Input: Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor (AR) gene.

metastatic prostate cancer


Input: Direct sequencing of the polymerase chain reaction-derived DNAs of 6 of 24 specimens revealed a codon 877 mutation (ACT--> GCT, Thr--> Ala) in the hormone-binding domain of the AR gene.


Input: This same AR mutation has been reported previously in a metastatic prostate cancer cell line, LNCaP, where this mutation confers upon the AR an altered ligand-binding specificity which is stimulated by estrogens, progestagens, and antiandrogens.

metastatic prostate cancer


Input: It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer.

advanced prostate cancer


Input: Although estrogens are used infrequently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer.

advanced prostate cancer


Input: The stimulatory effect of these therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease..


Input: The human gene for alkaptonuria (AKU) maps to chromosome 3q.

alkaptonuria

AKU


Input: Alkaptonuria (AKU; McKusick no. 203500) is a rare autosomal recessive disorder caused by the lack of homogentisic acid oxidase activity.

Alkaptonuria

AKU

autosomal recessive disorder


Input: Patients excrete large amounts of homogentisic acid in their urine and a black ochronotic pigment is deposited in their cartilage and collagenous tissues.


Input: Ochronosis is the predominant clinical complication of the disease leading to ochronotic arthropathy, dark urine, pigment changes of the skin, and other clinical features.

Ochronosis

ochronotic arthropathy


Input: A mutation causing alkaptonuria in the mouse has mapped to chromosome 16.

alkaptonuria


Input: Considering conserved synteny, we were able to map the human gene to chromosome 3q in six alkaptonuria pedigrees of Slovak origin..

alkaptonuria


Input: Structure of the human Na +/glucose cotransporter gene SGLT1.


Input: Intestinal uptake of dietary glucose and galactose is mediated by the SGLT1 Na +/glucose cotransporter of the brush border.


Input: An SGLT1 missense mutation underlies hereditary glucose/galactose malabsorption, characterized by potentially fatal diarrhea; conversely, oral rehydration therapy exploits normal transport to alleviate life-threatening diarrhea of infectious origin.

hereditary glucose/galactose malabsorption

diarrhea

diarrhea


Input: We have mapped the entire human SGLT1 Na +/glucose cotransporter gene from cosmid and lambda phage clones representing a genomic region of 112 kilobases.


Input: Transcription initiation occurred from a site 27 base pairs 3 of a TATAA sequence.


Input: All exon-flanking regions were sequenced, and the entire 112-kilobase region mapped with four restriction enzymes.


Input: SGLT1 is comprised of 15 exons (spanning 72 kilobases); a possible evolutionary origin from a six-membrane-span ancestral precursor via a gene duplication event is suggested from comparison of exons against protein secondary structure and from sequence considerations.


Input: A new missense mutation in exon 1 causing glucose/galactose malabsorption is also described.

glucose/galactose malabsorption


Input: This is the first Na (+)-dependent cotransporter gene structure reported.


Input: These data facilitate the search for new glucose/galactose malabsorption-related mutations in this important gene and provide a basis for future evolutionary comparisons with other Na (+)-dependent cotransporters..

glucose/galactose malabsorption


Input: Four novel PEPD alleles causing prolidase deficiency.

prolidase deficiency


Input: Mutations at the PEPD locus cause prolidase deficiency (McKusick 170100), a rare autosomal recessive disorder characterized by iminodipeptiduria, skin ulcers, mental retardation, and recurrent infections.

prolidase deficiency

autosomal recessive disorder

iminodipeptiduria

skin ulcers

mental retardation


Input: Four PEPD mutations from five severely affected individuals were characterized by analysis of reverse-transcribed, PCR-amplified (RT-PCR) cDNA.


Input: We used SSCP analysis on four overlapping cDNA fragments covering the entire coding region of the PEPD gene and detected abnormal SSCP bands for the fragment spanning all or part of exons 13-15 in three of the probands.


Input: Direct sequencing of the mutant cDNAs showed a G--> A, 1342 substitution (G448R) in two patients and a 3-bp deletion (delta E452 or delta E453) in another.


Input: In the other two probands the amplified products were of reduced size.


Input: Direct sequencing of these mutant cDNAs revealed a deletion of exon 5 in one patient and of exon 7 in the other.


Input: Intronic sequences flanking exons 5 and 7 were identified using inverse PCR followed by direct sequencing.


Input: Conventional PCR and direct sequencing then established the intron-exon borders of the mutant genomic DNA revealing two splice acceptor mutations a G--> C substitution at position-1 of intron 4 and an A--> G substitution at position-2 of intron 6.


Input: Our results indicate that the severe form of prolidase deficiency is caused by multiple PEPD alleles.

prolidase deficiency


Input: In this report we attempt to begin the process of describing these alleles and cataloging their phenotypic expression..


Input: Recombinations in individuals homozygous by descent localize the Friedreich ataxia locus in a cloned 450-kb interval.

Friedreich ataxia


Input: The locus for Friedreich ataxia (FRDA), a severe neurodegenerative disease, is tightly linked to markers D9S5 and D9S15, and analysis of rare recombination events has suggested the order cen-FRDA-D9S5-D9S15-qter.

Friedreich ataxia

FRDA

neurodegenerative disease


Input: We report here the construction of a YAC contig extending 800 kb centromeric to D9S5 and the isolation of five new microsatellite markers from this region.


Input: In order to map these markers with respect to the FRDA locus, all within a 1-cM confidence interval, we sought to increase the genetic information of available FRDA families by considering homozygosity by descent and association with founder haplotypes in isolated populations.

FRDA

FRDA


Input: This approach allowed us to identify one phase-known recombination and one probable historic recombination on haplotypes from Reunion Island patients, both of which place three of the five markers proximal to FRDA.

FRDA


Input: This represents the first identification of close FRDA flanking markers on the centromeric side.

FRDA


Input: The two other markers allowed us to narrow the breakpoint of a previously identified distal recombination that is > 180 kb from D9S5 (26P).


Input: Taken together, the results place the FRDA locus in a 450-kb interval, which is small enough for direct search of candidate genes.

FRDA


Input: A detailed rare cutter restriction map and a cosmid contig covering this interval were constructed and should facilitate the search of genes in this region..


Input: Investigation of thermoregulatory characteristics in patients with Prader-Willi syndrome.

Prader-Willi syndrome


Input: A survey instrument is used to assess temperature regulation characteristics in children with Prader-Willi syndrome (PWS) compared to 3 control groups sibs of PWS patients (SIB), neurodevelopmentally handicapped children (ND), and age and gender matched well children (WC).

Prader-Willi syndrome

PWS

PWS

neurodevelopmentally handicapped


Input: Significant differences were found between PWS patients, SIB controls, and WC controls in the prevalence of febrile convulsions, fever-associated symptoms, and temperature less than 94 degrees F.

PWS


Input: No differences were noted in any variable between the PWS patients and the ND controls, suggesting that these abnormalities are not unique to PWS, but can occur in any neurodevelopmentally handicapped individual, further suggesting these do not necessarily reflect syndrome-specific hypothalamic abnormalities..

PWS

PWS

neurodevelopmentally handicapped

hypothalamic abnormalities


Input: Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene.

retinitis pigmentosa

pattern dystrophy

fundus flavimaculatus


Input: BACKGROUND AND OBJECTIVES Mutations of the peripherin/RDS gene have been reported in autosomal dominant retinitis pigmentosa, pattern macular dystrophy, and retinitis punctata albescens.

autosomal dominant retinitis pigmentosa

macular dystrophy

retinitis punctata albescens


Input: We report herein the occurrence of three separate phenotypes within a single family with a novel 3-base pair deletion of codon 153 or 154 of the peripherin/RDS gene.


Input: DESIGN Case reports with clinical features, fluorescein angiography, kinetic perimetry, electrophysiological studies, and molecular genetics.


Input: SETTING University medical centers.


Input: PATIENTS A 75-year-old woman, her two daughters (aged 44 and 50 years), and her 49-year-old son were screened for peripherin/RDS mutations because of the presence of multiple phenotypes within the same family.


Input: RESULTS The mother presented at age 63 years with a profoundly abnormal electroretinogram (ERG) and adult-onset retinitis pigmentosa that progressed dramatically over 12 years, with marked loss of peripheral visual field.

retinitis pigmentosa


Input: One daughter developed pattern macular dystrophy at age 31 years.

pattern macular dystrophy


Input: At age 44 years, her ERG was moderately abnormal but her clinical disease was limited to the macula.


Input: Another daughter presented at age 42 years with macular degeneration and over 10 years developed the clinical picture of fundus flavimaculatus.

macular degeneration

fundus flavimaculatus


Input: Her peripheral visual field was preserved but her ERG was moderately abnormal.


