletion was detected by screening DNA from patients with radiolabeled whole cosmids, and two transcription units were identified within this deletion.


Input: The mRNA expression pattern of one of them, designated as XK, correlates closely to the McLeod phenotype.

McLeod


Input: XK encodes a novel protein with structural characteristics of prokaryotic and eukaryotic membrane transport proteins.


Input: Nucleotide sequence analysis of XK from two unrelated McLeod patients has identified point mutations at conserved splice donor and acceptor sites.

McLeod


Input: These findings provide direct evidence that XK is responsible for McLeod syndrome..

McLeod syndrome


Input: X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus.

X-linked spastic paraplegia

Pelizaeus-Merzbacher disease

allelic disorders


Input: Three forms of X-linked spastic paraplegia (SPG) have been defined.

X-linked spastic paraplegia

SPG


Input: One locus (SPG 1) maps to Xq28 while two clinically distinct forms map to Xq22 (SPG2).


Input: A rare X-linked dysmyelinating disorder of the central nervous system, Pelizaeus-Merzbacher disease (PMD), has also been mapped to Xq21-q22, and is caused by mutations in the proteolipid protein gene (PLP) which encodes two myelin proteins, PLP and DM20.

X-linked dysmyelinating disorder

Pelizaeus-Merzbacher disease

PMD


Input: While narrowing the genetic interval containing SPG2 in a large pedigree, we found that PLP was the closest marker to the disease locus, implicating PLP as a possible candidate gene.


Input: We have found that a point mutation (His139Tyr) in exon 3B of an affected male produces a mutant PLP but a normal DM20, and segregates with the disease (Zmax = 6. 63, theta = 0. 00).


Input: It appears, therefore, that SPG2 and PMD are allelic disorders

PMD


Input: Canavan disease: mutations among Jewish and non-Jewish patients.

Canavan disease


Input: Canavan disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA).

Canavan disease

autosomal recessive leukodystrophy

deficiency of aspartoacylase


Input: Sixty-four probands were analyzed for mutations in the ASPA gene.


Input: Three point mutations--693C--> A, 854A--> C, and 914C--> A--were identified in the coding sequence.


Input: The 693C--> A and 914C--> A base changes, resulting in nonsense tyr231--> ter and missense ala305--> glu mutations, respectively, lead to complete loss of ASPA activity in in vitro expression studies.


Input: The 854A--> C transversion converted glu to ala in codon 285.


Input: The glu285--> ala mutant ASPA has 2.


Input: 5% of the activity expressed by the wild-type enzyme.


Input: A fourth mutation, 433--2 (A--> G) transition, was identified at the splice-acceptor site in intron 2.


Input: The splice-site mutation would lead to skipping of exon 3, accompanied by a frameshift, and thus would produce aberrant ASPA.


Input: Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent.

Canavan


Input: The glu285--> ala mutation was predominant (82. 9%) in this population, followed by the tyr231--> ter (14. 8%) and 433--2 (A--> G) (1. 1%) mutations.


Input: The three mutations account for 98.


Input: 8% of the Canavan chromosomes of Ashkenazi Jewish origin.

Canavan


Input: The ala305--> glu mutation was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes.


Input: Predominant occurrence of certain mutations among Ashkenazi Jewish and non-Jewish patients with Canavan disease would suggest a founding-father effect in propagation of these mutant chromosomes

Canavan disease


Input: Intelligence quotient profile in myotonic dystrophy, intergenerational deficit, and correlation with CTG amplification.

myotonic dystrophy


Input: An abbreviated Wechsler Adult Intelligence Scale Revised (WAIS-R) was used to assess verbal and arithmetical cognitive performance in 55 subjects with myotonic dystrophy (DM), covering all grades of disease severity, and 31 controls at 50% risk of inheriting DM.

myotonic dystrophy

DM

DM


Input: Scaled scores from the assessment were converted into an intelligence quotient (IQ) estimation on each person.


