Input: BRCA1 is secreted and exhibits properties of a granin.


Input: Germline mutations in BRCA1 are responsible for most cases of inherited breast and ovarian cancer.

inherited breast and ovarian cancer


Input: However, the function of the BRCA1 protein has remained elusive.


Input: We now show that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to the granin protein family.


Input: Interestingly, BRCA2 also includes a motif similar to the granin consensus at the C terminus of the protein.


Input: Both BRCA1 and the granins localize to secretory vesicles, are secreted by a regulated pathway, are post-translationally glycosylated and are responsive to hormones.


Input: As a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumour suppressor gene products..

tumour


Input: Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus.

Ovarian cancer


Input: Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1).

breast cancer

ovarian cancer


Input: The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals.


Input: The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15. 5) is one possible genetic modifier of cancer penetrance.

cancer


Input: Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers, including breast cancer (2-4).

cancers

breast cancer


Input: To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique.

hereditary breast and ovarian cancer


Input: The risk for ovarian cancer was 2.

ovarian cancer


Input: 11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0. 015).


Input: The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer (5).

hereditary ovarian cancer


Input: Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles.

breast cancer


Input: This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome


Input: A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG) n repeat.

myotonic dystrophy


Input: Myotonic dystrophy (DM) is associated with a (CTG) n trinucleotide repeat expansion in the 3-untranslated region of a protein kinase-encoding gene, DMPK, which maps to chromosome 19q13.

Myotonic dystrophy

DM


Input: Characterisation of the expression of this gene in patient tissues has thus far generated conflicting data on alterations in the steady state levels of DMPK mRNA, and on the final DMPK protein levels in the presence of the expansion.


Input: The DM region of chromosome 19 is gene rich, and it is possible that the repeat expansion may lead to dysfunction of a number of transcription units in the vicinity, perhaps as a consequence of chromatin disruption.

DM


Input: We have searched for genes associated with a CpG island at the 3 end of DMPK.


Input: Sequencing of this region shows that the island extends over 3.


Input: 5 kb and is interrupted by the (CTG) n repeat.


Input: Comparison of genomic sequences downstream (centromeric) of the repeat in human and mouse identified regions of significant homology.


Input: These correspond to exons of a gene predicted to encode a homeodomain protein.


Input: RT-PCR analysis shows that this gene, which we have called DM locus-associated homeodomain protein (DMAHP), is expressed in a number of human tissues, including skeletal muscle, heart and brain.

DM


Input: Germline mutations in the RB1 gene in patients with hereditary retinoblastoma.

hereditary retinoblastoma


Input: We have analyzed the 27 exons and the promoter region of the RB1 gene in familial or sporadic bilateral retinoblastoma by using single-strand conformation polymorphism analysis.

familial or sporadic bilateral retinoblastoma


Input: For improvement over previous studies, a new set of primers has been designed, which allow for amplification of the coding and splicing sequences only.


Input: The positioning of the polymerase chain reaction (PCR) primers was such that the resulting PCR products were of different sizes, which enabled us to analyze two different exons simultaneously and still distinguish between the banding profiles for both (biplex analysis).


Input: By using this approach, we were able to identify mutation in 22 new patients, but the overall efficiency of the procedure when we used a single-pass regimen was only 48%.


Input: The mutations were small insertions and deletions and point mutations in roughly equal proportions..


Input: Type II human complement C2 deficiency.

Type II human complement C2 deficiency


Input: Allele-specific amino acid substitutions (Ser189--> Phe; Gly444--> Arg) cause impaired C2 secretion.


Input: Type II complement protein C2 deficiency is characterized by a selective block in C2 secretion.

Type II complement protein C2 deficiency


Input: The Type II C2 null allele (C2Q0) is linked to two major histocompatibility haplotypes (MHC) that differ from the MHC of the more common Type I C2 deficiency.

Type I C2 deficiency


Input: To determine the molecular basis of Type II deficiency the two Type II C2Q0 genes were isolated and transfected separately into L-cells.

Type II deficiency


Input: Subsequent molecular biology, biosynthetic, and immunofluorescence studies demonstrated that C2 secretion is impaired in Type II C2 deficiency because of different missense mutations at highly conserved residues in each of the C2Q0 alleles.

Type II C2 deficiency


Input: One is in exon 5 (nucleotide C566--> T; Ser189--> Phe) of the C2Q0 gene linked to the MHC haplotype A11, B35, DRw1, BFS, C4A0B1.


Input: The other is in exon 11 (G1930--> A; Gly444--> Arg) of the C2Q0 gene linked to the MHC haplotype A2, B5, DRw4, BFS, C4A3B1.


Input: Each mutant C2 gene product is retained early in the secretory pathway.


Input: These mutants provide models for elucidating the C2 secretory pathway..


Input: Defective dimerization of von Willebrand factor subunits due to a Cys-> Arg mutation in type IID von Willebrand disease.

von Willebrand

type IID von Willebrand disease


Input: The same heterozygous T-> C transition at nt 8567 of the von Willebrand factor (vWF) transcript was found in two unrelated patients with type IID von Willebrand disease, with no other apparent abnormality.

von Willebrand

type IID von Willebrand disease


Input: In one family, both alleles were normal in the parents and one sister; thus, the mutation originated de novo in the proposita.


Input: The second patient also had asymptomatic parents who, however, were not available for study.


Input: The structural consequences of the identified mutation, resulting in the CyS2010-> Arg substitution, were evaluated by expression of the vWF carboxyl-terminal domain containing residues 1366-2050.


Input: Insect cells infected with recombinant baculovirus expressing normal vWF sequence secreted a disulfide linked dimeric molecule with an apparent molecular mass of 150 kDa before reduction, yielding a single band of 80 kDa after disulfide bond reduction.


Input: In contrast, cells expressing the mutant fragment secreted a monomeric molecule of apparent molecular mass of 80 kDa, which remained unchanged after reduction.


Input: We conclude that CyS2010 is essential for normal dimerization of vWF subunits through disulfide bonding of carboxyl-terminal domains and that a heterozygous mutation in the corresponding codon is responsible for defective multimer formation in type IID von Willebrand disease..

type IID von Willebrand disease


Input: Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization.

Wiskott-Aldrich syndrome


Input: The Rho family of GTPases control diverse biological processes, including cell morphology and mitogenesis.


Input: We have identified WASP, the protein that is defective in Wiskott-Aldrich syndrome (WAS), as a novel effector for CDC42Hs, but not for the other Rho family members, Rac and Rho.

Wiskott-Aldrich syndrome

WAS


Input: This interaction is dependent on the presence of the G protein-binding domain.


Input: Cellular expression of epitope-tagged WASP produces clusters of WASP that are highly enriched in polymerized actin.


Input: This clustering is not observed with a C-terminally deleted WASP and is inhibited by coexpression with dominant negative CDC42Hs-N17, but not with dominant negative forms of Rac or Rho.


Input: Thus, WASP provides a novel link between CDC42Hs and the actin cytoskeleton, which suggests a molecular mechanism for many of the cellular abnormalities in WAS.

WASP


Input: The WASP sequence contains two novel domains that are homologous to other proteins involved in action organization..


Input: X-linked adrenoleukodystrophy is a frequent cause of idiopathic Addison' s disease in young adult male patients.

X-linked adrenoleukodystrophy

Addison' s disease


Input: X-Linked adrenoleukodystrophy (ALD) is a genetic disease associated with demyelination of the central nervous system, adrenal insufficiency, and accumulation of very long chain fatty acids in tissue and body fluids.

X-Linked adrenoleukodystrophy

ALD

genetic disease

demyelination of the central nervous system

adrenal insufficiency


Input: ALD is due to mutation of a gene located in Xq28 that encodes a peroxisomal transporter protein of unknown function.

ALD


Input: The most common phenotype of ALD is the cerebral form (45%) that develops in boys between 5-12 yr.

ALD


Input: Adrenomyeloneuropathy (AMN) involves the spinal cord and peripheral nerves in young adults (35%).

Adrenomyeloneuropathy

AMN


Input: Adrenal insufficiency (Addisons disease) is frequently associated with AMN or cerebral ALD and may remain the only clinical expression of ALD (8% of cases).

Adrenal insufficiency

Addisons disease

AMN

cerebral ALD

ALD


Input: The prevalence of ALD among adults with Addisons disease remains unknown.

ALD

Addisons disease


Input: To evaluate this prevalence, we performed biochemical analysis of very long chain fatty acids in 14 male patients (age ranging from 12-45 yr at diagnosis) previously diagnosed as having primary idiopathic adrenocortical insufficiency.

adrenocortical insufficiency


Input: In 5 of 14 patients (35%), elevated plasma concentrations of very long chain fatty acids were detected.


Input: None of these patients had adrenocortical antibodies.


Input: By electrophysiological tests and magnetic resonance imaging it was determined that two patients had cerebral ALD, one had adrenomyeloneuropathy with cerebral involvement, and two had preclinical AMN.

cerebral ALD

adrenomyeloneuropathy

AMN


Input: Our data support the hypothesis that ALD is a frequent cause of idiopathic Addisons disease in children and adults..

ALD

Addisons disease


Input: Tumor suppression and apoptosis of human prostate carcinoma mediated by a genetic locus within human chromosome 10pter-q11.

Tumor

prostate carcinoma


Input: Prostate cancer is the second leading cause of male cancer deaths in the United States.

Prostate cancer

cancer


Input: Yet, despite a large international effort, little is known about the molecular mechanisms that underlie this devastating disease.


Input: Prostate secretory epithelial cells and androgen-dependent prostate carcinomas undergo apoptosis in response to androgen deprivation and, furthermore, most prostate carcinomas become androgen independent and refractory to further therapeutic manipulations during disease progression.

prostate carcinomas

prostate carcinomas


Input: Definition of the genetic events that trigger apoptosis in the prostate could provide important insights into critical pathways in normal development as well as elucidate the perturbations of those key pathways in neoplastic transformation.


Input: We report the functional definition of a novel genetic locus within human chromosome 10pter-q11 that mediates both in vivo tumor suppression and in vitro apoptosis of prostatic adenocarcinoma cells.

prostatic adenocarcinoma


Input: A defined fragment of human chromosome 10 was transferred via microcell fusion into a prostate adenocarcinoma cell line.

prostate adenocarcinoma


Input: Microcell hybrids containing only the region 10pter-q11 were suppressed for tumorigenicity following injection of microcell hybrids into nude mice.