Input: The son had onset of macular degeneration at age 44 years.

macular degeneration


Input: Pericentral scotomas were present and the ERG was markedly abnormal.

Pericentral scotomas


Input: Fluorescein angiography revealed punctate pigment epithelial transmission defects.


Input: CONCLUSIONS A 3-base pair deletion of codon 153 or 154 of the peripherin/RDS gene can produce clinically disparate phenotypes even within the same family..


Input: Assignment of the human Na +/glucose cotransporter gene SGLT1 to chromosome 22q13. 1.


Input: The Na +/glucose cotransporter gene SGLT1 encodes the primary carrier protein responsible for the uptake of the dietary sugars glucose and galactose from the intestinal lumen.


Input: SGLT1 transport activity is currently exploited in oral rehydration therapy.


Input: The 75-kDa glycoprotein is localized in the brush border of the intestinal epithelium and is predicted to comprise 12 membrane spans.


Input: In two patients with the autosomal recessive disease glucose/galactose malabsorption, the underlying cause was found to be a missense mutation in SGLT1, and the Asp28--> Asn change was demonstrated in vitro to eliminate SGLT1 transport activity.

autosomal recessive disease glucose/galactose malabsorption


Input: The SGLT1 gene was previously shown to reside on the distal q arm of chromosome 22 (11. 2--> qter).


Input: We have used a cosmid probe for fluorescence in situ hybridization, which refines the localization to 22q13.


Input: 1, and provide an example of the utility of the SGLT1 probe as a diagnostic for genetic diseases associated with translocations of chromosome 22.

genetic diseases


Input: Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients.

APC

adenomatous polyposis coli


Input: In humans, alteration of the tumor suppressor gene, APC, causes adenomatous polyposis coli, a condition causing predisposition to colorectal cancer.

tumor

APC

adenomatous polyposis coli

colorectal cancer


Input: The syndrome inconsistently associates characteristic patches of congenital hypertrophy of the retinal pigment epithelium (CHRPE).

congenital hypertrophy of the retinal pigment epithelium

CHRPE


Input: Ocular examination revealed that patients expressing CHRPE tend to cluster within specific families.

CHRPE


Input: The exact APC mutation was identified in 42 unrelated patients.

APC


Input: In all cases these mutations were predicted to lead to the synthesis of a truncated protein.


Input: The extent of CHRPE was found to be dependent on the position of the mutation along the coding sequence.

CHRPE


Input: CHRPE lesions are almost always absent if the mutation occurs before exon 9, but are systematically present if it occurs after this exon.

CHRPE


Input: Thus, the range of phenotypic expression observed among affected patients may result in part from different allelic manifestations of APC mutations..

APC


Input: The effects of dystrophin gene mutations on the ERG in mice and humans.


Input: PURPOSE.


Input: The authors earlier findings of a negative electroretinogram (ERG) in a boy with Duchenne muscular dystrophy (DMD) led them to investigate dystrophin gene deletions and ERGs in five boys with DMD.

Duchenne muscular dystrophy

DMD

DMD


Input: The authors wanted to determined whether there were similar ERG findings in an animal model for DMD, the mdx mouse.

DMD


Input: METHODS.


Input: Ganzfeld ERGs were recorded in five boys with DMD after a complete ophthalmic examination.

DMD


Input: The dystrophin gene was analyzed by Southern blot hybridization.


Input: ERGs were recorded in anesthetized mdx and control mice with a modified Grass photostimulator (Grass Instrument Company, Quincy, MA).


Input: RESULTS.


Input: Ophthalmic examinations in all five boys had normal findings, yet an abnormal negative ERG was recorded for each subject.


Input: The subjects gene deletions were variable, ranging from large deletions to no detectable deletions.


Input: The ERGs of the mdx mice were normal and did not differ significantly from those of the control mice.


Input: CONCLUSIONS.


Input: The authors believe the unique ERG recorded for the human subjects is a manifestation of DMD associated with defects at the dystrophin gene locus and represents a new clinical entity.

DMD


Input: The ERG of the mdx mouse may be spared for several reasons, including milder effects of the mouse gene defect, differences in muscle and retinal gene product, or species differences in the biochemical role of dystrophin.


Input: The ERG shows promise of becoming a noninvasive diagnostic tool for DMD and its milder allelic forms..

DMD


Input: Association of the APC tumor suppressor protein with catenins.

APC tumor


Input: Mutations of APC appear to initiate sporadic and inherited forms of human colorectal cancer.

colorectal cancer


Input: Although these mutations have been well characterized, little is known about the function of the APC gene product.

APC


Input: Two cellular proteins that associate with APC were identified by nucleotide sequence analysis and peptide mapping as the E-cadherin-associated proteins alpha-and beta-catenin.

APC


Input: A 27-residue fragment of APC containing a 15-amino acid repeat was sufficient for the interaction with the catenins.


Input: These results suggest an important link between tumor initiation and cell adhesion..

tumor


Input: Difference in methylation patterns within the D15S9 region of chromosome 15q11-13 in first cousins with Angelman syndrome and Prader-Willi syndrome.

Angelman syndrome

Prader-Willi syndrome


Input: Abnormalities of chromosome region 15q11-13 are associated with Angelman syndrome (AS) and Prader-Willi syndrome (PWS).

Angelman syndrome

AS

Prader-Willi syndrome

PWS


Input: Differences between the methylation patterns of the region of chromosome 15q11-13 which hybridizes to the highly conserved DNA, DN34, in normal individuals and in patients with AS and PWS have been described.

AS

PWS


Input: We report on a family in which first cousins are affected by AS and PWS as a result of a familial paracentric inversion of 15q11-q13.

AS

PWS


Input: The results of the studies on this family demonstrate the differences in the methylation patterns in the 2 conditions and the phenomenon of genomic imprinting, whereby genetic information is expressed differently dependent on the parent of origin..


Input: Haplotype studies in Wilson disease.

Wilson disease


Input: In 51 families with Wilson disease, we have studied DNA haplotypes of dinucleotide repeat polymorphisms (CA repeats) in the 13q14.

Wilson disease


Input: 3 region, to examine these markers for association with the Wilson disease gene (WND).

Wilson disease

WND


Input: In addition to a marker (D13S133) described elsewhere, we have developed three new highly polymorphic markers (D13S314, D13S315, and D13S316) close to the WND locus.

WND


Input: We have examined the distribution of marker alleles at the loci studied and have found that D13S314, D13S133, and D13S316 each show nonrandom distribution on chromosomes carrying the WND mutation.

WND


Input: We have studied haplotypes of these three markers and have found that there are highly significant differences between WND and normal haplotypes in northern European families.

WND


Input: These findings have important implications for mutation detection and molecular diagnosis in families with Wilson disease.

Wilson disease


Input: Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1.


Input: We have analyzed a single multi-affected breast/ovarian cancer pedigree (BOV3) and have shown consistent inheritance of markers on chromosome 17q with the disease confirming that this family is due to the BRCA1 gene.

breast/ovarian cancer


Input: Analysis of 17q haplotypes shows a recombination event in a bilateral breast cancer case which suggests that the BRCA1 gene lies distal to D17S857; D17S857 is thus the new proximal boundary for the region containing BRCA1.

breast cancer


Input: Combining this information with previously published mapping information suggests that BRCA1 is contained in a region estimated at 1-1.


Input: 5 Mb in length.


Input: All seven breast tumour/blood pairs examined from this family show loss of heterozygosity in the tumours.

breast tumour

tumours


Input: The allel retained in each tumour was from the disease-bearing chromosome implicating BRCA1 as a tumour suppressor gene.

tumour

tumour


Input: We have sequenced the 17 beta-oestradiol dehydrogenase genes (EDH17B1 and EDH17B2) which have been suggested as candidate genes for BRCA1 in four members of this family.


Input: No germline mutations were detected.


Input: Myotonic dystrophy kinase is a component of neuromuscular junctions.

Myotonic dystrophy


Input: The clinical manifestation of myotonic dystrophy (DM) is correlated to the extent of expansion of an unstable [CTG] n DNA motif.

myotonic dystrophy

DM


Input: Recent studies have demonstrated that this trinucleotide motif forms part of the last, 3 untranslated exon of a gene which potentially encodes multiple protein isoforms of a serine/threonine protein kinase (myotonic dystrophy protein kinase, DM-PK).

myotonic dystrophy


Input: We report here on the development of antisera against synthetic DM-PK peptide antigens and their use in biochemical and histochemical studies.