Input: Significant IQ differences were found between (1) all 55 DM subjects (mean 90. 2, SD 16. 1) and 31 controls (102. 6, SD 9. 4), with no sex differences in either group; (2) 15 affected parents (99. 3, SD 12. 2) and their affected children (88. 1, SD 17. 2), where significance was dependent on parental sex being female; and (3) 15 pairs of affected sibs (89. 6, SD 13. 2) and their normal sibs (100. 2, SD 7. 6).

DM


Input: IQ steadily declined as (1) the age of onset of signs and symptoms decreased, and (2) the CTG expansion size increased.


Input: The correlation appeared to be more linear with age of onset.


Input: The correlation of IQ difference and CTG expansion difference in both the DM parent-child pairs and normal sib-affected sib pairs was poor, indicating that CTG expansion is not a reliable predictor of IQ either in individual persons or families.

DM


Input: Further analysis of cognitive function in DM is required to clarify specific deficits characteristic of this patient group

DM


Input: Adenomatous polyposis coli and a cytogenetic deletion of chromosome 5 resulting from a maternal intrachromosomal insertion.

Adenomatous polyposis coli


Input: We present the clinical and laboratory findings in an institutionalised adult patient originally referred for autism.

autism


Input: A high risk of colorectal cancer was predicted when an interstitial deletion of the long arm of chromosome 5, del (5) (q15q22. 3), was detected in her lymphocytes and deletion of the MCC and APC genes confirmed by molecular analysis.

colorectal cancer

APC


Input: Adenomatous polyposis coli and carcinoma of the rectum were subsequently diagnosed in the patient.

Adenomatous polyposis coli

carcinoma of the rectum


Input: She was profoundly mentally retarded, autistic, and had minor dysmorphic features consistent with those of previous patients with similar deletions.

mentally retarded

autistic

dysmorphic features


Input: The deletion arose as a result of recombination within the small insertion loop formed at meiosis by the direct insertion (dir ins (5) (q22. 3q14. 2q15)) found in the patients mother.


Input: This family further confirms the cytogenetic mapping of both MCC and APC genes to 5q22 and comparison with other recent cases suggests that both genes and their closely linked markers lie within the 5q22.

APC


Input: 1 subband


Input: Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q.

Familial male breast cancer


Input: Breast cancer in men is about a hundredfold less common than in women and this has hindered research into its genetic basis.

Breast cancer


Input: We have examined 22 families with at least one case of male breast cancer for linkage to the hereditary breast and ovarian cancer locus, BRCA1, on chromosome 17q.

male breast cancer

hereditary breast and ovarian cancer


Input: We found strong evidence against linkage to BRCA1 (lod score-16. 63) and the best estimate of the proportion of linked families was 0% (95% CI 0-18%).


Input: Our results indicate that there is a gene (s) other than BRCA1 which predisposes to early-onset breast cancer in women and which confers a higher risk of male breast cancer.

breast cancer

male breast cancer


Input: Identification of additional pedigrees that include cases of male breast cancer may therefore facilitate the mapping and isolation of this gene.

male breast cancer


Input: The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains.

Ewing family of tumors

malignant melanoma of soft parts

desmoplastic small round cell tumors


Input: The EWS gene, which maps to band q12 of human chromosome 22, is involved in a wide variety of human solid tumors including Ewing sarcoma, related primitive neuroectodermal tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors.

solid tumors

Ewing sarcoma

neuroectodermal tumors

malignant melanoma of soft parts

desmoplastic small round cell tumors


Input: In these tumors, the EWS is fused to genes encoding transcriptional activators/repressors, like Fli-1 or erg or ATF 1 or wt1.

tumors


Input: To better understand the function of the EWS protein, we cloned the EWS cDNA.


Input: Sequence analysis of this cDNA revealed differential splicing involving two exons encoding 72 amino acids.


Input: Both alternatively spliced transcripts, EWS and EWS-b, are expressed in a variety of cells.


Input: Because EWS proteins contain putative conserved RNA binding motifs, we studied the RNA binding properties of the EWS protein.


Input: The EWS-b protein binds to RNA in vitro and, specifically, to poly G and poly U.


Input: The RNA binding activity was localized to the carboxy terminal 86 amino acids, which constitute RGG box.