Input: Furthermore, the complemented hybrids undergo programmed cell death in vitro via a mechanism that does not require nuclear localization of p53.


Input: These data functionally define a novel genetic locus, designated PAC1, for prostate adenocarcinoma 1, involved in tumor suppression of human prostate carcinoma and furthermore strongly suggest that the cell death pathway can be functionally restored in prostatic adenocarcinoma..

prostate carcinoma

prostatic adenocarcinoma


Input: Low incidence of BRCA2 mutations in breast carcinoma and other cancers.

breast carcinoma

cancers


Input: Inherited mutant alleles of familial tumour suppressor genes predispose individuals to particular types of cancer.

tumour

cancer


Input: In addition to an involvement in inherited susceptibility to cancer, these tumour suppressor genes are targets for somatic mutations in sporadic cancers of the same type found in the familial forms.

cancer

tumour

sporadic cancers


Input: An exception is BRCA1, which contributes to a significant fraction of familial breast and ovarian cancer, but undergoes mutation at very low rates in sporadic breast and ovarian cancers.

familial breast and ovarian cancer

sporadic breast and ovarian cancers


Input: This finding suggests that other genes may be the principal targets for somatic mutation in breast carcinoma.

breast carcinoma


Input: A second, recently identified familial breast cancer gene, BRCA2 (refs 5-8), accounts for a proportion of breast cancer roughly equal to BRCA1.

familial breast cancer

breast cancer


Input: Like BRCA1, BRCA2 behaves as a dominantly inherited tumour suppressor gene.

tumour


Input: Individuals who inherit one mutant allele are at increased risk for breast cancer, and the tumours they develop lose the wild-type allele by heterozygous deletion.

breast cancer

tumours


Input: The BRCA2 coding sequence is huge, composed of 26 exons that span 10, 443 bp.


Input: Here we investigate the rate of BRCA2 mutation in sporadic breast cancers and in a set of cell lines that represent twelve other tumour types.

sporadic breast cancers

tumour


Input: Surprisingly, mutations in BRCA2 are infrequent in cancers including breast carcinoma.

cancers

breast carcinoma


Input: However, a probable germline mutation in a pancreatic tumour cell line suggests a role for BRCA2 in susceptibility to pancreatic cancer..

pancreatic tumour

pancreatic cancer


Input: Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden.

hereditary breast and ovarian cancer


Input: Nine different germ-line mutations in the BRCA1 breast and ovarian cancer susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing.

breast and ovarian cancer


Input: All but one of the mutations are predicted to give rise to premature translation termination and include seven frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation.


Input: The remaining mutation is a missense mutation (Cys61Gly) in the zinc-binding motif.


Input: Four novel Swedish founding mutations were identified the nucleotide 2595 deletion A was found in five families, the C 1806 T nonsense mutation in three families, the 3166 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families.


Input: Analysis of the intragenic polymorphism D17S855 supports common origins of the mutations.


Input: Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype.

breast-ovarian cancer

ovarian cancer


Input: The set of 32 families in which no BRCA1 alterations were detected included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors.

breast-ovarian cancer

tumors


Input: Other tumor types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma.

tumor

prostatic, pancreas, skin, and lung cancer

malignant melanoma

oligodendroglioma

carcinosarcoma


Input: In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P <. 001).

ovarian cancer


Input: The present study confirms the involvement of BRCA1 in disease predisposition for a subset of hereditary breast cancer families often characterized by ovarian cancers.

hereditary breast cancer

ovarian cancers


Input: Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex heteroduplex analysis.


Input: UKCCCR Familial Ovarian Cancer Study Group.

Ovarian Cancer


Input: Germ-line mutations of the BRCA1 gene are responsible for a substantial proportion of families with multiple cases of early-onset breast and/or ovarian cancer.

breast and/or ovarian cancer


Input: Since the isolation of BRCA1 last year, > 65 distinct mutations scattered throughout the coding region have been detected, making analysis of the gene time consuming and technically challenging.


Input: We have developed a multiplex heteroduplex analysis that is designed to analyze one-quarter of the coding sequence in a single-step screening procedure and that will detect approximately 50% of all BRCA1 mutations so far reported in breast/ovarian cancer families.

breast/ovarian cancer


Input: We have used this technique to analyze BRCA1 in 162 families with a history of breast and/or ovarian cancer and identified 12 distinct mutations in 35 families..

breast and/or ovarian cancer


Input: A previously undescribed mutation within the tetramerisation domain of TP53 in a family with Li-Fraumeni syndrome.

Li-Fraumeni syndrome


Input: We report details of a family with classic Li-Fraumeni syndrome in which there is a mutation in codon 344 of the tumour suppressor gene TP53.

Li-Fraumeni syndrome

tumour


Input: Codon 344 is a key residue within the tetramerisation domain, and the amino acid substitution of a proline for a leucine is predicted to have profound implications for tetramerisation and potentially DNA binding.


Input: This is the first report of a mutation at this residue in either sporadic tumours or in the germline and the first report of a germline mutation within the tetramerisation domain.

sporadic tumours


Input: The family does not appear to be remarkable in the spectrum of tumours, and there is loss of the wild-type allele in a leiomyosarcoma from the proband.

tumours

leiomyosarcoma


Input: A cell line has been established from the tumour of the proband and cytogenetic and molecular studies carried out, providing an extensive analysis in this family..

tumour


Input: The spectrum of RB1 germ-line mutations in hereditary retinoblastoma.

hereditary retinoblastoma


Input: We have searched for germ-line RB1 mutations in 119 patients with hereditary retinoblastoma.

hereditary retinoblastoma


Input: Previous investigations by Southern blot hybridization and PCR fragment-length analysis had revealed mutations in 48 patients.


Input: Here we report on the analysis of the remaining 71 patients.


Input: By applying heteroduplex analysis, nonisotopic SSCP, and direct sequencing, we detected germ-line mutations resulting in premature termination codons or disruption of splice signals in 51 (72%) of the 71 patients.


Input: Four patients also showed rare sequence variants.


Input: No region of the RB1 gene was preferentially involved in single base substitutions.


Input: Recurrent transitions were observed at most of the 14 codons within the RB1.


Input: No mutation was observed in exons 25-27, although this region contains two CGA codons.


Input: This suggests that mutations within the 3-terminal region of the RB1 gene may not be oncogenic.


Input: When these data were combined with the results of our previous investigations, mutations were identified in a total of 99 (83%) of 119 patients.


Input: The spectrum comprises 15% large deletions, 26% small length alterations, and 42% base substitutions.


Input: No correlation between the location of frameshift or nonsense mutations and phenotypic features, including age at diagnosis, the number of tumor foci, and manifestation of nonocular tumors was observed..

tumor

nonocular tumors


Input: Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats.

Huntington disease

HD

HD


Input: Abnormal CAG expansions in the IT-15 gene are associated with Huntington disease (HD).

Huntington disease

HD


Input: In the diagnostic setting it is necessary to define the limits of the CAG size ranges on normal and HD-associated chromosomes.

HD


Input: Most large analyses that defined the limits of the normal and pathological size ranges employed PCR assays, which included the CAG repeats and a CCG repeat tract that was thought to be invariant.


Input: Many of these experiments found an overlap between the normal and disease size ranges.


Input: Subsequent findings that the CCG repeats vary by 8 trinucleotide lengths suggested that the limits of the normal and disease size ranges should be reevaluated with assays that exclude the CCG polymorphism.


Input: Since patients with between 30 and 40 repeats are rare, a consortium was assembled to collect such individuals.


Input: All 178 samples were reanalyzed in Cambridge by using assays specific for the CAG repeats.


Input: We have optimized methods for reliable sizing of CAG repeats and show cases that demonstrate the dangers of using PCR assays that include both the CAG and CCG polymorphisms.


Input: Seven HD patients had 36 repeats, which confirms that this allele is associated with disease.

HD


Input: Individuals without apparent symptoms or signs of HD were found at 36 repeats (aged 74, 78, 79, and 87 years), 37 repeats (aged 69 years), 38 repeats (aged 69 and 90 years), and 39 repeats (aged 67, 90, and 95 years).

HD


Input: The detailed case histories of an exceptional case from this series will be presented a 95-year-old man with 39 repeats who did not have classical features of HD.

HD


Input: The apparently healthy survival into old age of some individuals with 36-39 repeats suggests that the HD mutation may not always be fully penetrant..

HD


Input: Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease.

Canavan disease


Input: Canavan disease is inherited as an autosomal recessive trait that is caused by the deficiency of aspartoacylase (ASPA).

Canavan disease

deficiency of aspartoacylase


Input: The majority of patients with Canavan disease are from an Ashkenazi Jewish background.

Canavan disease


Input: Mutations in ASPA that lead to loss of enzymatic activity have been identified, and E285A and Y231X are the two predominant mutations that account for 97% of the mutant chromosomes in Ashkenazi Jewish patients.


Input: The current study was aimed at finding the molecular basis of Canavan disease in 25 independent patients of non-Jewish background.

Canavan disease


Input: Eight novel and three previously characterized mutations accounted for 80% (40/50) of mutant chromosomes.


Input: The A305E missense mutation accounted for 48% (24/50) of mutant chromosomes in patients of western European descent, while the two predominant Jewish mutations each accounted for a single mutant chromosome.


Input: The eight novel mutations identified included 1-and 4-bp deletions (32 deltaT and 876 deltaAGAA, respectively) and I16T, G27R, D114E, G123E, C152Y, and R168C missense mutations.


Input: The homozygous 32 deltaT deletion was identified in the only known patient of African-American origin with Canavan disease.

Canavan disease


Input: The heterozygosity for 876 deltaAGAA mutation was identified in three independent patients from England.


Input: Six single-base changes leading to missense mutations were identified in patients from Turkey (D114E, R168C), The Netherlands (I16T), Germany (G27R), Ireland (C152Y), and Canada (G123E).


Input: A PCR-based protocol is described that was used to introduce mutations in wild-type cDNA.