Input: Immunoreactive DM-kinase protein of 53 kD is present at low levels in skeletal and cardiac muscle extracts of DM patients and normal controls.

DM


Input: Immunohistochemical staining revealed that DM-PK is localised prominently at sites of neuromuscular and myotendinous junctions (NMJs and MTJs) of human and rodent skeletal muscles.


Input: Furthermore, very low levels of immunoreactive DM-PK protein are present in the sarcoplasm of predominantly type I fibres in various muscles.


Input: Strikingly, presence of the protein can also be demonstrated for NMJs of muscular tissues of adult and congenital cases of DM, with no gross changes in structural organisation.

DM


Input: Our findings provide a basis for further characterisation of the role of the kinase in protein assembly processes or signal mediation at synaptic sites and ultimately for the understanding of the complex pathophysiology of DM..

DM


Input: Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease.

cholesterol acyltransferase deficiency

fish-eye disease


Input: Classic (complete) lecithin cholesterol acyltransferase (LCAT) deficiency and Fish-eye disease (partial LCAT deficiency) are genetic syndromes associated with markedly decreased plasma levels of high density lipoprotein (HDL) cholesterol but not with an increased risk of atherosclerotic cardiovascular disease.

Classic (complete) lecithin cholesterol acyltransferase (LCAT) deficiency

Fish-eye disease

partial LCAT deficiency

atherosclerotic cardiovascular disease


Input: We investigated the metabolism of the HDL apolipoproteins (apo) apoA-I and apoA-II in a total of five patients with LCAT deficiency, one with classic LCAT deficiency and four with Fish-eye disease.

LCAT deficiency

classic LCAT deficiency

Fish-eye disease


Input: Plasma levels of apoA-II were decreased to a proportionately greater extent (23% of normal) than apoA-I (30% of normal).


Input: In addition, plasma concentrations of HDL particles containing both apoA-I and apoA-II (LpA-I A-II) were much lower (18% of normal) than those of particles containing only apoA-I (LpA-I) (51% of normal).


Input: The metabolic basis for the low levels of apoA-II and LpA-I A-II was investigated in all five patients using both exogenous radiotracer and endogenous stable isotope labeling techniques.


Input: The mean plasma residence time of apoA-I was decreased at 2.


Input: 08 +/-0.


Input: 27 d (controls 4. 74 +/-0. 65 days); however, the residence time of apoA-II was even shorter at 1.


Input: 66 +/-0.


Input: 24 d (controls 5. 25 +/-0. 61 d).


Input: In addition, the catabolism of apoA-I in LpA-I A-II was substantially faster than that of apoA-I in LpA-I.


Input: In summary, genetic syndromes of either complete or partial LCAT deficiency result in low levels of HDL through preferential hypercatabolism of apoA-II and HDL particles containing apoA-II.

complete or partial LCAT deficiency


Input: Because LpA-I has been proposed to be more protective than LpA-I A-II against atherosclerosis, this selective effect on the metabolism of LpA-I A-II may provide a potential explanation why patients with classic LCAT deficiency and Fish-eye disease are not at increased risk for premature atherosclerosis despite markedly decreased levels of HDL cholesterol and apoA-I

atherosclerosis

classic LCAT deficiency

Fish-eye disease

atherosclerosis


Input: X linked recessive thrombocytopenia.

X linked recessive thrombocytopenia


Input: A Saudi Arab boy presented in early childhood with thrombocytopenia, morphologically large and normal sized platelets, increased mean platelet volume, and a hypermegakaryocytic bone marrow.

thrombocytopenia


Input: There was no clinical and laboratory evidence of any significant immunological abnormalities.

immunological abnormalities


Input: Similar findings in two other brothers suggested strongly that they were all suffering from an X linked recessive thrombocytopenic disorder.

X linked recessive thrombocytopenic disorder


Input: Results of DNA analysis with the probe M27 beta are consistent with X linkage and indicate also that the locus of the relevant gene lies close to or is identical to the locus of the gene for the Wiskott-Aldrich syndrome (WAS).

Wiskott-Aldrich syndrome

WAS


Input: Because of various features which include the presence of large and normal sized platelets (rather than small platelets) and freedom from significant immune deficiencies, it is likely that the X linked recessive thrombocytopenia in this family is an isolated entity quite distinct from the classical WAS phenotype.

immune deficiencies

X linked recessive thrombocytopenia

WAS


Input: However, a modified expression of the WAS gene producing a mild phenotypic variant cannot be excluded entirely..

WAS


Input: Macular dystrophy associated with mutations at codon 172 in the human retinal degeneration slow gene.

Macular dystrophy

retinal degeneration


Input: BACKGROUND Recently, mutations in the retinal degeneration slow (rds) gene which codes for peripherin-rds have been implicated as a cause of autosomal dominant retinitis pigmentosa.

retinal degeneration

autosomal dominant retinitis pigmentosa


Input: Because this gene is expressed in both rods and cones, mutations in the rds gene might be expected to cause degeneration affecting either the scotopic or photopic systems.


Input: Mutations at codon 172 of the rds gene have been identified in three families with autosomal dominantly inherited, progressive macular dystrophy.

macular dystrophy


Input: METHODS Affected individuals underwent ophthalmic examination, scotopic perimetry, dark adaptometry, measurement of color-contrast sensitivity, and electroretinography to characterize the photoreceptor dysfunction.


Input: RESULTS In all but one affected member, symptoms of progressive central visual loss developed in the third or fourth decade of life accompanied by central scotoma and well-demarcated atrophy of the retinal pigment epithelium and choriocapillaris of the macula.

visual loss

central scotoma

atrophy of the retinal pigment epithelium

choriocapillaris of the macula


Input: In general, cone and rod thresholds were elevated, and color-contrast sensitivity was absent in the central visual field.


Input: Peripherally, the scotopic sensitivities were normal, as was the recovery from bleach.


Input: Cone electroretinograms were diminished in amplitude, and delayed in all affected adults except one.


Input: Rod electroretinograms were normal or near normal in amplitude, and had normal implicit times.


Input: Affected asymptomatic children had macular changes, abnormal color-contrast sensitivity, and reduced pattern and cone electroretinograms.


Input: CONCLUSION These results indicate that mutations in the rds gene can be expressed as a macular dystrophy, with evidence of primary cone dysfunction and preservation of peripheral rod function..

macular dystrophy

cone dysfunction


Input: Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

hemochromatosis


Input: The hemochromatosis gene (HFE) maps to 6p21.

hemochromatosis


Input: 3 and is less than 1 cM from the HLA class I genes; however, the precise physical location of the gene has remained elusive and controversial.


Input: The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex-and age-related penetrance of the disease.

hemochromatosis


Input: For these practical considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE.


Input: We therefore embarked upon a linkage-disequilibrium analysis of HFE and normal chromosomes from the Brittany population.


Input: In the present report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.

hemochromatosis

hemochromatosis


Input: 7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively.


Input: The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.


Input: 7 interval (approximately 250 kb).


Input: The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE.


Input: These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F.


Input: Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.


Input: 7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.


Input: 7 locus within the linkage-disequilibrium zone.


Input: Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele.

hemochromatosis


Input: Overall, the establishment of a likely " hemochromatosis critical region " centromeric boundary and the identification of a linkage-disequilibrium zone both significantly contribute to a reduction in the amount of DNA required to be searched for novel coding sequences constituting the HFE defect

hemochromatosis


Input: Genomic structure of the EWS gene and its relationship to EWSR1, a site of tumor-associated chromosome translocation.

tumor


Input: The EWS gene has been identified based on its location at the chromosome 22 breakpoint of the t (11; 22) (q24; q12) translocation that characterizes Ewing sarcoma and related neuroectodermal tumors.

Ewing sarcoma

neuroectodermal tumors


Input: The EWS gene spans about 40 kb of DNA and is encoded by 17 exons.


Input: The nucleotide sequence of the exons is identical to that of the previously described cDNA.


Input: The first 7 exons encode the N-terminal domain of EWS, which consists of a repeated degenerated polypeptide of 7 to 12 residues rich in tyrosine, serine, threonine, glycine, and glutamine.


Input: Exons 11, 12, and 13 encode the putative RNA binding domain.


Input: The three glycine-and arginine-rich motifs of the gene are mainly encoded by exons 8-9, 14, and 16.


Input: The DNA sequence in the 5 region of the gene has features of a CpG-rich island and lacks canonical promoter elements, such as TATA and CCAAT consensus sequences.


Input: Positions of the chromosome 22 breakpoints were determined for 19 Ewing tumors.

Ewing tumors


Input: They were localized in introns 7 or 8 in 18 cases and in intron 10 in 1 case..


Input: Norrie disease gene: characterization of deletions and possible function.