Input: Thus the amino terminal domain of EWS (NTD-EWS), which is involved in chromosome translocation may regulate the specificity of RNA binding activity of EWS.


Input: An EWS-erg chimeric protein, which is found in Ewings sarcoma cells, functions as a transcriptional activator.

Ewings sarcoma


Input: Mutational analysis of EWS-erg chimeric protein revealed that NTD-EWS functions as a regulatory domain for the transcriptional activation properties of EWS-erg chimeric protein..


Input: Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.

Canavan disease


Input: Canavan disease, or spongy degeneration of the brain, is a severe leukodystrophy caused by the deficiency of aspartoacylase (ASPA).

Canavan disease

spongy degeneration of the brain

leukodystrophy

deficiency of aspartoacylase


Input: Recently, a missense mutation was identified in human ASPA coding sequence from patients with Canavan disease.

Canavan disease


Input: The human ASPA gene has been cloned and found to span 29 kb of the genome.


Input: Human aspartoacylase is coded by six exons intervened by five introns.


Input: The exons vary from 94 (exon III) to 514 (exon VI) bases.


Input: The exon/intron splice junction sites follow the gt/ag consensus sequence rule.


Input: Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines localized ASPA to human chromosome 17.


Input: The human ASPA locus was further mapped in the 17p13-ter region by fluorescence in situ hybridization.


Input: The bovine aspa gene has also been cloned, and its exon/intron organization is identical to that of the human gene.


Input: The 500-base sequence upstream of the initiator ATG codon in the human gene and that in the bovine gene are 77% identical.


Input: Human ASPA coding sequences cross-hybridize with genomic DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey.


Input: The specificity of cross-species hybridization of coding sequences suggests that aspartoacylase has been conserved during evolution.


Input: It should now be possible to identify mutations in the noncoding genomic sequences that lead to Canavan disease and to study the regulation of ASPA..

Canavan disease


Input: Myotonic dystrophy: size-and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism.

Myotonic dystrophy


Input: Myotonic dystrophy (DM) is a progressive neuromuscular disorder which results from elongations of an unstable (CTG) n repeat, located in the 3 untranslated region of the DM gene.

Myotonic dystrophy

DM

neuromuscular disorder

DM


Input: A correlation has been demonstrated between the increase in the repeat number of this sequence and the severity of the disease.


Input: However, the clinical status of patients cannot be unambiguously ascertained solely on the basis of the number of CTG repeats.


Input: Moreover, the exclusive maternal inheritance of the congenital form remains unexplained.


Input: Our observation of differently sized repeats in various DM tissues from the same individual may explain why the size of the mutation observed in lymphocytes does not necessarily correlate with the severity and nature of symptoms.

DM


Input: Through a molecular and genetic study of 142 families including 418 DM patients, we have investigated the dynamics of the CTG repeat meiotic instability.

DM


Input: A positive correlation between the size of the repeat and the intergenerational enlargement was observed similarly through male and female meioses for < or = 0.


Input: 5-kb CTG sequences.


Input: Beyond 0.


Input: 5 kb, the intergenerational variation was more important through female meioses, whereas a tendency to compression was observed almost exclusively in male meioses, for > or = 1.


Input: 5-kb fragments.


Input: This implies a size-and sex-dependent meiotic instability.


Input: Moreover, segregation analysis supports the hypothesis of a maternal as well as a familial predisposition for the occurrence of the congenital form.


Input: Finally, this analysis reveals a significant excess of transmitting grandfathers partially accounted for by increased fertility in affected males


Input: Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria.

phenylketonuria


Input: Taking advantage of the illegitimate transcription of the phenylalanine hydroxylase (PAH) gene, we have been able to analyse the PAH cDNA sequence of hyperphenylalaninemic children in circulating lymphocytes.

hyperphenylalaninemic


Input: Using this approach, we have also identified 3 novel mutations in cDNA from liver and lymphocytes of two patients.


Input: One mutation, detected by the abnormal pattern of migration of an amplified fragment, is a C to T transition in the splice acceptor site of intron 10, which resulted in the skipping of exon 11 with the premature termination of RNA translation downstream from exon 12 (-3 IVS10).