Input: In vitro expression of mutant cDNA clones demonstrated that all of these mutations led to a deficiency of ASPA and should therefore result in Canavan disease..

deficiency of ASPA

Canavan disease


Input: Identification and chromosomal localization of Atm, the mouse homolog of the ataxia-telangiectasia gene.

ataxia-telangiectasia


Input: Atm, the mouse homolog of the human ATM gene defective in ataxia-telangiectasia (A-T), has been identified.

ataxia-telangiectasia

A-T


Input: The entire coding sequence of the Atm transcript was cloned and found to contain an open reading frame encoding a protein of 3066 amino acids with 84% overall identity and 91% similarity to the human ATM protein.


Input: Variable levels of expression of Atm were observed in different tissues.


Input: Fluorescence in situ hybridization and linkage analysis located the Atm gene on mouse chromosome 9, band 9C, in a region homologous to the ATM region on human chromosome 11q22-q23..


Input: The mouse homolog of the Wiskott-Aldrich syndrome protein (WASP) gene is highly conserved and maps near the scurfy (sf) mutation on the X chromosome.

Wiskott-Aldrich syndrome


Input: The mouse WASP gene, the homolog of the gene mutated in Wiskott-Aldrich syndrome, has been isolated and sequenced. the predicted amino acid sequence is 86% identical to the human WASP sequence.

Wiskott-Aldrich syndrome


Input: A distinct feature of the mouse gene is an expanded polymorphic GGA trinucleotide repeat that codes for polyglycine and varies from 15 to 17 triplets in different Mus musculus strains.


Input: The genomic structure of the mouse WASP gene is expressed as an approximately 2.


Input: 4-kb mRNA in thymus and spleen.


Input: Chromosomal mapping in an interspecific M.


Input: Musculus/M. spretus backcross placed the Wasp locus near the centromere of the mouse X chromosome, inseparable from Gata1, Tcfe3, and scurfy (sf).


Input: This localization makes Wasp a candidate for involvement in scurfy, a T cell-mediated fatal lymphoreticular disease of mice that has previously been proposed as a mouse homolog of Wiskott-Aldrich syndrome.

fatal lymphoreticular disease

Wiskott-Aldrich syndrome


Input: Northern analysis of sf tissue samples indicated the presence of WASP mRNA in liver and skin, presumably as a consequence of lymphocytic infiltration, but non abnormalities in the amount or size of mRNA present.


Input: Colchicine in breast milk of patients with familial Mediterranean fever.

familial Mediterranean fever


Input: OBJECTIVE.


Input: To clarify whether colchicine is excreted in breast milk, and to compare its concentrations in the serum and breast milk of lactating women who have familial Mediterranean fever (FMF).

familial Mediterranean fever

FMF


Input: METHODS.


Input: Using a specific radioimmunoassay, we determined colchicine concentrations in the serum and breast milk of 4 patients at various time points, following oral administration of the drug.


Input: The study evaluated 4 patients with FMF who had been taking colchicine on a long-term basis.

FMF


Input: RESULTS.


Input: Colchicine was found to be excreted in breast milk.


Input: Its levels ranged between 1.


Input: 9 and 8.


Input: 6 ng/ml, which were similar to those found in the serum (parallel concentration time curves).


Input: However, there appeared to be a considerable variation in colchicine milk concentration among the different patients, which might be related to individual breast milk composition and, possibly, to other nutritional or metabolic factors.


Input: CONCLUSION.


Input: The extensive peripheral tissue binding and relatively low concentration of colchicine in breast milk suggests that the amount ingested by the infant is small.


Input: Furthermore, based on our clinical experience, nursing appears to be safe for lactating women with FMF who continue to take colchicine.

FMF


Input: Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice.

myotonic dystrophy

myopathy


Input: Myotonic dystrophy (DM) is commonly associated with CTG repeat expansions within the gene for DM-protein kinase (DMPK).

Myotonic dystrophy

DM


Input: The effect of altered expression levels of DMPK, which is ubiquitously expressed in all muscle cell lineages during development, was examined by disrupting the endogenous Dmpk gene and overexpressing a normal human DMPK transgene in mice.


Input: Nullizygous (-/-) mice showed only inconsistent and minor size changes in head and neck muscle fibres at older age, animals with the highest DMPK transgene expression showed hypertrophic cardiomyopathy and enhanced neonatal mortality.

hypertrophic cardiomyopathy


Input: However, both models lack other frequent DM symptoms including the fibre-type dependent atrophy, myotonia, cataract and male-infertility.

DM

atrophy

myotonia

cataract

male-infertility


Input: These results strengthen the contention that simple loss-or gain-of-expression of DMPK is not the only crucial requirement for development of the disease..


Input: Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy.

myotonic dystrophy

myopathy


Input: Myotonic dystrophy (DM) is an autosomal dominant disorder resulting from the expansion of a CTG repeat in the 3 untranslated region of a putative protein kinase (DMPK).

Myotonic dystrophy

DM

autosomal dominant disorder


Input: To elucidate the role of DMPK in DM pathogenesis we have developed Dmpk deficient (Dmpk-/-) mice.

DMPK

Dmpk deficient


Input: Dmpk-/-mice develop a late-onset, progressive skeletal myopathy that shares some pathological features with DM.

progressive skeletal myopathy

DM


Input: Muscles from mature mice show variation in fibre size, increased fibre degeneration and fibrosis.

fibre degeneration

fibrosis


Input: Adult Dmpk-/-mice show ultrastructural changes in muscle and a 50% decrease in force generation compared to young mice.


Input: Our results indicate that DMPK may be necessary for the maintenance of skeletal muscle structure and function and suggest that a decrease in DMPK levels may contribute to DM pathology..

DMPK


Input: The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.

tumor


Input: Mutations of the BRCA1 gone in humans are associated with predisposition to breast and ovarian cancers.

breast and ovarian cancers


Input: We show here that Brca1 +/-mice are normal and fertile and lack tumors by age eleven months.

tumors


Input: Homozygous Brca1 (5-6) mutant mice die before day 7.


Input: 5 of embryogenesis.


Input: Mutant embryos are poorly developed, with no evidence of mesoderm formation.


Input: The extraembryonic region is abnormal, but aggregation with wild-type tetraploid embryos does not rescue the lethality.


Input: In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity.


Input: The expression of cyclin-dependent kinase inhibitor p21 is dramatically increased in the mutant embryos.


Input: Buttressing these in vivo observations is the fact that mutant blastocyst growth is grossly impaired in vitro.


Input: Thus, the death of Brca1 (5-6) mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers.


Input: Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.

coronary heart disease


Input: Plasma high density lipoprotein (HDL) levels are strongly genetically determined and show a general inverse relationship with coronary heart disease (CHD).

coronary heart disease

CHD


Input: The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key participant in the reverse transport of cholesterol from the periphery to the liver.


Input: A high prevalence of two different CETP gene mutations (D442G, 5. 1%; intron 14G A, 0. 5%), was found in 3, 469 men of Japanese ancestry in the Honolulu Heart Program and mutations were associated with decreased CETP (-35%) and increased HDL chol levels (+ 10% for D442G).


Input: However, the overall prevalence of definite CHD was 21% in men with mutations and 16% in men without mutations.

CHD


Input: The relative risk (RR) of CHD was 1.

CHD


Input: 43 in men with mutations (P <. 05); after adjustment for CHD risk factors, the RR was 1.

CHD


Input: 55 (P =. 02); after additional adjustment for HDL levels, the RR was 1.


Input: 68 (P =. 008).


Input: Similar RR values were obtained for the D442G mutation alone.


Input: Increased CHD in men with mutations was primarily observed for HDL chol 41-60 mg/dl; for HDL chol > 60 mg/dl men with and without mutations had low CHD prevalence.

CHD

CHD


Input: Thus, genetic CETP deficiency appears to be an independent risk factor for CHD, primarily due to increased CHD prevalence in men with the D442G mutation and HDL cholesterol between 41 and 60 mg/dl.

CETP deficiency

CHD

CHD


Input: The findings suggest that both HDL concentration and the dynamics of cholesterol transport through HDL (i. e., reverse cholesterol transport) determine the anti-atherogenicity of the HDL fraction.


Input: Mapping the homolog of the human Rb1 gene to chromosome 14 of higher primates.


Input: The Rb1 gene has been implicated with retinoblastoma and is located on human Chromosome (Chr) 13q14.

retinoblastoma


Input: 2 2.


Input: A unique sequence human Rb1 cosmid DNA probe has been used to localize this region on apes Chr 14 by the FISH technique.


Input: The conservation of the Rb1 gene in higher primates at the corresponding equivalent chromosome locus (14q14) of the human may serve as a phylogenetic marker to further trace the evolutionary pathway of human descent.


Input: Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product.

Wiskott-Aldrich syndrome


Input: The Wiskott-Aldrich syndrome protein (WASP) gene was found to be mutated in patients presenting with WAS and in patients showing X-linked thrombocytopenia.

Wiskott-Aldrich syndrome

WASP

X-linked thrombocytopenia


Input: Mutation analysis in 19 families of German, Swiss and Turkish descent by single-strand conformation polymorphism and sequencing resulted in the detection of seven novel and 10 known mutations.


Input: A striking clustering of missense mutations in the first four exons contrasted with a random distribution of nonsense mutations.


Input: More than 85% of all known missense mutations were localized in the amino-terminal stretch of the WASP gene product; this region contained a mutational hot spot at codon 86.


Input: No genotype-phenotype correlation emerged after a comparison of the identified mutations with the resulting clinical picture for a classical WAS phenotype.

WAS


Input: A substitution at codon 86 resulted in an extremely variable expression of the disease in a large Swiss family.


Input: An extended homology search revealed a distant relationship of this stretch to the vasodilator-stimulated phosphoprotein (VASP), which is involved in the maintenance of cyto-architecture by interacting with actin-like filaments..


Input: Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities.

eye abnormalities


Input: Aniridia in man and Small eye in mice are semidominant developmental disorders caused by mutations within the paired box gene PAX6.

Aniridia

semidominant developmental disorders


Input: Whereas heterozygotes suffer from iris hypoplasia, homozygous mice lack eyes and nasal cavities and exhibit brain abnormalities.

iris hypoplasia

brain abnormalities


Input: To investigate the role of gene dosage in more detail, we have generated yeast artificial chromosome transgenic mice carrying the human PAX6 locus.


Input: When crossed onto the Small eye background, the transgene rescues the mutant phenotype.


Input: Strikingly, mice carrying multiple copies on a wild-type background show specific developmental abnormalities of the eye, but not of other tissues expressing the gene.

developmental abnormalities of the eye


Input: Thus, at least five different eye phenotypes are associated with changes in PAX6 expression.