Norrie disease


Input: Positional cloning experiments have resulted recently in the isolation of a candidate gene for Norrie disease (pseudoglioma; NDP), a severe X-linked neurodevelopmental disorder.

Norrie disease

pseudoglioma

NDP

X-linked neurodevelopmental disorder


Input: Here we report the isolation and analysis of human genomic DNA clones encompassing the NDP gene.

NDP


Input: The gene spans 28 kb and consists of 3 exons, the first of which is entirely contained within the 5 untranslated region.


Input: Detailed analysis of genomic deletions in Norrie patients shows that they are heterogeneous, both in size and in position.

Norrie


Input: By PCR analysis, we found that expression of the NDP gene was not confined to the eye or to the brain.

NDP


Input: An extensive DNA and protein sequence comparison between the human NDP gene and related genes from the database revealed homology with cysteine-rich protein-binding domains of immediate--early genes implicated in the regulation of cell proliferation.

NDP


Input: We propose that NDP is a molecule related in function to these genes and may be involved in a pathway that regulates neural cell differentiation and proliferation..


Input: The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD.

Huntington disease

HD

HD


Input: We evaluated the hypothesis that Huntington disease (HD) is influenced by the normal HD allele by comparing transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring.

Huntington disease

HD

HD


Input: Analysis of information from 21 sibships in 14 kindreds showed a significant tendency for sibs who have similar onset ages to share the same D4S10 allele from the normal parent.


Input: Affected sibs who inherited different D4S10 alleles from the normal parent tended to have more variable ages at onset.


Input: These findings suggest that the expression of HD is modulated by the normal HD allele or by a closely linked locus..

HD

HD


Input: Further investigation of the HEXA gene intron 9 donor splice site mutation frequently found in non-Jewish Tay-Sachs disease patients from the British Isles.

Tay-Sachs disease


Input: In a previous study we found that a Tay-Sachs disease (TSD) causing mutation in the intron 9 donor splice site of the HEXA gene occurs at high frequency in non-Jewish patients and carriers from the British Isles.

Tay-Sachs disease

TSD


Input: It was found more frequently in subjects of Irish, Scottish, and Welsh origin compared with English origin (63% and 31% respectively).


Input: We have now tested, in a blind study, 26 American TSD carriers and 28 non-carriers who have British ancestry for the intron 9 splice site mutation.

TSD


Input: Six of the carriers and none of the controls were positive for the mutation.


Input: All six had Irish ancestry, compared with nine of the 20 other (intron 9 mutation negative) TSD carriers (p < 0. 05).

TSD


Input: These results confirm the previously found high frequency of the intron 9 mutation in non-Jewish TSD families of British Isles, particularly Irish, origin, and reinforce the need to screen such families for this mutation.

TSD


Input: Molecular mechanisms of oncogenic mutations in tumors from patients with bilateral and unilateral retinoblastoma.

tumors

bilateral and unilateral retinoblastoma


Input: The RB1 gene from 12 human retinoblastoma tumors has been analyzed exon-by-exon with the single-strand conformation polymorphism technique.

retinoblastoma tumors


Input: Mutations were found in all tumors, and one-third of the tumors had independent mutations in both alleles neither of which were found in the germ line, confirming their true sporadic nature.

tumors

tumors


Input: In the remaining two-thirds of the tumors only one mutation was found, consistent with the loss-of-heterozygosity theory of tumorigenesis.

tumors


Input: Point mutations, the majority of which were C--> T transitions, were the most common abnormality and usually resulted in the conversion of an arginine codon to a stop codon.


Input: Small deletions were the second most common abnormality and most often created a downstream stop codon as the result of a reading frameshift.


Input: Deletions and point mutations also affected splice junctions.


Input: Direct repeats were present at the breakpoint junctions in the majority of deletions, supporting a slipped-mispairing mechanism.


Input: Point mutations generally produced DNA sequences which resulted in perfect homology with endogenous sequences which lay within 14 bp..


Input: PAX6 mutations in aniridia.

aniridia


Input: Aniridia is a congenital malformation of the eye, chiefly characterised by iris hypoplasia, which can cause blindness.

Aniridia

congenital malformation of the eye

iris hypoplasia

blindness


Input: The PAX6 gene was isolated as a candidate aniridia gene by positional cloning from the smallest region of overlap of aniridia-associated deletions.

aniridia

aniridia


Input: Subsequently PAX6 intragenic mutations were demonstrated in Smalleye, a mouse mutant which is an animal model for aniridia, and six human aniridia patients.

aniridia

aniridia


Input: In this paper we describe four additional PAX6 point mutations in aniridia patients, both sporadic and familial.

aniridia


Input: These mutations highlight regions of the gene which are essential for normal PAX6 function.


Input: In addition, the frequency at which we have found PAX6 mutations suggests that lesions in PAX6 will account for most cases of aniridia..

aniridia


Input: Detection of a novel arginine vasopressin defect by dideoxy fingerprinting.


Input: Autosomal dominant neurohypophyseal diabetes insipidus is a familial form of diabetes insipidus.

Autosomal dominant neurohypophyseal diabetes insipidus

diabetes insipidus


Input: This disorder is associated with variable levels of arginine vasopressin (AVP) and diabetes insipidus of varying severity, which responds to exogenous AVP.

diabetes insipidus


Input: To determine the molecular basis of autosomal dominant neurohypophyseal diabetes insipidus, the AVP genes of members of a large kindred were analyzed.

autosomal dominant neurohypophyseal diabetes insipidus


Input: A new method, called dideoxy fingerprinting, was used to detect an AVP mutation that was characterized by DNA sequencing.


Input: The novel defect found changes the last codon of the AVP signal peptide from alanine to threonine, which should perturb cleavage of mature AVP from its precursor protein and inhibit its secretion or action..


Input: Germinal mosaicism in a Duchenne muscular dystrophy family: implications for genetic counselling.

Duchenne muscular dystrophy


Input: In this study we describe a three-generation family in which two siblings were affected by Duchenne muscular dystrophy (DMD).

Duchenne muscular dystrophy

DMD


Input: Immunohistochemical analysis of muscle dystrophin and haplotype analysis of the DMD locus revealed that the X chromosome carrying the DMD gene was transmitted from the healthy maternal grandfather to his three daughters, including the probands mother.

DMD

DMD


Input: These findings indicate that the grandfather was a germinal mosaic for the DMD gene.

DMD


Input: The definition of the carrier status in two possible carriers led us to give accurate genetic counselling and to prevent the birth of an affected boy.


Input: The results of this study demonstrate the usefulness of haplotype analysis and immunohistochemical muscle dystrophin studies to detect hidden germinal mosaicism and to improve genetic counselling..


Input: Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA.

breast-ovarian cancer syndrome


Input: A susceptibility gene for hereditary breast-ovarian cancer, BRCA1, has been assigned by linkage analysis to chromosome 17q21.

hereditary breast-ovarian cancer


Input: Candidate genes in this region include EDH17B2, which encodes estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II), and RARA, the gene for retinoic acid receptor alpha.


Input: We have typed 22 breast and breast-ovarian cancer families with eight polymorphisms from the chromosome 17q12-21 region, including two in the EDH17B2 gene.

breast and breast-ovarian cancer


Input: Genetic recombination with the breast cancer trait excludes RARA from further consideration as a candidate gene for BRCA1.

breast cancer


Input: Both BRCA1 and EDH17B2 map to a 6 cM interval (between THRA1 and D17S579) and no recombination was observed between the two genes.


Input: However, direct sequencing of overlapping PCR products containing the entire EDH17B2 gene in four unrelated affected women did not uncover any sequence variation, other than previously described polymorphisms.


Input: Mutations in the EDH17B2 gene, therefore do not appear to be responsible for the hereditary breast-ovarian cancer syndrome.

hereditary breast-ovarian cancer syndrome


Input: Single meiotic crossovers in affected women suggest that BRCA1 is flanked by the loci RARA and D17S78..


Input: A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins.


Input: Plasma HDL are a negative risk factor for atherosclerosis.

atherosclerosis


Input: Cholesteryl ester transfer protein (CETP; 476 amino acids) transfers cholesteryl ester from HDL to other lipoproteins.


Input: Subjects with homozygous CETP deficiency caused by a gene splicing defect have markedly elevated HDL; however, heterozygotes have only mild increases in HDL.

CETP deficiency


Input: We describe two probands with a CETP missense mutation (442 D G).


Input: Although heterozygous, they have threefold increases in HDL concentration and markedly decreased plasma CETP mass and activity, suggesting that the mutation has dominant effects on CETP and HDL in vivo.


