Input: We report a Japanese family with adrenoleukodystrophy (ALD) with a three base pair deletion (delGAG 291) in the ALD gene.

adrenoleukodystrophy

ALD

ALD


Input: A variety of phenotypes were observed within this family.


Input: While the proband (patient 1) was classified as having a rare intermediate type of adult cerebral and cerebello-brain stem forms, his younger brother (patient 2) and nephew (patient 3) had a childhood ALD type.

ALD


Input: Another nephew (patient 4) of patient 1 was classified as having an adolescent form.


Input: The tau level in the cerebrospinal fluid (CSF) in patient 1 was as high as that of patients with Alzheimers disease (AD).

Alzheimers disease

AD


Input: His brain magnetic resonance image (MRI) showed abnormalities in the bilateral cerebellar hemispheres and brain stem, but not in the cerebral white matter, where marked reductions of the cerebral blood flow and oxygen metabolism were clearly demonstrated by positron emission tomography (PET).

abnormalities in the bilateral cerebellar hemispheres


Input: In patients 2 and 3, the autopsy findings showed massive demyelination of the cerebral white matter with sparing of the U-fibers, compatible with the findings of childhood ALD.

demyelination of the cerebral white matter

ALD


Input: Oleic and erucic acids (Lorenzos Oil) were administered to patients 1 and 4, but sufficient effectiveness was not obtained.


Input: The findings in this family suggest that delGAG291 is part of the cause of Japanese ALD with phenotypic variations.

ALD


Input: Moreover, although the scale of the study is limited, there is a possibility that PET can detect an insidious lesion which is undetectable by computed tomogram (CT) or MRI analysis, and that the higher level of tau reflects the process of neuronal degeneration in ALD.

insidious lesion

neuronal degeneration

ALD


Input: Lorenzos Oil should be given in the early stage..


Input: Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency.

complement C9 deficiency


Input: Deficiency of the ninth component of human complement (C9) is the most common complement deficiency in Japan but is rare in other countries.

Deficiency of the ninth component of human complement

complement deficiency


Input: We studied the molecular basis of C9 deficiency in four Japanese C9-deficient patients who had suffered from meningococcal meningitis.

C9 deficiency

meningococcal meningitis


Input: Direct sequencing of amplified C9 cDNA and DNA revealed a nonsense substitution (CGA--> TGA) at codon 95 in exon 4 in the four C9-deficient individuals.


Input: An allele-specific polymerase chain reaction system designed to detect exclusively only one of the normal and mutant alleles indicated that all the four patients were homozygous for the mutation in exon 4 and that the parents of patient 2 were heterozygous.


Input: The common mutation at codon 95 in exon 4 might be responsible for most Japanese C9 deficiency..

C9 deficiency


Input: BRCA1 required for transcription-coupled repair of oxidative DNA damage.


Input: The breast and ovarian cancer susceptibility gene BRCA1 encodes a zinc finger protein of unknown function.

breast and ovarian cancer


Input: Association of the BRCA1 protein with the DNA repair protein Rad51 and changes in the phosphorylation and cellular localization of the protein after exposure to DNA-damaging agents are consistent with a role for BRCA1 in DNA repair.


Input: Here, it is shown that mouse embryonic stem cells deficient in BRCA1 are defective in the ability to carry out transcription-coupled repair of oxidative DNA damage, and are hypersensitive to ionizing radiation and hydrogen peroxide.

deficient in BRCA1


Input: These results suggest that BRCA1 participates, directly or indirectly, in transcription-coupled repair of oxidative DNA damage..


Input: Truncation mutations in the transactivation region of PAX6 result in dominant-negative mutants.


Input: PAX6 is a transcription factor with two DNA-binding domains (paired box and homeobox) and a proline-serine-threonine (PST)-rich transactivation domain.


Input: PAX6 regulates eye development in animals ranging from jellyfish to Drosophila to humans.


Input: Heterozygous mutations in the human PAX6 gene result in various phenotypes, including aniridia, Peters anomaly, autosomal dominant keratitis, and familial foveal dysplasia.

aniridia

Peters anomaly

autosomal dominant keratitis

familial foveal dysplasia


Input: It is believed that the mutated allele of PAX6 produces an inactive protein and aniridia is caused due to genetic haploinsufficiency.

aniridia


Input: However, several truncation mutations have been found to occur in the C-terminal half of PAX6 in patients with Aniridia resulting in mutant proteins that retain the DNA-binding domains but have lost most of the transactivation domain.

Aniridia


Input: It is not clear whether such mutants really behave as loss-of-function mutants as predicted by haploinsufficiency.


Input: Contrary to this theory, our data showed that these mutants are dominant-negative in transient transfection assays when they are coexpressed with wild-type PAX6.


Input: We found that the dominant-negative effects result from the enhanced DNA binding ability of these mutants.


Input: Kinetic studies of binding and dissociation revealed that various truncation mutants have 3-5-fold higher affinity to various DNA-binding sites when compared with the wild-type PAX6.