Input: We provide evidence that not only reduced, but also increased levels of transcriptional regulators can cause developmental defects..

developmental defects


Input: Heterodimer formation and activity in the human enzyme galactose-1-phosphate uridylyltransferase.


Input: One of the fundamental questions concerning expression and function of dimeric enzymes involves the impact of naturally occurring mutations on subunit assembly and heterodimer activity.


Input: This question is of particular interest for the human enzyme galactose-l-phosphate uridylyl-transferase (GALT), impairment of which results in the inherited metabolic disorder galactosemia, because many if not most patients studied to date are compound heterozygotes rather than true molecular homozygotes.

inherited metabolic disorder galactosemia


Input: Furthermore, the broad range of phenotypic severity observed in these patients raises the possibility that allelic combination, not just allelic constitution, may play some role in determining outcome.


Input: In the work described herein, we have selected two distinct naturally occurring null mutations of GALT, Q188R and R333W, and asked the questions (i) what are the impacts of these mutations on subunit assembly, and (ii) if heterodimers do form, are they active?


Input: To answer these questions, we have established a yeast system for the coexpression of epitope-tagged alleles of human GALT and investigated both the extent of specific GALT subunit interactions and the activity of defined heterodimer pools.


Input: We have found that both homodimers and heterodimers do form involving each of the mutant subunits tested and that both heterodimer pools retain substantial enzymatic activity.


Input: These results are significant not only in terms of their implications for furthering our understanding of galactosemia and GALT holoenzyme structure-function relationships but also because the system described may serve as a model for similar studies of other complexes composed of multiple subunits..

galactosemia


Input: Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract.


Input: Apoptosis has recently been recognized as a mode of cell death in Huntington disease (HD).

Huntington disease

HD


Input: Apopain, a human counterpart of the nematode cysteine protease death-gene product, CED-3, has a key role in proteolytic events leading to apoptosis.


Input: Here we show that apoptotic extracts and apopain itself specifically cleave the HD gene product, huntingtin.

HD


Input: The rate of cleavage increases with the length of the huntingtin polyglutamine tract, providing an explanation for the gain-of-function associated with CAG expansion.


Input: Our results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis..

HD

disorder of inappropriate apoptosis


Input: The 5' end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21.


Input: To begin to address the hypothesis that abnormal regulation of the breast/ovarian cancer susceptibility gene BRCA1 is a critical step in sporadic breast/ovarian tumorigenesis, we have determined the detailed structure of the BRCA1 genomic region.

breast/ovarian cancer


Input: We show that this region of the genome contains a tandem duplication of approximately 30 kilobases, which results in two copies of BRCA1 exons 1 and 2, of exons 1 and 3 of the adjacent 1A1-3B gene and of the previously reported 295 base pair intergenic region.


Input: Sequence analysis of the duplicated exons of BRCA1 and 1A1-3B and flanking genomic DNA reveals maintenance of the intron-exon structure and a high degree of nucleotide sequence identity, suggesting that these are non-processed pseudogenes and that the duplication is a recent event in evolutionary terms.


Input: We also show that a processed pseudogene of the acidic ribosomal phosphoprotein P1 (ARPP1) is inserted directly upstream of pseudo-BRCA1 exon 1A.


Input: We believe that these findings could not only confound BRCA1 mutation analysis, but could have implications for the normal and abnormal regulation of BRCA1 transcription, translation and function..


Input: Deletion of small nuclear ribonucleoprotein polypeptide N (SNRPN) in Prader-Willi syndrome detected by fluorescence in situ hybridization: two sibs with the typical phenotype without a cytogenetic deletion in chromosome 15q.

Prader-Willi syndrome


Input: The small nuclear ribonucleoprotein polypeptide N (SNRPN) gene is regarded as one of the candidates for Prader-Willi syndrome (PWS).

Prader-Willi syndrome

PWS


Input: We describe two sibs with typical PWS presenting deletion of SNRPN detected by fluorescence in situ hybridization (FISH).

PWS


Input: Neither a cytogenetically detectable 15q12 deletion nor a deletion for the D15S11, D15S10, and GABRB3 cosmid probes were found in either patient.


Input: This implies a smaller deletion limited to the PWS critical region.

PWS


Input: FISH with a SNRPN probe will permit analysis of PWS patients with limited deletions not detectable with other probes..

PWS


Input: Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis.

von Hippel-Lindau disease tumour


Input: The von Hippel-Lindau (VHL) disease product is thought to down-regulate transcription by antagonizing elongin-enhanced transcriptional elongation.

von Hippel-Lindau (VHL) disease


Input: Germline VHL gene mutations predispose to the development of retinal, cerebellar and spinal haemangioblastomas, renal cell carcinoma and phaeochromocytoma.

VHL

retinal, cerebellar and spinal haemangioblastomas

renal cell carcinoma

phaeochromocytoma


Input: In addition, somatic Inactivation of the VHL gene is frequent in sporadic renal cell carcinoma and haemangioblastoma.

VHL

sporadic renal cell carcinoma

haemangioblastoma


Input: Regulation of transcript elongation is an important control mechanism for gene expression and the VHL gene might modify the expression of proto-oncogenes and growth suppressor genes during embryogenesis.

VHL


Input: We therefore investigated the expression of VHL mRNA during human embryogenesis by in situ hybridization studies at 4, 6 and 10 weeks post conception.

VHL


Input: Although VHL mRNA was expressed in all three germ layers, strong expression was noted in the central nervous system, kidneys, testis and lung.

VHL


Input: Within the kidney, VHL mRNA was differentially expressed within renal tubules suggesting that the VHL gene product may have a specific role in kidney development.

VHL

VHL


Input: Two alternatively spliced VHL mRNAs characterized by inclusion (isoform I) or exclusion (isoform II) of exon 2 are transcribed in adult tissues.

VHL


Input: To investigate if the two isoforms are differentially expressed during embryogenesis, VHL mRNA was reverse transcribed from 13 fetal tissues (8-10 weeks gestation).

VHL


Input: The quantitative distribution of VHL mRNA within fetal tissues reflected that seen by in situ hybridization and the ratio of the two VHL isoforms was similar between tissues.

VHL

VHL


Input: Although the genes regulated by the VHL gene product have not yet been identified, our findings are compatible with the hypothesis that VHL-mediated control of transcriptional elongation may have a role in normal human development..

VHL

VHL


Input: Genetic heterogeneity in hereditary breast cancer: role of BRCA1 and BRCA2.

hereditary breast cancer


Input: The common hereditary forms of breast cancer have been largely attributed to the inheritance of mutations in the BRCA1 or BRCA2 genes.

breast cancer


Input: However, it is not yet clear what proportion of hereditary breast cancer is explained by BRCA1 and BRCA2 or by some other unidentified susceptibility gene (s).

hereditary breast cancer


Input: We describe the proportion of hereditary breast cancer explained by BRCA1 or BRCA2 in a sample of North American hereditary breast cancers and assess the evidence for additional susceptibility genes that may confer hereditary breast or ovarian cancer risk.

hereditary breast cancer

hereditary breast cancers

hereditary breast or ovarian cancer


Input: Twenty-three families were identified through two high-risk breast cancer research programs.

breast cancer


Input: Genetic analysis was undertaken to establish linkage between the breast or ovarian cancer cases and markers on chromosomes 17q (BRCA1) and 13q (BRCA2).

breast or ovarian cancer


Input: Mutation analysis in the BRCA1 and BRCA2 genes was also undertaken in all families.


Input: The pattern of hereditary cancer in 14 (61%) of the 23 families studied was attributed to BRCA1 by a combination of linkage and mutation analyses.

hereditary cancer


Input: No families were attributed to BRCA2.


Input: Five families (22%) provided evidence against linkage to both BRCA1 and BRCA2.


Input: No BRCA1 or BRCA2 mutations were detected in these five families.


Input: The BRCA1 or BRCA2 status of four families (17%) could not be determined.


Input: BRCA1 and BRCA2 probably explain the majority of hereditary breast cancer that exists in the North American population.

hereditary breast cancer


Input: However, one or more additional genes may yet be found that explain some proportion of hereditary breast cancer..

hereditary breast cancer


Input: An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease).

inherited human disorder

fish-eye disease


Input: The first step in the splicing of an intron from nuclear precursors of mRNA results in the formation of a lariat structure.


Input: A distinct intronic nucleotide sequence, known as the branchpoint region, plays a central role in this process.


Input: We here describe a point mutation in such a sequence.


Input: Three sisters were shown to suffer from fish-eye disease (FED), a disorder which is caused by mutations in the gene coding for lecithin cholesterol acyltransferase (LCAT).

fish-eye disease

FED


Input: Sequencing of the LCAT gene of all three probands revealed compound heterozygosity for a missense mutation in exon 4 which is reported to underlie the FED phenotype, and a point mutation located in intron 4 (IVS4 T-22C).

FED


Input: By performing in vitro expression of LCAT minigenes and reverse transcriptase PCR on mRNA isolated from leukocytes of the patient, this gene defect was shown to cause a null allele as the result of complete intron retention.


Input: In conclusion, we demonstrated that a point mutation in a lariat branchpoint consensus sequence causes a null allele in a patient with FED.

FED


Input: In addition, our finding illustrates the importance of this sequence for normal human mRNA processing.


Input: Finally, this report provides a widely applicable strategy which ensures fast and effective screening for intronic defects that underlie differential gene expression..


Input: Mutations associated with variant phenotypes in ataxia-telangiectasia.

ataxia-telangiectasia


Input: We have identified 14 families with ataxia-telangiectasia (A-T) in which mutation of the ATM gene is associated with a less severe clinical and cellular phenotype (approximately 10%-15% of A-T families identified in the United Kingdom).

ataxia-telangiectasia

A-T

A-T


Input: In 10 of these families, all the homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice-donor site.


Input: The second A-T allele has a different mutation in each patient.

A-T


Input: We show that the less severe phenotype in these patients is caused by some degree of normal splicing, which occurs as an alternative product from the insertion-containing allele.


Input: The level of the 137-bp PCR product containing the insertion was lowest in two patients who showed a later onset of cerebellar ataxia.

cerebellar ataxia


Input: A further four families who do not have this insertion have been identified.


Input: Mutations detected in two of four of these are missense mutations, normally rare in A-T patients.