Input: Cellular expression of mutant cDNA results in secretion of only 30% of wild type CETP activity.


Input: Moreover, coexpression of wild type and mutant cDNAs leads to inhibition of wild type secretion and activity.


Input: The dominant effects of the CETP missense mutation during cellular expression probably explains why the probands have markedly increased HDL in the heterozygous state, and suggests that the active molecular species of CETP may be multimeric..


Input: Familial Mediterranean fever in the colchicine era: the fate of one family.

Familial Mediterranean fever


Input: In order to demonstrate the effect of prophylactic colchicine treatment on the natural history of familial Mediterranean fever (FMF), a family is presented with 6 out of 9 siblings affected by FMF.

familial Mediterranean fever

FMF

FMF


Input: Each patient represents a different stage of the amyloidotic kidney disease of FMF and the effect of continuous colchicine treatment on its course.

amyloidotic kidney disease

FMF


Input: Considered together, the members of this family present an almost complete clinical, genetic, and behavioral picture of the disease..


Input: Detection of a new submicroscopic Norrie disease deletion interval with a novel DNA probe isolated by differential Alu PCR fingerprint cloning.

Norrie disease


Input: Differential Alu PCR fingerprint cloning was used to isolate a DNA probe from the Xp11.


Input: 4--> p11.


Input: 21 region of the human X chromosome.


Input: This novel sequence, cpXr318 (DXS742), detects a new submicroscopic deletion interval at the Norrie disease locus (NDP).

Norrie disease


Input: Combining our data with the consensus genetic map of the proximal short arm of the X chromosome, we propose the physical order Xcen-DXS14-DXS255-(DXS426, TIMP)-(DXS742-([MAOB-MAOA-DXS7], NDP)-DXS77-DXS228)-DXS209-DXS148-DXS196-+ + + Xpter.


Input: The cpXr318 probe and a subclone from a cosmid corresponding to the DXS7 locus were converted into sequence-tagged sites.


Input: Finally, DXS742, DSX7, DXS77, and MAOA were integrated into a physical map spanning the Norrie disease locus

Norrie disease


Input: Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters.

X-linked adrenoleukodystrophy


Input: Adrenoleukodystrophy (ALD) is an X-linked disease affecting 1/20, 000 males either as cerebral ALD in childhood or as adrenomyeloneuropathy (AMN) in adults.

Adrenoleukodystrophy

ALD

X-linked disease

cerebral ALD

adrenomyeloneuropathy

AMN


Input: Childhood ALD is the more severe form, with onset of neurological symptoms between 5-12 years of age.

ALD


Input: Central nervous system demyelination progresses rapidly and death occurs within a few years.

Central nervous system demyelination


Input: AMN is a milder form of the disease with onset at 15-30 years of age and a more progressive course.

AMN


Input: Adrenal insufficiency (Addisons disease) may remain the only clinical manifestation of ALD.

Adrenal insufficiency

Addisons disease

ALD


Input: The principal biochemical abnormality of ALD is the accumulation of very-long-chain fatty acids (VLCFA) because of impaired beta-oxidation in peroxisomes.

ALD


Input: The normal oxidation of VLCFA-CoA in patients fibroblasts suggested that the gene coding for the VLCFA-CoA synthetase could be a candidate gene for ALD.

ALD


Input: Here we use positional cloning to identify a gene partially deleted in 6 of 85 independent patients with ALD.

ALD


Input: In familial cases, the deletions segregated with the disease.


Input: An identical deletion was detected in two brothers presenting with different clinical ALD phenotypes.

ALD


Input: Candidate exons were identified by computer analysis of genomic sequences and used to isolate complementary DNAs by exon connection and screening of cDNA libraries.


Input: The deduced protein sequence shows significant sequence identity to a peroxisomal membrane protein of M (r) 70K that is involved in peroxisome biogenesis and belongs to the ATP-binding cassette superfamily of transporters..


Input: Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice.

hypobetalipoproteinemia

developmental abnormalities


Input: Familial hypobetalipoproteinemia is an autosomal codominant disorder resulting in a dramatic reduction in plasma concentrations of apolipoprotein (apo) B, cholesterol, and beta-migrating lipoproteins.

Familial hypobetalipoproteinemia

autosomal codominant disorder


Input: A benefit of hypobetalipoproteinemia is that mildly affected individuals may be protected from coronary vascular disease.

hypobetalipoproteinemia

coronary vascular disease


Input: We have used gene targeting to generate mice with a modified Apob allele.


Input: Mice containing this allele display all of the hallmarks of human hypobetalipoproteinemia they produce a truncated apoB protein, apoB70, and have markedly decreased plasma concentrations of apoB, beta-lipoproteins, and total cholesterol.

hypobetalipoproteinemia


Input: In addition, the mice manifest several characteristics that are occasionally observed in human hypobetalipoproteinemia, including reduced plasma triglyceride concentrations, fasting chylomicronemia, and reduced high density lipoprotein cholesterol.

hypobetalipoproteinemia

chylomicronemia


Input: An unexpected finding is that the modified Apob allele is strongly associated with exencephalus and hydrocephalus.

exencephalus

hydrocephalus


Input: These mice should help increase our understanding of hypobetalipoproteinemia, atherogenesis, and the etiology of exencephalus and hydrocephalus..

hypobetalipoproteinemia

atherogenesis

exencephalus

hydrocephalus


Input: A novel disease with deficiency of mitochondrial very-long-chain acyl-CoA dehydrogenase.

deficiency of mitochondrial very-long-chain acyl-CoA dehydrogenase


Input: Palmitoyl-CoA dehydrogenase activity in skin fibroblasts from seven patients with unidentified defects of fatty acid oxidation was measured in the presence and absence of antibodies against medium-chain, long-chain, and very-long-chain acyl-CoA dehydrogenases (VLCAD).


Input: Two of the patients, 4-5 month old boys, were found to have a novel disease, VLCAD deficiency, as judged from the results of very low palmitoyl-CoA dehydrogenase activity and the lack of immunoreactivity toward antibody raised to purified VLCAD..

VLCAD deficiency


Input: Molecular characterization of glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients of Chinese descent and identification of new base substitutions in the human G6PD gene.

glucose-6-phosphate dehydrogenase (G6PD) deficiency


Input: The underlying DNA changes associated with glucose-6-phosphate dehydrogenase (G6PD)-deficient Asians have not been extensively investigated.

glucose-6-phosphate dehydrogenase (G6PD)-deficient


Input: To fill this gap, we sequenced the G6PD gene of 43 G6PD-deficient Chinese whose G6PD was well characterized biochemically.


Input: DNA samples were obtained from peripheral blood of these individuals for sequencing using a direct polymerase chain reaction (PCR) sequencing procedure.


Input: From these 43 samples, we have identified five different types of nucleotide substitutions in the G6PD gene at cDNA 1388 from G to A (Arg to His); at cDNA 1376 from G to T (Arg to Leu); at cDNA 1024 from C to T (Leu to Phe); at cDNA 392 from G to T (Gly to Val); at cDNA 95 from A to G (His to Arg).


Input: These five nucleotide substitutions account for over 83% of our 43 G6PD-deficient samples and these substitutions have not been reported in non-Asians.


Input: The substitutions found at cDNA 392 and cDNA 1024 are new findings.


Input: The substitutions at cDNA 1376 and 1388 account for over 50% of the 43 samples examined indicating a high prevalence of these two alleles among G6PD-deficient Chinese.


Input: Our findings add support to the notion that diverse point mutations may account largely for much of the phenotypic heterogeneity of G6PD deficiency..

G6PD deficiency


Input: Identification of mutations in Danish choroideremia families.

choroideremia


Input: We have searched for mutations in the choroideremia gene (CHM) in patients from 12 Danish families in which CHM is segregating.

choroideremia

CHM

CHM


Input: Employing polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP) analysis, and direct DNA sequencing, different mutations have been identified in 6 patients.


Input: All the mutations will interfere with the correct translation of the mRNA predicting a truncated protein or no gene product at all..


Input: Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene.

myotonic dystrophy

DM


Input: The mutation causing myotonic dystrophy (DM) has recently been identified as an unstable CTG trinucleotide repeat located in the 3 untranslated region of a gene encoding for a protein with putative serine-threonine protein kinase activity.

myotonic dystrophy

DM


Input: In this report we present the genomic sequences of the human and murine DM kinase gene.

DM


Input: A comparison of these sequences with each other and with known cDNA sequences from both species, led us to predict a translation initiation codon, as well as determine the organization of the DM kinase gene.

DM


Input: Several polymorphisms within the human DM kinase gene have been identified, and PCR assays to detect two of these are described.