Input: The other two mutations are missense mutations in exons 10 and 11 (respectively, L333F and E390G).


Input: The present study supports the view that circulating lymphocytes give easy access to PAH gene transcripts whose nucleotide sequence is identical to that reported in liver and therefore represent a useful tool for molecular genetic studies in phenylketonuria..

phenylketonuria


Input: High residual arylsulfatase A (ARSA) activity in a patient with late-infantile metachromatic leukodystrophy.

late-infantile metachromatic leukodystrophy


Input: We identified a patient suffering from late-infantile metachromatic leukodystrophy (MLD) who has a residual arylsulfatase A (ARSA) activity of about 10%.

late-infantile metachromatic leukodystrophy

MLD


Input: Fibroblasts of the patient show significant sulfatide degradation activity exceeding that of adult MLD patients.

adult MLD


Input: Analysis of the ARSA gene in this patient revealed heterozygosity for two new mutant alleles in one allele, deletion of C 447 in exon 2 leads to a frameshift and to a premature stop codon at amino acid position 105; in the second allele, a G--> A transition in exon 5 causes a Gly309--> Ser substitution.


Input: Transient expression of the mutant Ser309-ARSA resulted in only 13% enzyme activity of that observed in cells expressing normal ARSA.


Input: The mutant ARSA is correctly targeted to the lysosomes but is unstable.


Input: These findings are in contrast to previous results showing that the late-infantile type of MLD is always associated with the complete absence of ARSA activity.

late-infantile type of MLD


Input: The expression of the mutant ARSA protein may be influenced by particular features of oligodendrocytes, such that the level of mutant enzyme is lower in these cells than in others..


Input: An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy.

late-infantile metachromatic leukodystrophy


Input: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA; EC 3. 1. 6. 8).

Metachromatic leukodystrophy

MLD

autosomal recessive lysosomal storage disorder

deficiency of arylsulfatase A


Input: The 8 ARSA exons and adjacent intron boundaries from a patient with late-infantile metachromatic leukodystrophy were polymerase chain reaction (PCR) amplified in seven discrete reactions.

late-infantile metachromatic leukodystrophy


Input: Amplified ARSA exons were analysed for the presence of sequence alterations by single-strand conformation polymorphism analysis, followed by direct sequencing of PCR products.


Input: The patient was found to be homozygous for a C--> T transition in exon IV that results in the substitution of a highly conserved threonine residue at amino acid 274 with a methionine (T274M).


Input: Analysis of a further 29 MLD patients revealed the presence of five additional homozygotes for T274M.

MLD


Input: All 6 T274M homozygotes (representing four families) were of Lebanese descent, and all were known to be the result of consanguineous marriages.


Input: The altered amino acid is rigidly conserved among 10 sulfatases from Escherichia coli to humans; therefore, it is most likely that the resultant mutant protein will have little or no enzyme activity.


Input: This is consistent with the very low ARSA activity measured in these patients and their uniformly severe clinical presentation


Input: Mutations in the PAX6 gene in patients with hereditary aniridia.

aniridia


Input: The 14 exons of the PAX6 gene have been analysed exon-by-exon using SSCP in 6 aniridia families.

aniridia


Input: In each family band shifts were observed on the SSCP gels for only one exon and direct PCR-sequencing revealed mutations in each case.


Input: Two mutations involved C--> T transitions in CGAarg codons in exons 9 and 11.


Input: Another C--> T transition converted a CAG-glutamine to a TAG-stop in exon 7.


Input: Small insertions created frameshifts which produced downstream stop codons in another two patients and an A--> T mutation disrupted the splice donor site of exon 5 in the remaining family.


Input: Thus, complete inactivation of the PAX6 gene is predicted in all cases.


Input: Analysis of other affected members of the families showed that, in each case, all affected individuals carried the same family-specific mutation.


Input: One polymorphism was found in exon 7.


Input: This data strongly supports the candidature of PAX6 as the gene responsible for hereditary aniridia..

aniridia


Input: Three novel mutations in five unrelated subjects with hereditary protein S deficiency type I.

protein S deficiency type I


Input: A panel of eight unrelated subjects with inherited type I protein S deficiency was screened for mutations in the PROS1 gene.

type I protein S deficiency


Input: In five subjects an abnormality was found but mutations were not detected in the remaining three subjects.