A-T


Input: The demonstration of mutations giving rise to a slightly milder phenotype in A-T raises the interesting question of what range of phenotypes might occur in individuals in whom both mutations are milder.

A-T


Input: One possibility might be that individuals who are compound heterozygotes for ATM mutations are more common than we realize..


Input: Mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinomas.

non-papillary renal cell carcinomas


Input: To define the possible role of the VHL gene in the development of sporadic renal cell carcinomas, 91 different parenchymal tumours of the kidney have been investigated for mutation of the VHL gene by single strand conformation polymorphism (SSCP) and/or heteroduplex (HD) techniques.

VHL

sporadic renal cell carcinomas

parenchymal tumours of the kidney

VHL


Input: Chromosome 3p deletion was detected in 98 per cent of non-papillary renal cell carcinomas and in 25 per cent of chromophobe renal cell carcinomas.

non-papillary renal cell carcinomas

renal cell carcinomas


Input: In 22 of the 43 non-papillary renal cell carcinomas, abnormally migrating DNA bands were detected by SSCP and/or HD analysis.

non-papillary renal cell carcinomas


Input: No mobility shift was seen in any of the 23 chromophobe renal cell carcinomas.

renal cell carcinomas


Input: In addition, 15 papillary renal cell tumours and ten renal oncocytomas, which are characterized by genetic changes other than loss of chromosome 3p sequences, were analysed for mutation of the VHL gene.

papillary renal cell tumours

renal oncocytomas

VHL


Input: None of these tumours showed abnormal migration patterns.

tumours


Input: The results indicate that mutation of the VHL gene is associated exclusively with the development of non-papillary renal cell carcinoma..

VHL

non-papillary renal cell carcinoma


Input: The Emery-Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein.

Emery-Dreifuss muscular dystrophy


Input: A large fragment of emerin cDNA was prepared by PCR and expressed as a recombinant protein in Escherichia coli.


Input: Using this as immunogen, we prepared a panel of 12 monoclonal antibodies which recognise at least four different epitopes on emerin in order to ensure that emerin can be distinguished from non-specific cross-reacting proteins.


Input: All the mAbs recognised a 34 kDa protein in all tissues tested, though minor emerin-related bands were also detected in some tissues.


Input: Immunofluorescence microscopy showed that emerin is located at the nuclear rim in all tissues examined.


Input: A muscle biopsy from an Emery-Dreifuss muscular dystrophy (EMDM) patient showed complete absence of emerin by both Western blotting and immunohistochemistry, suggesting a simple diagnostic antibody test for EDMD families.

Emery-Dreifuss muscular dystrophy

EMDM

EDMD


Input: Biochemical fractionation of brain and liver tissues showed that emerin was present in nuclei purified by centrifugation through 65% sucrose and was absent from soluble fractions (post-100, 000 g).


Input: From these results, together with sequence and structural homologies between emerin, thymopoietins and the nuclear lamina-associated protein, LAP2, we suggest that emerin will prove to be one member of a family of inner nuclear membrane proteins..


Input: Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair.

endometrial cancer


Input: Many human tumours have length alterations in repetitive sequence elements.

tumours


Input: Although this microsatellite instability has been attributed to mutations in four DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) kindreds, many sporadic tumours exhibit instability but no detectable mutations in these genes.

microsatellite instability

hereditary nonpolyposis colorectal cancer

HNPCC

sporadic tumours


Input: It is therefore of interest to identify other genes that contribute to this instability.


Input: In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability.


Input: Thus, we screened 16 endometrial carcinomas with microsatellite instability for alterations in FEN1 (the human homolog of RTH) and in MSH3 (refs 12-14).

endometrial carcinomas


Input: Although we found no FEN1 mutations, a frameshift mutation in MSH3 was observed in an endometrial carcinoma and in an endometrial carcinoma cell line.

endometrial carcinoma

endometrial carcinoma


Input: Extracts of the cell line were deficient in repair of DNA substrates containing mismatches or extra nucleotides.


Input: Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stability of some but not all microsatellites.


Input: Extracts of these cells repaired certain substrates containing extra nucleotides, but were deficient in repair of those containing mismatches or other extra nucleotides.


Input: A subsequent search revealed a second gene mutation in HHUA cells, a missense mutation in the MSH6 gene.


Input: Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair..

tumours


Input: Comparative genome mapping of the ataxia-telangiectasia region in mouse, rat, and Syrian hamster.

ataxia-telangiectasia


Input: Chromosomal locations of the Atm (ataxia-telangiectasia (AT)-mutated) and Acat1 (mitochondrial acetoacetyl-CoA thiolase) genes in mouse, rat, and Syrian hamster were determined by direct R-banding FISH.

ataxia-telangiectasia

AT


Input: Both genes were colocalized to the C-D band of mouse chromosome 9, the proximal end of q24.


Input: 1 of rat chromosome 8, and qa4-qa5 of Syrian hamster chromosome 12.


Input: The regions in the mouse and rat were homologous to human chromosome 11q.


Input: Fine genetic linkage mapping of the mouse AT region was performed using the interspecific backcross mice.

AT


Input: Atm, Acat1, and Npat, which is a new gene isolated from the AT region, and 12 flanking microsatellite DNA markers were examined.


Input: No recombinations were found among the Atm, Npat, Acat1, and D9Mit6 loci, and these loci were mapped 2.


Input: 0 cM distal to D9Mit99 and 1.


Input: 3 cM proximal to D9Mit102.


Input: Comparison of the linkage map of mouse chromosome 9 (MMU9) and that of human chromosome 11 (HSA11) indicates that there is a chromosomal rearrangement due to an inversion between Ets1 and Atm-Npat-Acat1 and that the inversion of MMU9 originated from the chromosomal breakage at the boundary between Gria4 and Atm-Npat-Acat1 on HSA11.


Input: This type of inversion appeared to be conserved in the three rodent species, mouse, rat, and Syrian hamster, using additional comparative mapping data with the Rck gene


Input: An animal model for Norrie disease (ND): gene targeting of the mouse ND gene.

Norrie disease

ND

ND


Input: In order to elucidate the cellular and molecular processes which are involved in Norrie disease (ND), we have used gene targeting technology to generate ND mutant mice.

Norrie disease

ND

ND


Input: The murine homologue of the ND gene was cloned and shown to encode a polypeptide that shares 94% of the amino acid sequence with its human counterpart.

ND


Input: RNA in situ hybridization revealed expression in retina, brain and the olfactory bulb and epithelium of 2 week old mice.


Input: Hemizygous mice carrying a replacement mutation in exon 2 of the ND gene developed retrolental structures in the vitreous body and showed an overall disorganization of the retinal ganglion cell layer.

ND


Input: The outer plexiform layer disappears occasionally, resulting in a juxtaposed inner and outer nuclear layer.


Input: At the same regions, the outer segments of the photoreceptor cell layer are no longer present.


Input: These ocular findings are consistent with observations in ND patients and the generated mouse line provides a faithful model for study of early pathogenic events in this severe X-linked recessive neurological disorder..

ND

X-linked recessive neurological disorder


Input: The hybrid PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma transforms fibroblasts in culture.

alveolar rhabdomyosarcoma


Input: Pediatric alveolar rhabdomyosarcoma is characterized by a chromosomal translocation that fuses parts of the PAX3 and FKHR genes.

Pediatric alveolar rhabdomyosarcoma


Input: PAX3 codes for a transcriptional regulator that controls developmental programs, and FKHR codes for a forkhead-winged helix protein, also a likely transcription factor.


Input: The PAX3-FKHR fusion product retains the DNA binding domains of the PAX3 protein and the putative activator domain of the FKHR protein.


Input: The PAX3-FKHR protein has been shown to function as a transcriptional activator.


Input: Using the RCAS retroviral vector, we have introduced the PAX3-FKHR gene into chicken embryo fibroblasts.


Input: Expression of the PAX3-FKHR protein in these cells leads to transformation the cells become enlarged, grow tightly packed and in multiple layers, and acquire the ability for anchorage-independent growth.


Input: This cellular transformation in vitro will facilitate studies on the mechanism of PAX3-FKHR-induced oncogenesis..


Input: Somatic-cell selection is a major determinant of the blood-cell phenotype in heterozygotes for glucose-6-phosphate dehydrogenase mutations causing severe enzyme deficiency.

enzyme deficiency


Input: X-chromosome inactivation in mammals is regarded as an essentially random process, but the resulting somatic-cell mosaicism creates the opportunity for cell selection.


Input: In most people with red-blood-cell glucose-6-phosphate dehydrogenase (G6PD) deficiency, the enzyme-deficient phenotype is only moderately expressed in nucleated cells.

glucose-6-phosphate dehydrogenase (G6PD) deficiency


Input: However, in a small subset of hemizygous males who suffer from chronic nonspherocytic hemolytic anemia, the underlying mutations (designated class I) cause more-severe G6PD deficiency, and this might provide an opportunity for selection in heterozygous females during development.

chronic nonspherocytic hemolytic anemia

G6PD deficiency


Input: In order to test this possibility we have analyzed four heterozygotes for class I G6PD mutations two with G6PD Portici (1178G--> A) and two with G6PD Bari (1187C--> T).


Input: We found that in fractionated blood cell types (including erythroid, myeloid, and lymphoid cell lineages) there was a significant excess of G6PD-normal cells.


Input: The significant concordance that we have observed in the degree of imbalance in the different blood-cell lineages indicates that a selective mechanism is likely to operate at the level of pluripotent blood stem cells.


Input: Thus, it appears that severe G6PD deficiency affects adversely the proliferation or the survival of nucleated blood cells and that this phenotypic characteristic is critical during hematopoiesis..

G6PD deficiency


Input: Analysis of meiotic segregation, using single-sperm typing: meiotic drive at the myotonic dystrophy locus.

myotonic dystrophy


Input: Meiotic drive at the myotonic dystrophy (DM) locus has recently been suggested as being responsible for maintaining the frequency, in the human population, of DM chromosomes capable of expansion to the disease state.

myotonic dystrophy

DM

DM


Input: In order to test this hypothesis, we have studied samples of single sperm from three individuals heterozygous at the DM locus, each with one allele larger and one allele smaller than 19 CTG repeats.

DM


Input: To guard against the possible problem of differential PCR amplification rates based on the lengths of the alleles, the sperm were also typed at another closely linked marker whose allele size was unrelated to the allele size at the DM locus.