DM


Input: The complete sequence and characterization of the structure of the DM kinase gene, as well as the identification of novel polymorphisms within the gene, represent an important step in a further understanding of the genetics of myotonic dystrophy and the molecular biology of the gene..

DM

myotonic dystrophy


Input: Autosomal recessive transmission of hemophilia A due to a von Willebrand factor mutation.

hemophilia A

von Willebrand


Input: The differential diagnosis of the genetic bleeding disorders, hemophilia A and von Willebrand disease, is occasionally confounded by the close molecular relationship of coagulation factor VIII and von Willebrand factor (vWF).

genetic bleeding disorders

hemophilia A

von Willebrand disease

von Willebrand


Input: This report describes the autosomal inheritance of a hemophilia A phenotype due to a mutation of vWF that results in defective factor VIII binding.

hemophilia A


Input: The proband was a female patient with low levels of factor VIII activity.


Input: Polymerase chain reaction (PCR) amplification and DNA sequencing were employed to examine exons encoding the putative factor VIII binding domain of vWF.


Input: The patient was found to be homozygous for a single point mutation causing a Thr--> Met substitution at amino acid position 28 in the mature vWF subunit.


Input: The phenotypic expression of the mutation was determined to be recessive because heterozygous family members were clinically unaffected.


Input: Recombinant vWF containing the observed amino acid substitution was expressed in COS-1 cells.


Input: The mutant vWF was processed and secreted normally, and was functionally equivalent to wild-type vWF in its ability to bind to platelets.


Input: However, the mutant failed to bind factor VIII, demonstrating that the mutation was functionally related to the observed hemophilia phenotype.

hemophilia


Input: The family we describe demonstrates the recessive inheritance of a recently recognized class of genetic bleeding disorders, we call " autosomal hemophilia.

hemophilia


Input: " We conclude that vWF mutation may be an under recognized cause of hemophilia, especially in cases where the inheritance pattern is not consistent with X-linked transmission.

hemophilia


Input: Somatic von Hippel-Lindau mutation in clear cell papillary cystadenoma of the epididymis.

von Hippel-Lindau

papillary cystadenoma of the epididymis


Input: Papillary cystadenoma of the epididymis is an uncommon benign lesion that may occur sporadically or as a manifestation of von Hippel-Lindau (VHL) disease.

Papillary cystadenoma of the epididymis

von Hippel-Lindau (VHL) disease


Input: Neither immunohistochemical studies nor molecular genetic analyses of the VHL gene have been reported previously for this lesion.

VHL


Input: The authors describe two cases of clear cell papillary cystadenoma of the epididymis, both of which were initially confused with metastatic renal cell carcinoma.

papillary cystadenoma of the epididymis

metastatic renal cell carcinoma


Input: Both lesions showed positive immunohistochemical staining for low and intermediate molecular weight keratins (Cam 5. 2 and AE1/AE3), EMA, vimentin, alpha 1-antitrypsin, and alpha 1-antichymotrypsin.


Input: Each was negative for CEA.


Input: Because clear cell papillary cystadenoma is similar to renal cell carcinoma histologically, and because both occur as components of the von Hippel-Lindau disease complex, the authors analyzed both cases for the presence of mutations in the VHL gene.

papillary cystadenoma

renal cell carcinoma

von Hippel-Lindau disease

VHL


Input: A somatic VHL gene mutation was detected in one of the two tumors by polymerase chain reaction followed by single-strand conformation polymorphism analysis.

VHL

tumors


Input: Direct sequencing revealed a cytosine to thymine transition at nucleotide 694, resulting in the replacement of an arginine with a stop codon after the sixth amino acid of exon 3.


Input: As the VHL gene is believed to function as a tumor suppressor gene, VHL gene mutations may play a role in the initiation of tumorigenesis in sporadic cystadenomas of the epididymis.

VHL

tumor

VHL

cystadenomas of the epididymis


Input: Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus.

Wiskott-Aldrich syndrome

isolated thrombocytopenia

WAS


Input: Mutation in the gene encoding the recently isolated WASP protein has now been identified as the genetic defect responsible for the X-linked Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disease associated with extensive phenotypic variability.

genetic defect

X-linked Wiskott-Aldrich syndrome

WAS

immunodeficiency disease


Input: To elucidate the range of WASP mutations responsible for WAS, we used PCR-SSCP analysis to screen for WASP gene mutation in 19 unrelated boys with the diagnosis of classical or attenuated WAS or isolated thrombocytopenia.

WASP

WAS

isolated thrombocytopenia


Input: All 19 patients had WASP mutations, each of which localized to the initial three or terminal three exons of the gene, and the majority of which were unique in each case.


Input: However, a missense mutation which results in substitution of the arginine at WAS codon 86 was identified in three boys with severe WAS as well as in one boy presenting with thrombocytopenia alone.

WAS

WAS

thrombocytopenia


Input: While the three mutations found in the isolated thrombocytopenia patients leave the reading frame intact, about one-half of the gene alterations detected in both severe and attenuated WAS patients result in frameshifted transcript and premature translation termination.

isolated thrombocytopenia

WAS


Input: These findings therefore confirm the association of WAS with WASP mutation and identify WASP mutation as a cause for isolated congenital thrombocytopenia in males.

WAS

congenital thrombocytopenia


Input: While the WASP gene defects responsible for isolated thrombocytopenia and other mild presentations of WAS do not appear distinct from those resulting in severe WAS, these data indicate that analysis of WASP gene mutation provides a valuable tool for distinguishing the spectrum of WAS patients and the subset of males with isolated thrombocytopenia who represent mild cases of WAS..

isolated thrombocytopenia

WAS

WAS

WASP

isolated thrombocytopenia

WAS


Input: WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia.

Wiskott-Aldrich syndrome

X-linked thrombocytopenia


Input: The WASP gene has been recently cloned from Xp11.


Input: 23 and shown to be mutated in three patients with the Wiskott-Aldrich syndrome (WAS).

Wiskott-Aldrich syndrome

WAS


Input: We have developed a screening protocol for identifying WASP gene alterations in genomic DNA and have identified a spectrum of novel mutations in 12 additional unrelated families.


Input: These missense, nonsense and frameshift mutations involve eight of the 12 exons of the gene.


Input: Two mutations creating premature termination codons were associated with lack of detectable mRNA on Northern blots.


Input: Four amino acid substitutions, Leu27Phe, Thr48Ile, Val75Met and Arg477Lys, were found in patients with congenital thrombocytopenia and no clinically evident immune defect indicating that the WASP gene is the site for mutations in X-linked thrombocytopenia as well as in WAS.

congenital thrombocytopenia

X-linked thrombocytopenia

WAS


Input: A T-cell line from a WAS patient contained two independent DNA alterations, a constitutional frameshift mutation, also present in peripheral blood leukocytes from the patient, and compensatory splice site mutation unique to the cell line.

WAS


Input: The distribution of eight missense mutations provides valuable information on amino acids which are essential for normal protein function, and suggests that sites in the first two exons are hot-spots for mutation.


Input: Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease.

Machado-Joseph disease


Input: The size of the (CAG) n repeat array in the 3' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD).

Machado-Joseph disease

MJD


Input: Our data provide five novel observations.


Input: First, MJD is associated with expansion fo the array from the normal range of 14-37 repeats to 68-84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups.

MJD

MJD


Input: Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meioses, and this instability was associated with the clinical phenomenon of anticipation.

MJD


Input: Third, the size of the expanded allele is not only inversely correlated with the age-of-onset of MJD (r =-0. 738, p < 0. 001), but is also correlated with the frequency of other clinical features [e. g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats (p < 0. 001 and p < 0. 05 respectively)].

MJD


Input: Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD.

Huntington disease

HD

HD


Input: Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.

MJD


Input: Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease.

Machado-Joseph disease


Input: The size of the (CAG) n repeat array in the 3' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD).

Machado-Joseph disease

MJD


Input: Our data provide five novel observations.


Input: First, MJD is associated with expansion fo the array from the normal range of 14-37 repeats to 68-84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups.

MJD

MJD


Input: Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meioses, and this instability was associated with the clinical phenomenon of anticipation.

MJD


Input: Third, the size of the expanded allele is not only inversely correlated with the age-of-onset of MJD (r =-0. 738, p < 0. 001), but is also correlated with the frequency of other clinical features [e. g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats (p < 0. 001 and p < 0. 05 respectively)].

MJD


Input: Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD.

Huntington disease

HD

HD


Input: Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.

MJD


Input: A 4-megabase YAC contig that spans the Langer-Giedion syndrome region on human chromosome 8q24. 1: use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes (TRPS1 and EXT1).