Input: Two subjects shared a G--> A transition at position + 5 of the donor splice site consensus sequence of intron 10.


Input: Also in two subjects an A--> T transversion was detected in the stopcodon of the PROS1 gene; this transversion predicts a protein S molecule that is extended by 14 amino acids.


Input: The fifth subject was found to possess two sequence abnormalities.


Input: One allele carried a G--> A transition near the donor splice junction of intron 2, but this abnormality is probably neutral, since it was inherited from the parent with normal protein S antigen levels.


Input: In the other allele a single T insertion in codon-25 was found.


Input: Analysis of platelet RNA showed that only the mRNA with the A--> T mutation in the stopcodon is present in amounts comparable to wildtype RNA.


Input: mRNA from the alleles with the other two mutations was either undetectable or present in greatly reduced amounts.


Input: The latter indicates that a mRNA based approach is not feasible for the genetic analysis of protein S deficiency type I..

protein S deficiency type I


Input: Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy.

myotonic dystrophy


Input: In myotonic dystrophy (DM), the size of a CTG repeat in the DM kinase gene generally increases in successive generations with clinical evidence of anticipation.

myotonic dystrophy

DM

DM


Input: However, there have also been cases with an intergenerational contraction of the repeat.


Input: We examined 1, 489 DM parent-offspring pairs, of which 95 (6. 4%) showed such contractions in peripheral blood leukocytes (PBL).

DM


Input: In 56 of the 95 pairs, clinical data allowed an analysis of their anticipation status.


Input: It is surprising that anticipation occurred in 27 (48%) of these 56 pairs, while none clearly showed a later onset of DM in the symptomatic offspring.

DM


Input: The contraction occurred in 76 (10%) of 753 paternal transmissions and in 19 (3%) of 736 maternal transmissions.


Input: Anticipation was observed more frequently in maternal (85%) than in paternal (37%) transmissions (P <. 001).


Input: The parental repeat size correlated with the size of intergenerational contraction (r2 =. 50, P < <. 001), and the slope of linear regression was steeper in paternal (-. 62) than in maternal (-. 30) transmissions (P < <. 001).


Input: Sixteen DM parents had multiple DM offspring with the CTG repeat contractions.

DM

DM


Input: This frequency was higher than the frequency expected from the probability of the repeat contractions (6. 4%) and the size of DM sib population (1. 54 DM offspring per DM parent, in 968 DM parents).

DM

DM

DM

DM


Input: We conclude that (1) intergenerational contractions of the CTG repeat in leukocyte DNA frequently accompanies apparent anticipation, especially when DM is maternally transmitted, and (2) the paternal origin of the repeat and the presence of the repeat contraction in a sibling increase the probability of the CTG repeat contraction

DM


Input: Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG) n repeat variation and selection against extreme expansion in sperm.

myotonic dystrophy


Input: Myotonic dystrophy (DM) is caused by abnormal expansion of a polymorphic (CTG) n repeat, located in the DM protein kinase gene.

Myotonic dystrophy

DM

DM


Input: We determined the (CTG) n repeat lengths in a broad range of tissue DNAs from patients with mild, classical, or congenital manifestation of DM.

DM


Input: Differences in the repeat length were seen in somatic tissues from single DM individuals and twins.

DM


Input: Repeats appeared to expand to a similar extent in tissues originating from the same embryonal origin.


Input: In most male patients carrying intermediate-or small-sized expansions in blood, the repeat lengths covered a markedly wider range in sperm.


Input: In contrast, male patients with large allele expansions in blood (> 700 CTGs) had similar or smaller repeats in sperm, when detectable.


Input: Sperm alleles with > 1, 000 CTGs were not seen.


Input: We conclude that DM patients can be considered gonosomal mosaics, i.

DM


Input: e e., combined somatic and germ-line tissue mosaics.


Input: Most remarkably, we observed multiple cases where the length distributions of intermediate-or small-sized alleles in fathers sperm were significantly different from that in their offsprings blood.