DM


Input: Using statistical models specifically designed to study single-sperm segregation data, we find no evidence of meiotic segregation distortion.


Input: The upper limit of the two-sided 95% confidence interval for the estimate of the common segregation probability for the three donors is at or below.


Input: 515 for all models considered, and no statistically significant difference from.


Input: 5 is detected in any of the models.


Input: This suggests that any greater amount of segregation distortion at the myotonic dystrophy locus must result from events following sperm ejaculation.

myotonic dystrophy


Input: LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family.

lipomas


Input: A major cytogenetic subgroup of lipomas is characterized by recurrent chromosome aberrations, mainly translocations, that involve chromosome segment 12q13-q15.

lipomas


Input: Multiple chromosomes have been found as the translocation partners of chromosome 12 but 3q27-q28 is preferentially involved.


Input: In previous studies, it has been shown that the high mobility group (HMG) protein gene HMGIC at 12q15 is consistently rearranged as a consequence of these translocations.


Input: Here, we report the identification and characterization of the chromosome 3-derived translocation partner gene, which we have designated LPP (lipoma preferred partner gene).

lipoma


Input: Using 3-RACE analysis of HMGIC fusion transcripts in lipoma cell line Li-501/SV40, ectopic genetic sequences were obtained, which by CASH (chromosome assignment using somatic cell hybrids) and FISH (fluorescence in situ hybridization) analysis were found to originate from chromosome segment 3q27-q28.

lipoma


Input: In Northern blot analysis, an mRNA of over 10 kb was detected by these ectopic sequences in a variety of human tissues but not in brain and peripheral blood leukocytes.


Input: Upon partial cDNA cloning, features of the genetic organization of LPP were established.


Input: The gene was found to span a genomic region of over 400 kb.


Input: Nucleotide sequence analysis of a composite cDNA of LPP revealed an open reading frame of 1836 nucleotides encoding a proline-rich protein containing a leucine-zipper motif in its amino-terminal region and three LIM domains in its carboxy-terminal region.


Input: The LPP-encoded protein should be classified as a novel member of the group 3 proteins of the LIM protein gene family.


Input: Using reverse transcriptase combined with polymerase chain reactions in the analysis of a number of lipoma cell lines and primary lipomas, it appeared that LPP is frequently rearranged also in cases without a cytogenetically detectable involvement of 3q27-q28.

lipoma

primary lipomas


Input: Two alternative HMGIC/LPP hybrid transcripts have been detected; the difference between them is mainly the presence of either two or three LIM domains in the predicted HMGI-C/LPP fusion proteins..


Input: Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the human Huntington disease transcript.

Huntington disease


Input: The mutation underlying Huntington disease (HD) is CAG expansion in the first exon of the HD gene.

Huntington disease

HD

HD


Input: In order to investigate the role of CAG expansion in the pathogenesis of HD, we have produced transgenic mice containing the full length human HD cDNA with 44 CAG repeats.

HD

HD


Input: By 1 year, these mice have no behavioral abnormalities and morphometric analysis at 6 (one animal) and 9 (two animals) months age revealed no changes.

behavioral abnormalities


Input: Despite high levels of mRNA expression, there was no evidence of the HD gene product in any of these transgenic mice.

HD


Input: In vitro transfection studies indicated that the inclusion of 120 bp of the 5 UTR in the cDNA construct and the presence of a frameshift mutation at nucleotide 2349 prevented expression of the HD cDNA.

HD


Input: These findings suggest that the pathogenesis of HD is not mediated through DNA-protein interaction and that presence of the RNA transcript with an expanded CAG repeat is insufficient to cause the disease.

HD


Input: Rather, translation of the CAG is crucial for the pathogenesis of HD.

HD


Input: In contrast to that seen in humans, the CAG repeat in these mice was remarkably stable in 97 meioses.


Input: This suggests that genomic sequences may play a critical role in influencing repeat instability..


Input: FISH studies in a patient with sporadic aniridia and t (7; 11) (q31. 2; p13).

sporadic aniridia


Input: A 2 year old female presenting with bilateral sporadic aniridia was found to have an apparently balanced reciprocal translocation with a chromosome 11 breakpoint within band p13.

bilateral sporadic aniridia


Input: Fluorescence in situ hybridisation (FISH) studies with distal 11p13 specific cosmids showed that the chromosome 11 breakpoint lay between the aniridia (PAX6) locus and a region approximately 100 kb distal to PAX6 defined by the cosmid FO2121.

aniridia


Input: Although this patient did not have a detectable deletion within PAX6, her aniridia may have resulted from a disruption of the distal chromatin domain containing either enhancers or regulators for PAX6.

aniridia


Input: This case may therefore be another example of aniridia caused by a position effect as recently described in two familial aniridia patients in which the phenotype cosegregated with chromosome abnormalities with 11p13 breakpoints..

aniridia

familial aniridia

chromosome abnormalities


Input: Muscle expression of glucose-6-phosphate dehydrogenase deficiency in different variants.

glucose-6-phosphate dehydrogenase deficiency


Input: Muscle expression of G6PD deficiency has been investigated in Mediterranean, Seattle-like and A-variants.

G6PD deficiency


Input: G6PD activity was detected in samples obtained from biopsies on the quadriceps muscle of seven males and one female.


Input: The type of genetic variant was determined by molecular analysis of DNA, extracted from blood samples.


Input: All variants showed the enzyme defect in muscle.


Input: A statistically significant relationship was found in the activity of G6PD between erythrocytes and muscle of the male subjects (r = 0. 968; p = 0. 00008).


Input: The equation for the best fit line was Y = 0.


Input: 390X + 0.


Input: 198 198.


Input: The results suggest that, for a given variant, the extent of the enzyme defect in muscle may be determined, using this equation, from the G6PD activity of erythrocytes


Input: Gene therapy for phenylketonuria.

phenylketonuria


Input: Classical phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH).

phenylketonuria

PKU

autosomal recessive disorder

deficiency of hepatic phenylalanine hydroxylase


Input: Limitations of the current dietary treatment for PKU have led to the development of potential treatments based on somatic gene transfer.

PKU


Input: Three different vector systems have been examined.


Input: Vectors derived from a recombinant retrovirus or a DNA/protein complex can efficiently transduce the PAH cDNA into PAH-deficient hepatocytes in vitro, but the application of these vector systems is presently limited by their low transduction efficiency in vivo.

PAH-deficient


Input: In contrast, a vector derived from a recombinant adenovirus can restore 10%-80% of normal hepatic PAH activity into PAH-deficient mice, which completely normalizes serum phenylalanine levels.

PAH-deficient


Input: This treatment is transient and cannot be effectively re-administered due to the presence of neutralizing antibodies directed against the recombinant adenoviral vector.


Input: However, these findings suggest that PKU can be completely corrected by somatic gene therapy, and provide some direction for the future development of adenoviral vectors..

PKU


Input: Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4).


Input: The human neuronal nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) is located in the candidate region for three different phenotypes benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and low-voltage EEG.

benign familial neonatal convulsions

autosomal dominant nocturnal frontal lobe epilepsy


Input: Recently, a missense mutation in transmembrane domain 2 of CHRNA4 was found to be associated with autosomal dominant nocturnal frontal lobe epilepsy in one extended pedigree.

autosomal dominant nocturnal frontal lobe epilepsy


Input: We have determined the genomic organization of CHRNA4, which consists of six exons distributed over approximately 17 kb of genomic DNA.


Input: The nucleotide sequence obtained from the genomic regions adjacent to the exon boundaries enabled us to develop a set of primer pairs for PCR amplification of the complete coding region.


Input: The sequence analysis provides the basis for a comprehensive mutation screening of CHRNA4 in the above-mentioned phenotypes and possibly in other types of idiopathic epilepsies..

idiopathic epilepsies


Input: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.


Input: BRCA1 and BRCA2 are the two major identified causes of inherited breast cancer, with mutations in either gene conferring up to 80-90% lifetime risk of breast cancer in carrier females.

inherited breast cancer

breast cancer


Input: Mutations in BRCA1 account for approximately 45% of familial breast cancer and 90% of inherited breast/ovarian cancer, whereas mutations in BRCA2 account for a comparable percentage of inherited breast cancer cases.

familial breast cancer

inherited breast/ovarian cancer

inherited breast cancer


Input: Over 85 distinct BRCA1 mutations and a growing list of BRCA2 mutations have been identified, with the majority resulting in protein truncation.


Input: A specific BRCA1 mutation, 185delAG, has a reported increased carrier frequency of approximately 0.


Input: 9% in the Ashkenazi Jewish population, but is also found in rare non-Jewish patients with a different haplotype.


Input: The 6174delT mutation in BRCA2 was recently identified as a frequent mutation in 8 out of 107 Ashkenazi Jewish women diagnosed with breast cancer by age 50 (ref. 8), as well as in three Ashkenazi male breast cancer patients.

breast cancer

male breast cancer


Input: We have conducted a large-scale population study to investigate the prevalence of specific BRCA1 and BRCA2 mutations in Ashkenazi Jewish individuals who were unselected for breast cancer.

breast cancer


Input: BRCA1 mutation screening on approximately 3, 000 Ashkenazi Jewish samples determined a carrier frequency of 1.


Input: 09% for the 185delAG mutation and 0.


Input: 13% for the 5382insC mutation.


Input: BRCA2 analysis on 3, 085 individuals from the same population showed a carrier frequency of 1.


Input: 52% for the 6174delT mutation.


Input: This expanded population-based study confirms that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constitute the two most frequent mutation alleles predisposing to hereditary breast cancer among the Ashkenazim, and suggests a relatively lower penetrance for the 6174delT mutation in BRCA2

hereditary breast cancer


Input: Dual roles of ATM in the cellular response to radiation and in cell growth control.


Input: The gene mutated in ataxia-telangiectasia (AT) patients, denoted ATM, encodes a putative protein or lipid kinase.

ataxia-telangiectasia

AT


Input: To elucidate the functions of ATM, we disrupted the mouse ATM gene through homologous recombination in mice.


Input: Consistent with cellular defects of AT patients, the ATM-/-cells are hypersensitive to gamma-irradiation and defective in cell-cycle arrest following radiation, correlating with a defective up-regulation of p53.

AT


Input: In addition, ATM-/-mouse thymocytes are more resistant to apoptosis induced by gamma-irradiation than normal thymocytes.