Langer-Giedion syndrome

trichorhinophalangeal syndrome


Input: We have constructed a physical map covering over 4 Mb of human chromosome 8q24.


Input: 1 and used this map to refine the locations of the genes responsible for Langer-Giedion syndrome.

Langer-Giedion syndrome


Input: The map is composed of overlapping YAC clones that were identified and ordered in relation to sequence tagged sites mapped to the Langer-Giedion chromosomal region on somatic cell hybrids.


Input: The minimal region of overlap of Langer-Giedion syndrome deletions, previously identified by analysis of 15 patients, was placed on the map by analysis of 2 patients whose deletions define the endpoints.

Langer-Giedion syndrome


Input: The chromosome 8 breakpoint of a balanced t (8; 9) (q24. 11; q33. 3) translocation from a patient with trichorhinophalangeal syndrome (TRPS I) was found to be located just within the proximal end of the minimal deletion region.

trichorhinophalangeal syndrome

TRPS


Input: A deletion of 8q24.


Input: 3 in a patient with multiple exostoses was found to overlap the distal end of the LGS deletion region, indicating that the EXT1 gene is distal to the TRPS1 gene and supporting the hypothesis that Langer-Giedion syndrome is due to loss of functional copies of both the TRPS1 and the EXT1 genes

LGS

Langer-Giedion syndrome


Input: BRCA1 mutations in a population-based sample of young women with breast cancer.

breast cancer


Input: BACKGROUND.


Input: Inherited mutations in the BRCA1 gene are associated with a high risk of breast and ovarian cancer in some families.

breast and ovarian cancer


Input: However, little is known about the contribution of BRCA1 mutations to breast cancer in the general population.

breast cancer


Input: We analyzed DNA samples from women enrolled in a population-based study of early-onset breast cancer to assess the spectrum and frequency of germ-line BRCA1 mutations in young women with breast cancer.

breast cancer

breast cancer


Input: METHODS.


Input: We studied 80 women in whom breast cancer was diagnosed before the age of 35, and who were not selected on the basis of family history.

breast cancer


Input: Genomic DNA was studied for BRCA1 mutations by analysis involving single-strand conformation polymorphisms and with allele-specific assays.


Input: Alterations were defined by DNA sequencing.


Input: RESULTS.


Input: Germ-line BRCA1 mutations were identified in 6 of the 80 women.


Input: Four additional rare sequence variants of unknown functional importance were also identified.


Input: Two of the mutations and three of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer.

breast or ovarian cancer


Input: None of the mutations and only one of the rare variants was identified in a reference population of 73 unrelated subjects.


Input: CONCLUSIONS.


Input: Alterations in BRCA1 were identified in approximately 10 percent of this cohort of young women with breast cancer.

breast cancer


Input: The risk of harboring a mutation was not limited to women with family histories of breast or ovarian cancer.

breast or ovarian cancer


Input: These results represent a minimal estimate of the frequency of BRCA1 mutations in this population.


Input: Comprehensive methods of identifying BRCA1 mutations and understanding their importance will be needed before testing of women in the general population can be undertaken..


Input: Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.


Input: Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1.

breast cancer

breast and ovarian cancer


Input: Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families.


Input: Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1.


Input: Expressivity of 185delAG in these families varied, from early-onset breast cancer without ovarian cancer.

breast cancer

ovarian cancer


Input: Mutation 4184delTCAA occurred independently in two families.


Input: In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years.

breast cancer

ovarian cancer

prostatic cancer

breast cancer


Input: Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer.

breast cancer

ovarian cancer


Input: A 665-nt segment of the BRCA1 3-UTR and 1.


Input: 3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations.


Input: Overall in our series, BRCA1 mutations have been detected in 26 families 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage.

breast cancers


Input: Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2.


Input: A new glucose-6-phosphate dehydrogenase variant, G6PD Orissa (44 Ala--> Gly), is the major polymorphic variant in tribal populations in India.


Input: Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is usually found at high frequencies in areas of the world where malaria has been endemic.

Deficiency of glucose-6-phosphate dehydrogenase

malaria


Input: The frequency and genetic basis of G6PD deficiency have been studied in Africa, around the Mediterranean, and in the Far East, but little such information is available about the situation in India.

G6PD deficiency


Input: To determine the extent of heterogeneity of G6PD, we have studied several different Indian populations by screening for G6PD deficiency, followed by molecular analysis of deficient alleles.

G6PD deficiency


Input: The frequency of G6PD deficiency varies between 3% and 15% in different tribal and urban groups.

G6PD deficiency


Input: Remarkably, a previously unreported deficient variant, G6PD Orissa (44 Ala--> Gly), is responsible for most of the G6PD deficiency in tribal Indian populations but is not found in urban populations, where most of the G6PD deficiency is due to the G6PD Mediterranean (188 Ser--> Phe) variant.

G6PD deficiency

G6PD deficiency


Input: The KmNADP of G6PD Orissa is fivefold higher than that of the normal enzyme.


Input: This may be due to the fact that the alanine residue that is replaced by glycine is part of a putative coenzyme-binding site..


Input: Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect.

bipolar disorder


Input: A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD).

bipolar affective disorder

BPAD


Input: We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype, by using 31 polymorphic markers spanning chromosome 18.

BPAD


Input: Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype.


Input: The affected-sibpair analyses indicated excess allele sharing for markers on 18p within the region reported previously.


Input: The greatest sharing was at D18S37 64% in bipolar and recurrent unipolar (RUP) sib pairs (P =. 0006).


Input: In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at three markers on 18q at D18S41, 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles, and 21 pairs were discordant (P = 0004).


Input: The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i.


Input: e e., those in which the father or one of the fathers sibs is affected.


Input: In these pedigrees, the greatest allele sharing (81%; P =. 00002) and the highest LOD score (3. 51; phi = 0. 0) were observed at D18S41.


Input: Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder.

BPAD


Input: The number of loci involved, and their precise location, require further study


Input: A prevalent mutation for galactosemia among black Americans.

galactosemia


Input: OBJECTIVE To define the mutation causing galactosemia in patients of black American origin who have no galactose-1-phosphate uridyltransferase (GALT) activity in erythrocytes but good clinical outcome.

galactosemia


Input: METHODS We discovered a mutation caused by a C--> T transition at base-pair 1158 of the GALT gene that results in a serine-to-leucine substitution at codon 135 (S135L).


Input: We developed a method with which to screen populations for its prevalence.


Input: We compared galactose-1-phosphate uridyltransferase among erythrocytes, leukocytes, and transformed lymphoblasts, as well as total body oxidation of D-(13C)-galactose to 13CO2 among three genotypes for GALT (S135L/S135L, Q188R/Q188R, and Normal/Normal).


Input: RESULTS We found a 48% prevalence of the S135L mutation among 17 black American patients with classic galactosemia and a 1% prevalence in a population of 50 black Americans without galactosemia.

classic galactosemia

galactosemia


Input: The S135L mutation was not found in 84 white patients with G/G galactosemia nor in 87 white control subjects without galactosemia.

galactosemia

galactosemia


Input: We found normal whole body oxidation of D-(13C)-galactose by the patient homozygous for S135L and various degrees of enzyme impairment among different tissues.


Input: CONCLUSIONS The S135L mutation in the GALT gene is a prevalent cause of galactosemia among black patients.

galactosemia


Input: Because GALT activity varies in different tissues of patients homozygous for S135L, they may have a better clinical outcome than patients who are homozygous for Q188R when both are treated from infancy..


Input: A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families.

breast-ovarian cancer


Input: We have analyzed 20 breast-ovarian cancer families, the majority of which show positive evidence of linkage to chromosome 17q12 for germ-line mutations in the BRCA1 gene.

breast-ovarian cancer


Input: BRCA1 mutations cosegregating with breast and ovarian cancer susceptibility were identified in 16 families, including 1 family with a case of male breast cancer.

breast and ovarian cancer

male breast cancer


Input: Nine of these mutations have not been reported previously.


Input: The majority of mutations were found to generate a premature stop codon leading to the formation of a truncated BRCA1 protein of 2%-88% of the expected normal length.


Input: Two mutations altered the RING finger domain.


Input: Sequencing of genomic DNA led to the identification of a mutation in the coding region of BRCA1 in 12 families, and cDNA analysis revealed an abnormal or missing BRCA1 transcript in 4 of the 8 remaining families.


Input: A total of eight mutations were associated with a reduced quantity of BRCA1 transcript.


Input: We were unable to detect BRCA1 mutations in 4 of the 20 families, but only 1 of these was clearly linked to BRCA1.