Input: Our combined findings indicate that intergenerational length changes in the unstable CTG repeat are most likely to occur during early embryonic mitotic divisions in both somatic and germ-line tissue formation.


Input: Both the initial CTG length, the overall number of cell divisions involved in tissue formation, and perhaps a specific selection process in spermatogenesis may influence the dynamics of this process.


Input: A model explaining mitotic instability and sex-dependent segregation phenomena in DM manifestation is discussed

DM


Input: Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli.

APC

adenomatous polyposis coli


Input: Germline mutation in APC at 5q21-22 results in the dominantly inherited syndrome adenomatous polyposis coli (APC).

adenomatous polyposis coli

APC


Input: Somatic mutation in this gene is an early event in colorectal tumourigenesis.


Input: Both types of mutation are concentrated in the 5 half of exon 15.


Input: We have used single strand conformational polymorphism (SSCP) and heteroduplex analysis to screen for variants in this region of the gene in a total of 45 affected but unrelated individuals.


Input: Eighteen patients had no family history of the disease; of these 11 were classified as having a severe phenotype, based on an early age at presentation or cancer development.

cancer


Input: This compared with 6 of 27 familial cases.


Input: A 5 bp deletion at codon 1309 reported to occur in 10-15% of unselected APC patients worldwide, was found in 5 of the 18 new mutation cases and 4 of the 27 familial cases all nine were classed as severe.

APC


Input: A further 3 new mutations and 1 familial mutation were located downstream from codon 1309, these individuals similarly being classed as phenotypically severe.


Input: In contrast all of the APC mutations detected in affected individuals with an average phenotype were located prior to codon 1309.

APC


Input: The frequent association of a severe phenotype with fresh mutation may explain the apparent conflict of a high mutation rate (20-30%) in a condition, which on average, is lethal at a post-reproductive age..


Input: Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly.

anterior segment malformations

Peters' anomaly


Input: Mutation or deletion of the PAX6 gene underlies many cases of aniridia.

aniridia


Input: Three lines of evidence now converge to implicate PAX6 more widely in anterior segment malformations including Peters anomaly.

anterior segment malformations

Peters anomaly


Input: First, a child with Peters anomaly is deleted for one copy of PAX6.

Peters anomaly


Input: Second, affected members of a family with dominantly inherited anterior segment malformations, including Peters anomaly are heterozygous for an R26G mutation in the PAX6 paired box.

anterior segment malformations

Peters anomaly


Input: Third, a proportion of Sey/+ Smalleye mice, heterozygous for a nonsense mutation in murine Pax-6, have an ocular phenotype resembling Peters anomaly.

Peters anomaly


Input: We therefore propose that a variety of anterior segment anomalies may be associated with PAX6 mutations..

anterior segment anomalies


Input: Huntington disease without CAG expansion: phenocopies or errors in assignment?

Huntington disease


Input: Huntington disease (HD) has been shown to be associated with an expanded CAG repeat within a novel gene on 4p16.

Huntington disease

HD


Input: 3 (IT15).


Input: A total of 30 of 1, 022 affected persons (2. 9% of our cohort) did not have an expanded CAG in the disease range.


Input: The reasons for not observing expansion in affected individuals are important for determining the sensitivity of using repeat length both for diagnosis of affected patients and for predictive testing programs and may have biological relevance for the understanding of the molecular mechanism underlying HD.

HD


Input: Here we show that the majority (18) of the individuals with normal sized alleles represent misdiagnosis, sample mix-up, or clerical error.


Input: The remaining 12 patients represent possible phenocopies for HD.

HD


Input: In at least four cases, family studies of these phenocopies excluded 4p16.


Input: 3 as the region responsible for the phenotype.


Input: Mutations in the HD gene that are other than CAG expansion have not been excluded for the remaining eight cases; however, in as many as seven of these persons, retrospective review of these patients clinical features identified characteristics not typical for HD.

HD

HD


Input: This study shows that on rare occasions mutations in other, as-yet-undefined genes can present with a clinical phenotype very similar to that of HD


Input: Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers.

advanced prostate cancers