Input: ATM-/-fibroblasts are inefficient in G1 to S-phase progression following serum stimulation and senesce after only a few passages in culture.


Input: They have an increased constitutive level of p21CP1/WAF1.


Input: The ATM protein is therefore critical both for cellular responses to ionizing radiation and for normal cell-cycle progression.


Input: ATM +/-fibroblasts and thymocytes showed intermediately defective responses to irradiation but no growth defect, suggesting that the increased cancer risk of AT heterozygotes could be attributable to poor checkpoint function..

cancer

AT


Input: Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma.

growth retardation

chromosomal fragmentation during meiosis

immune defects

thymic lymphoma


Input: ATM, the gene mutated in the inherited human disease ataxia-telangiectasia, is a member of a family of kinases involved in DNA metabolism and cell-cycle checkpoint control.

inherited human disease ataxia-telangiectasia


Input: To help clarify the physiological roles of the ATM protein, we disrupted the ATM gene in mice through homologous recombination.


Input: Initial evaluation of the ATM knockout animals indicates that inactivation of the mouse ATM gene recreates much of the phenotype of ataxia-telangiectasia.

ataxia-telangiectasia


Input: The homozygous mutant (ATM-/-) mice are viable, growth-retarded, and infertile.


Input: The infertility of ATM-/-mice results from meiotic failure.

infertility


Input: Meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation.


Input: Immune defects also are evident in ATM-/-mice, including reduced numbers of B220 + CD43-pre-B cells, thymocytes, and peripheral T cells, as well as functional impairment of T-cell-dependent immune responses.

Immune defects


Input: The cerebella of ATM-/-mice appear normal by histologic examination at 3 to 4 months and the mice have no gross behavioral abnormalities.

behavioral abnormalities


Input: The majority of mutant mice rapidly develop thymic lymphomas and die before 4 months of age.

thymic lymphomas


Input: These findings indicate that the ATM gene product plays an essential role in a diverse group of cellular processes, including meiosis, the normal growth of somatic tissues, immune development, and tumor suppression..

tumor


Input: Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene.


Input: Very-long-chain acyl-CoA dehydrogenase (VLCAD) is one of four straight-chain acyl-CoA dehydrogenase (ACD) enzymes, which are all nuclear encoded mitochondrial flavoproteins catalyzing the initial step in fatty acid beta-oxidation.


Input: We have used the very fast, Rapid Amplification of cDNA Ends (RACE) based strategy to obtain the sequence of cDNAs encoding human VLCAD from placenta and fibroblasts.


Input: Alignment of the predicted amino acid sequence of human VLCAD with those of the other human ACD enzymes revealed extensive sequence homology.


Input: Moreover, human VLCAD and human acyl-CoA oxidase showed extensive sequence homology corroborating the notion that these genes are evolutionarily related.


Input: Southern blot analysis of genomic DNA from hybrid cell lines was used to localize the VLCAD gene to human chromosome 17p11.


Input: Using Northern and Western blot analysis to investigate the tissue specific distribution of VLCAD mRNA and protein in several human tissues we showed that VLCAD is most abundant in heart and skeletal muscle.


Input: This agrees well with the fact that cardiac and muscle symptoms are characteristic for patients with VLCAD deficiency.

VLCAD deficiency


Input: Northern blot analysis and sequencing of cloned PCR amplified VLCAD cDNA from four unrelated patients with VLCAD deficiency showed that VLCAD mRNA was undetectable in one patient and that the other three have mutations in both VLCAD alleles.

VLCAD deficiency


Input: Western blot analysis of patient fibroblasts showed that the identified mutations result in severely reduced amounts of VLCAD protein.


Input: Molecular bases of combined subtotal deficiencies of C6 and C7: their effects in combination with other C6 and C7 deficiencies.

combined subtotal deficiencies of C6 and C7

C6 and C7 deficiencies


Input: Combined subtotal deficiency of C6 and C7, in which both proteins are expressed at very low levels, has been observed in homozygous form in two families.

Combined subtotal deficiency of C6 and C7


Input: A defect at the 5 splice donor site of intron 15 of the C6 gene explains the low molecular weight of the C6 protein and is probably responsible for its low expressed concentration.


Input: The C7 defect is more enigmatic the protein is of normal molecular weight, low circulating concentration, and altered isoelectric point.


Input: An Arg > Ser codon substitution in exon 11 is the only molecular alteration within the mature C7 protein.


Input: These defects are associated with a characteristic set of polymorphic DNA markers in the C6/C7 region, forming a distinct haplotype.


Input: The haplotype has been found in combination with a number of other haplotypes containing defective genes that lead either to C6 or C7 deficiency, but with different consequences.

C6 or C7 deficiency


Input: Where it is combined with a C6-deficient gene, the serum C7 levels can be surprisingly high, possibly because there is no C6 generating C56 to consume the C7.


Input: In contrast, where the C7 genes are both defective (but still partially functional), there may be a profound deficit of circulating C7 because there is ample C6 to produce C56 and consume the already small amount of C7.


Input: Each molecular defect has also been found in isolation and has the expected effect..


Input: Genetic bases of human complement C7 deficiency.

complement C7 deficiency


Input: Complement C7 deficiency (C7D) is associated frequently with recurrent bacterial infections, especially meningitis caused by Neisseria meningitidis.

Complement C7 deficiency

bacterial infections

meningitis

Neisseria meningitidis


Input: We report in this work the molecular bases of C7D in two unrelated Japanese males.


Input: We used exon-specific PCR/single-strand conformation polymorphism analysis as a screening step for mutations.


Input: Subsequent direct sequencing of the target exons identified homozygous mutations in exon 16 of case 1 and in exon 15 of case 2.


Input: The mutation of case 1 was a homozygous T to A transversion at nucleotide 2250, the third nucleotide of the codon TGT for Cys728, leading to a stop codon TGA (C728X).


Input: In case 2, a homozygous 2-bp deletion (2137delTG/2138delGT/2139delTG) caused a frameshift, generating a premature termination codon 4 to 6 nucleotides downstream.


Input: Family study in case 1 confirmed the genetic nature of the defect.


Input: Moreover, we detected a novel polymorphism in intron 11 that presumably is linked to the mutation responsible for C7D in case 1.


Input: Our results indicate that the pathogenesis of C7D is heterogeneous like most of the other deficiencies of complement components..

deficiencies of complement components


Input: HPRT-APRT-deficient mice are not a model for lesch-nyhan syndrome.

HPRT-APRT-deficient

lesch-nyhan syndrome


Input: Complete hypoxanthine-guanine phosphoribosyl-transferase (HPRT) deficiency in humans results in the Lesch-Nyhan syndrome which is characterized, among other features, by compulsive self-injurious behavior.

Complete hypoxanthine-guanine phosphoribosyl-transferase (HPRT) deficiency

Lesch-Nyhan syndrome


Input: HPRT-deficient mice generated using mouse embryonic stem cells exhibit none of the behavioral symptoms associated with the Lesch-Nyhan syndrome.

HPRT-deficient

Lesch-Nyhan syndrome


Input: Administration of drugs that inhibit adenine phosphoribosyltransferase (APRT) in HPRT-deficient mice has produced the suggestion that deficiency of APRT in combination with HPRT-deficiency in mice may lead to self-mutilation behavior [C. L. Wu and D. W. Melton (1993) Nature Genet. 3, 235-240].

HPRT-deficient

deficiency of APRT

HPRT-deficiency


Input: To test this proposition, we bred HPRT-APRT-deficient mice.

HPRT-APRT-deficient


Input: Although the doubly-deficient mice excrete adenine and its highly insoluble derivative, 2, 8-dihydroxyadenine, which are also associated with human APRT deficiency, additional abnormalities or any self-injurious behavior were not detected.

APRT deficiency


Input: Thus, APRT-HPRT-deficient mice, which are devoid of any purine salvage pathways, show no novel phenotype and are not a model for the behavioral abnormalities associated with the Lesch-Nyhan syndrome as previously suggested

APRT-HPRT-deficient

behavioral abnormalities

Lesch-Nyhan syndrome


Input: Somatic alterations of the DPC4 gene in human colorectal cancers in vivo.

colorectal cancers


Input: BACKGROUND & AIMS The chromosome region 18q21 has been shown to be frequently deleted in colorectal cancers, and such frequent allelic loss is a hallmark of the presence of a tumor-suppressor gene.

colorectal cancers


Input: The DPC4 gene, which is located at 18q21, has been identified as a tumor-suppressor gene from examination of pancreatic cancers.

pancreatic cancers


Input: The aim of the present study was to determine if it might also be altered in colorectal cancers.

colorectal cancers


Input: METHODS Mutation analyses of the DPC4 gene were performed on complementary DNA samples from 31 primary colorectal cancer specimens using a combination of polymerase chain reaction, single-strand conformation polymorphism, and DNA sequencing.

colorectal cancer


Input: RESULTS Four missense mutations producing amino acid substitutions and a somatic 12-base pair deletion in the coding region of the DPC4 gene were detected in the 31 cancers (16%; 5 of 31).

cancers


Input: CONCLUSIONS The DPC4 gene may play a role as a tumor-suppressor gene in a fraction of colorectal cancers; however, while allelic loss at 18q21 is very often seen in colorectal cancers, only a minority show DPC4 mutations, suggesting that there might be another tumor-suppressor gene in this chromosome region..

colorectal cancers

colorectal cancers


Input: Pleiotropic defects in ataxia-telangiectasia protein-deficient mice.

ataxia-telangiectasia


Input: We have generated a mouse model for ataxia-telangiectasia by using gene targeting to generate mice that do not express the Atm protein.

ataxia-telangiectasia


Input: Atm-deficient mice are retarded in growth, do not produce mature sperm, and exhibit severe defects in T cell maturation while going on to develop thymomas.

thymomas


Input: Atm-deficient fibroblasts grow poorly in culture and display a high level of double-stranded chromosome breaks.


Input: Atm-deficient thymocytes undergo spontaneous apoptosis in vitro significantly more than controls.


Input: Atm-deficient mice then exhibit many of the same symptoms found in ataxia-telangiectasia patients and in cells derived from them.

ataxia-telangiectasia


Input: Furthermore, we demonstrate that the Atm protein exists as two discrete molecular species, and that loss of one or of both of these can lead to the development of the disease..