Input: It is expected that the majority of clear examples of the breast-ovarian syndrome will be associated with germ-line mutations in the coding region of BRCA1..

breast-ovarian syndrome


Input: Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities.

Brca1 deficiency

embryonic lethality

neuroepithelial abnormalities


Input: The breast and ovarian cancer susceptibility gene, BRCA1, has been cloned and shown to encode a zinc-finger protein of unknown function.

breast and ovarian cancer


Input: Mutations in BRCA1 account for at least 80% of families with both breast and ovarian cancer, as well as some non-familial sporadic ovarian cancers.

breast and ovarian cancer

ovarian cancers


Input: The loss of wild-type BRCA1 in tumours of individuals carrying one nonfunctional BRCA1 allele suggests that BRCA1 encodes a tumour suppressor that may inhibit the proliferation of mammary epithelial cells.

tumours

tumour


Input: To examine the role of BRCA1 in normal tissue growth and differentiation, and to generate a potential model for the cancer susceptibility associated with loss of BRCA1 function, we have created a mouse line carrying a mutation in one Brca1 allele.

cancer


Input: Analysis of mice homozygous for the mutant allele indicate that Brca1 is critical for normal development, as these mice died in utero between 10 and 13 days of gestation (E10-E13).


Input: Abnormalities in Brca1-deficient embryos were most evident in the neural tube, with 40% of the embryos presenting with varying degrees of spina bifida and anencephaly.

spina bifida

anencephaly


Input: In addition, the neuroepithelium in Brca1-deficient embryos appeared disorganized, with signs of both rapid proliferation and excessive cell death..


Input: Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy.

adrenoleukodystrophy

adrenomyeloneuropathy


Input: Adrenoleukodystrophy (ALD), an X-linked inherited metabolic disorder, is the most frequent inborn peroxisomal disease.

Adrenoleukodystrophy

ALD

X-linked inherited metabolic disorder

inborn peroxisomal disease


Input: It leads to demyelination in the central and peripheral nervous system.

demyelination in the central and peripheral nervous system


Input: Defective beta-oxidation of saturated very long chain fatty acids (VLCFAs; C22 0-C26 0) in peroxisomes has been shown to lead to an accumulation of VLCFAs in leukoid areas of the central nervous system, peripheral nerves, adrenal gland, and blood.


Input: The ALD gene has been recently identified and encodes a 745-amino-acid protein.

ALD


Input: We screened patients with adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN) from 20 kindreds for mutations in the ALD gene.

adrenoleukodystrophy

adrenomyeloneuropathy

ALD

AMN

ALD


Input: Eleven missense and two nonsense mutations, five deletions, and one insertion were detected by direct sequencing of eight reverse transcribed fragments of the ALD-gene mRNA.

ALD


Input: Four mutations could be shown to be de novo.


Input: All mutations could be confirmed in carriers by sequencing genomic DNA.


Input: No correlation between the type of mutation and the severity of the phenotype could be observed.


Input: The mutations were not detected in the ALD gene of 30 healthy persons..

ALD


Input: The murine homolog of the human breast and ovarian cancer susceptibility gene Brca1 maps to mouse chromosome 11D.

breast and ovarian cancer


Input: The recently cloned human breast and ovarian cancer susceptibility gene, BRCA1, is located on human chromosome 17q21.

breast and ovarian cancer


Input: We have isolated murine genomic clones containing Brca1 as a first step in generating a mouse model for the loss of BRCA1 function.


Input: A mouse genomic library was screened using probes corresponding to exon 11 of the human BRCA1 gene.


Input: Two overlapping mouse clones were identified that hybridized to human BRCA1 exons 9-12.


Input: Sequence analysis of 1.


Input: 4 kb of the region of these clones corresponding to part of human exon 11 revealed 72% nucleic acid identity but only 50% amino acid identity with the human gene.


Input: The longest of the mouse Brca1 genomic clones maps to chromosome 11D, as determined by two-color fluorescence in situ hybridization.


Input: The synteny to human chromosome 17 was confirmed by cohybridization with the mouse probe for the NF1-gene.


Input: This comparative study confirms that the relative location of the BRCA1 gene has been conserved between mice and humans.


Input: Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias.

Atelosteogenesis type II

diastrophic dysplasia

chondrodysplasias


Input: Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD).

Atelosteogenesis type II

AO II

chondrodysplasia

chondrodysplasia

diastrophic dysplasia

DTD


Input: The similarity suggests a shared pathogenesis involving lesions in the same biochemical pathway and perhaps the same gene.


Input: DTD is caused by mutations in the recently identified diastrophic dysplasia sulfate-transporter gene (DTDST).

DTD

diastrophic dysplasia


Input: Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro.

AOII


Input: Together with our recent observation that a third even more severe chondrodysplasia, achondrogenesis type IB, is also caused by mutations in DTDST, these results demonstrate a phenotypic series of three chondrodysplasias of increasing severity caused by lesions in a single sulfate-transporter gene.

chondrodysplasia

chondrodysplasias


Input: The severity of the phenotype appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein..


Input: Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.


Input: Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families.

breast and ovarian cancer


Input: To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations.

breast/ovarian cancer


Input: Tests of both mutations and family-specific differences in age at diagnosis were not significant.


Input: A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P =. 069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1.

breast and ovarian cancer

ovarian cancer


Input: For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago.


Input: In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed.


Input: For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events.


Input: Isolation of the mouse homologue of BRCA1 and genetic mapping to mouse chromosome 11.


Input: The BRCA1 gene is in large part responsible for hereditary human breast and ovarian cancer.

hereditary human breast and ovarian cancer


Input: Here we report the isolation of the murine Brca1 homologue cDNA clones.


Input: In addition, we identified genomic P1 clones that contain most, if not all, of the mouse Brca1 locus.


Input: DNA sequence analysis revealed that the mouse and human coding regions are 75% identical at the nucleotide level while the predicted amino acid identity is only 58%.


Input: A DNA sequence variant in the Brca1 locus was identified and used to map this gene on a (Mus m. musculus Czech II x C57BL/KsJ) F1 x C57BL/KsJ intersubspecific backcross to distal mouse chromosome 11.


Input: The mapping of this gene to a region highly syntenic with human chromosome 17, coupled with Southern and Northern analyses, confirms that we isolated the murine Brca1 homologue rather than a related RING finger gene.


Input: The isolation of the mouse Brca1 homologue will facilitate the creation of mouse models for germline BRCA1 defects..

BRCA1 defects


Input: Emerin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy.

Emerin deficiency

Emery-Dreifuss muscular dystrophy


Input: Mutations in the STA gene at the Xq28 locus have been found in patients with X-linked Emery-Dreifuss muscular dystrophy (EDMD).

X-linked Emery-Dreifuss muscular dystrophy

EDMD


Input: This gene encodes a hitherto unknown protein named emerin.


Input: To elucidate the subcellular localization of emerin, we raised two antisera against synthetic peptide fragments predicted from emerin cDNA.


Input: Using both antisera, we found positive nuclear membrane staining in skeletal, cardiac and smooth muscles in the normal controls and in patients with neuromuscular diseases other than EDMD.

neuromuscular diseases

EDMD


Input: In contrast, a deficiency in immunofluorescent staining of skeletal and cardiac muscle from EDMD patients was observed.

EDMD


Input: A 34 kD protein is immunoreactive with the antisera--the protein is equivalent to that predicted for emerin.


Input: Together, our findings suggest the specific deficiency of emerin in the nuclear membrane of muscle cells in patients with EDMD..

deficiency of emerin

EDMD


Input: Growth retardation and tumour inhibition by BRCA1.

Growth retardation

tumour


Input: Inherited mutations in BRCA1 predispose to breast and ovarian cancer, but the role of BRCA1 in sporadic breast and ovarian cancer has previously been elusive.

breast and ovarian cancer

breast and ovarian cancer


Input: Here, we show that retroviral transfer of the wild-type BRCA1 gene inhibits growth in vitro of all breast and ovarian cancer cell lines tested, but not colon or lung cancer cells or fibroblasts.

breast and ovarian cancer

colon or lung cancer


Input: Mutant BRCA1 has no effect on growth of breast cancer cells; ovarian cancer cell growth is not affected by BRCA1 mutations in the 5 portion of the gene, but is inhibited by 3 BRCA1 mutations.

breast cancer

ovarian cancer


Input: Development of MCF-7 tumours in nude mice is inhibited when MCF-7 cells are transfected with wild-type, but not mutant, BRCA1.

MCF-7 tumours


Input: Most importantly, among mice with established MCF-7 tumours, peritoneal treatment with a retroviral vector expressing wild-type BRCA1 significantly inhibits tumour growth and increased survival..

MCF-7 tumours

tumour