Input: The DCC protein and prognosis in colorectal cancer.

colorectal cancer


Input: BACKGROUND Allelic loss of chromosome 18q predicts a poor outcome in patients with stage II colorectal cancer.

stage II colorectal cancer


Input: Although the specific gene inactivated by this allelic loss has not been elucidated, the DCC (deleted in colorectal cancer) gene is a candidate.

colorectal cancer


Input: We investigated whether the expression of the DCC protein in tumor cells is a prognostic marker in colorectal carcinoma.

tumor

colorectal carcinoma


Input: METHODS The expression of DCC was evaluated immunohistochemically in 132 paraffin-embedded samples from patients with curatively resected stage II and III colorectal carcinomas.

stage II and III colorectal carcinomas


Input: The Cox proportional-hazards model was used to adjust for covariates including age, sex, tumor site, degree of tumor differentiation, and use of adjuvant therapy.

tumor

tumor


Input: RESULTS The expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas.

stage II and stage III colorectal carcinomas


Input: In patients with stage II disease whose tumors expressed DCC, the five-year survival rate was 94.

tumors


Input: 3 percent, whereas in patients with DCC-negative tumors, the survival rate was 61.

DCC-negative tumors


Input: 6 percent (P < 0. 001).


Input: In patients with stage III disease, the respective survival rates were 59.

stage III disease


Input: 3 percent and 33.


Input: 2 percent (P = 0. 03).


Input: CONCLUSIONS DCC is a prognostic marker in patients with stage II or stage III colorectal cancer.

stage II or stage III colorectal cancer


Input: In stage II colorectal carcinomas, the absence of DCC identifies a subgroup of patients with lesions that behave like stage III cancers.

stage II colorectal carcinomas

stage III cancers


Input: These findings may thus have therapeutic implications in this group of patients


Input: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.

anxiety-related traits


Input: Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs.

anxiety


Input: Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region.


Input: The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts.


Input: Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships..

anxiety-related personality traits


Input: Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia.

atelosteogenesis type 2

diastrophic dysplasia


Input: Mutations in the diastrophic dysplasia sulfate transporter gene DTDST have been associated with a family of chondrodysplasias that comprises, in order of increasing severity, diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and achondrogenesis type 1B (ACG1B).

diastrophic dysplasia

chondrodysplasias

diastrophic dysplasia

DTD

atelosteogenesis type 2

achondrogenesis type 1B


Input: To learn more about the molecular basis of DTDST chondrodysplasias and about genotype-phenotype correlations, we studied fibroblast cultures of three new patients one with AO-2, one with DTD, and one with an intermediate phenotype (AO2/DTD).

DTDST chondrodysplasias

DTD

DTD


Input: Reduced incorporation of inorganic sulfate into macromolecules was found in all three.


Input: Each of the three patients was found to be heterozygous for a c862t transition predicting a R279W substitution in the third extracellular loop of DTDST.


Input: In two patients (DTD and AO2/DTD), no other structural mutation was found, but polymerase chain reaction amplification and single-strand conformation polymorphism analysis of fibroblast cDNA showed reduced mRNA levels of the wild-type DTDST allele these two patients may be compound heterozygotes for the " Finnish " mutation (as yet uncharacterized at the DNA level), which causes reduced expression of DTDST.

DTD

DTD


Input: The third patient (with AO2) had the R279W mutation compounded with a novel mutation, the deletion of cytosine 418 (delta c418), predicting a frameshift with premature termination.


Input: Also the delta c418 allele was underrepresented in the cDNA, in accordance with previous observations that premature stop codons reduce mRNA levels.


Input: The presence of the DTDST R279W mutation in a total of 11 patients with AO2 or DTD emphasizes the overlap between these conditions.

DTD


Input: This mutation has not been found so far in 8 analyzed ACG1B patients, suggesting that it allows some residual activity of the sulfate transporter..


Input: Identification of WASP mutations, mutation hotspots and genotype-phenotype disparities in 24 patients with the Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome


Input: The Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disease caused by mutation in the recently isolated gene encoding WAS protein (WASP), is known to be associated with extensive clinical heterogeneity.

Wiskott-Aldrich syndrome

WAS

X-linked immunodeficiency disease

WAS


Input: Cumulative mutation data have revealed that WASP genotypes are also highly variable among WAS patients, but the relationship of phenotype with genotype in this disease remains unclear.

WASP


Input: To address this issue we characterized WASP mutations in 24 unrelated WAS patients, including 18 boys with severe classical WAS and 6 boys expressing mild forms of the disease, and then examined the degree of correlation of these as well as all previously published WASP mutations with disease severity.

WASP

WAS


Input: By analysis of these compiled mutation data, we demonstrated clustering of WASP mutations within the four most N-terminal exons of the gene and also identified several sites within this region as hotspots for WASP mutation.


Input: These characteristics were observed, however, in both severe and mild cases of the disease.


Input: Similarly, while the cumulative data revealed a predominance of missense mutations among the WASP gene lesions observed in boys with isolated thrombocytopenia, missense mutations were not exclusively associated with milder WAS phenotypes, but also comprised a substantial portion (38%) of the WASP gene defects found in patients with severe disease.

isolated thrombocytopenia

WAS


Input: These findings, as well as the detection of identical WASP mutations in patients with disparate phenotypes, reveal a lack of phenotype concordance with genotype in WAS and thus imply that phenotypic outcome in this disease cannot be reliably predicted solely on the basis of WASP genotypes..

WASP


Input: Germline mutations in the 3' part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli.

APC

adenomatous polyposis coli


Input: Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer characterized by the development of numerous adenomatous polyps predominantly in the colorectal region.

Familial adenomatous polyposis

FAP

colorectal cancer

adenomatous polyps


Input: Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for most cases of FAP.

adenomatous polyposis coli

APC

FAP


Input: Mutations at the 5 end of APC are known to be associated with a relatively mild form of the disease, called attenuated adenomatous polyposis coli (AAPC).

APC

attenuated adenomatous polyposis coli

AAPC


Input: We identified a frameshift mutation in the 3 part of exon 15, resulting in a stop codon at 1862, in a large Dutch kindred with AAPC.

AAPC


Input: Western blot analysis of lymphoblastoid cell lines derived from affected family members from this kindred, as well as from a previously reported Swiss family carrying a frameshift mutation at codon 1987 and displaying a similar attenuated phenotype, showed only the wild-type APC protein.

APC


Input: Our study indicates that chain-terminating mutations located in the 3 part of APC do not result in detectable truncated polypeptides and we hypothesize that this is likely to be the basis for the observed AAPC phenotype..

APC

AAPC


Input: Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.


Input: Over 100 distinct disease-associated mutations have been identified in the breast-ovarian cancer susceptibility gene BRCA1.

breast-ovarian cancer


Input: Loss of the wild-type allele in > 90% of tumors from patients with inherited BRCA1 mutations indicates tumor suppressive function.

tumors

tumor


Input: The low incidence of somatic mutations suggests that BRCA1 inactivation in sporadic tumors occurs by alternative mechanisms, such as interstitial chromosomal deletion or reduced transcription.

tumors


Input: To identify possible features of the BRCA1 genomic region that may contribute to chromosomal instability as well as potential transcriptional regulatory elements, a 117, 143-bp DNA sequence encompassing BRCA1 was obtained by random sequencing of four cosmids identified from a human chromosome 17 specific library.


Input: The 24 exons of BRCA1 span an 81-kb region that has an unusually high density of Alu repetitive DNA (41. 5%), but relatively low density (4. 8%) of other repetitive sequences.


Input: BRCA1 intron lengths range in size from 403 bp to 9.


Input: 2 kb and contain the intragenic microsatellite markers D17S1323, D17S1322, and D17S855, which localize to introns 12, 19, and 20, respectively.


Input: In addition to BRCA1, the contig contains two complete genes Rho7, a member of the rho family of GTP binding proteins, and VAT1, an abundant membrane protein of cholinergic synaptic vesicles.


Input: Partial sequences of the 1A1-3B B-box protein pseudogene and IFP 35, an interferon induced leucine zipper protein, reside within the contig.


Input: An L21 ribosomal protein pseudogene is embedded in BRCA1 intron 13.


Input: The order of genes on the chromosome is centromere-1FP 35-VAT1-Rho7-BRCA1-1A1-3B-telomere


Input: Identification of a RING protein that can interact in vivo with the BRCA1 gene product.


Input: The hereditary breast and ovarian cancer gene, BRCA1, encodes a large polypeptide that contains the cysteine-rich RING motif, a zinc-binding domain found in a variety of regulatory proteins.

hereditary breast and ovarian cancer


Input: Here we describe a novel protein that interacts in vivo with the N-terminal region of BRCA1.


Input: This BRCA1-associated RING domain (BARD1) protein contains an N-terminal RING motif, three tandem ankyrin repeats, and a C-terminal sequence with significant homology to the phylogenetically conserved BRCT domains that lie near the C terminus of BRCA1.


Input: The BARD1/BRCA1 interaction is disrupted by BRCA1 missense mutations that segregate with breast cancer susceptibility, indicating that BARD1 may be involved in mediating tumour suppression by BRCA1..

breast cancer

tumour


Input: Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two-colour fluorescence analysis.


Input: The ability to scan a large gene rapidly and accurately for all possible heterozygous mutations in large numbers of patient samples will be critical for the future of medicine.


Input: We have designed high-density arrays consisting of over 96, 600 oligonucleotides 20-nucleotides (nt) in length to screen for a wide range of heterozygous mutations in the 3.


Input: 45-kilobases (kb) exon 11 of the hereditary breast and ovarian cancer gene BRCA1.

hereditary breast and ovarian cancer


Input: Reference and test samples were co-hybridized to these arrays and differences in hybridization patterns quantitated by two-colour analysis.


Input: Fourteen of fifteen patient samples with known mutations were accurately diagnosed, and no false positive mutations were identified in 20 control samples.


Input: Eight single nucleotide polymorphisms were also readily detected.


Input: DNA chip-based assays may provide a valuable new technology for high-throughput cost-efficient detection of genetic alterations.


Input: Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas.

hyperparathyroidism and jaw tumor syndrome

renal hamartomas

cystic kidney disease

renal hamartomas


Input: Hereditary hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2).

Hereditary hyperparathyroidism-jaw tumor syndrome

HPT-JT

autosomal dominant disease


Input: Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome.

HPT-JT syndrome

adult renal hamartomas

cystic kidney disease

HPT-JT syndrome