Input: These results provide a new insight into the role of mutant PAX6 in causing aniridia..

aniridia


Input: Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very-long-chain acyl-coenzyme A dehydrogenase deficiency.

hypertrophic cardiomyopathy

very-long-chain acyl-coenzyme A dehydrogenase deficiency


Input: Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is a disorder of fatty acid beta oxidation that reportedly has high rates of morbidity and mortality.

Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency


Input: We describe the outcome of a 5-year-old girl with VLCAD deficiency who was first seen at 5 months of age with severe hypertrophic cardiomyopathy, hepatomegaly, encephalopathy, and hypotonia.

VLCAD deficiency

hypertrophic cardiomyopathy

hepatomegaly

encephalopathy

hypotonia


Input: Biochemical studies indicated VLCAD deficiency caused by a stable yet inactive enzyme.

VLCAD deficiency


Input: Molecular genetic analysis of her VLCAD gene revealed a T1372C (F458L) missense mutation and a 1668 ACAG 1669 splice site mutation.


Input: After initial treatment with intravenous glucose and carnitine, the patient has thrived on a low-fat diet supplemented with medium-chain triglyceride oil and carnitine and avoidance of fasting.


Input: Her ventricular hypertrophy resolved significantly over 1 year, and cognitively, she is in the superior range for age.


Input: Clinical recognition of VLCAD deficiency is important because it is one of the few directly treatable causes of cardiomyopathy in children..

VLCAD deficiency

cardiomyopathy


Input: Cloning of a novel member of the low-density lipoprotein receptor family.


Input: A gene encoding a novel transmembrane protein was identified by DNA sequence analysis within the insulin-dependent diabetes mellitus (IDDM) locus IDDM4 on chromosome 11q13.

insulin-dependent diabetes mellitus

IDDM


Input: Based on its chromosomal position, this gene is a candidate for conferring susceptibility to diabetes.

diabetes


Input: The gene, termed low-density lipoprotein receptor related protein 5 (LRP5), encodes a protein of 1615 amino acids that contains conserved modules which are characteristic of the low-density lipoprotein (LDL) receptor family.


Input: These modules include a putative signal peptide for protein export, four epidermal growth factor (EGF) repeats with associated spacer domains, three LDL-receptor (LDLR) repeats, a single transmembrane spanning domain, and a cytoplasmic domain.


Input: The encoded protein has a unique organization of EGF and LDLR repeats; therefore, LRP5 likely represents a new category of the LDLR family.


Input: Both human and mouse LRP5 cDNAs have been isolated and the encoded mature proteins are 95% identical, indicating a high degree of evolutionary conservation..


Input: The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history.

APC

colorectal tumors


Input: Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene.

familial adenomatous polyposis

FAP

autosomal dominant disease

colorectal adenomas and carcinoma

APC


Input: A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5 and 3 regions of the APC gene.

FAP

attenuated adenomatous polyposis coli

APC


Input: Attenuated adenomatous polyposis coli patients have " multiple " colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP.

Attenuated adenomatous polyposis coli

colorectal adenomas

FAP


Input: Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome.

adenomas

APC


Input: Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim.

APC

colorectal tumors

adenomas


Input: We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants.

colorectal adenomas and/or carcinoma

APC


Input: Three patients with the I1307K allele were detected, each of Ashkenazi descent.


Input: Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum.

metaplastic polyps of the colorectum


Input: There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population..

APC

colorectal adenomas and carcinoma

FAP

colorectal cancer


Input: Genomic structure of the human congenital chloride diarrhea (CLD) gene.

congenital chloride diarrhea

CLD


Input: Congenital chloride diarrhea (CLD) is caused by mutations in a gene which encodes an intestinal anion transporter.

Congenital chloride diarrhea

CLD


Input: We report here the complete genomic organization of the human CLD gene which spans approximately 39kb, and comprises 21 exons.

CLD


Input: All exon/intron boundaries conform to the GT/AG rule.


Input: An analysis of the putative promoter region sequence shows a putative TATA box and predicts multiple transcription factor binding sites.


Input: The genomic structure was determined using DNA from several sources including multiple large-insert libaries and genomic DNA from Finnish CLD patients and controls.

CLD


Input: Exon-specific primers developed in this study will facilitate mutation screening studies of patients with the disease.


Input: Genomic sequencing of a BAC clone H _ RG364P16 revealed the presence of another, highly homologous gene 3 of the CLD gene, with a similar genomic structure, recently identified as the Pendred syndrome gene (PDS)..

CLD

Pendred syndrome

PDS


Input: The APCI1307K allele and cancer risk in a community-based study of Ashkenazi Jews.

cancer


Input: Mutations in APC are classically associated with familial adenomatous polyposis (FAP), a highly penetrant autosomal dominant disorder characterized by multiple intestinal polyps and, without surgical intervention, the development of colorectal cancer (CRC).

familial adenomatous polyposis

FAP

autosomal dominant disorder

polyps

colorectal cancer

CRC


Input: APC is a tumour-suppressor gene, and somatic loss occurs in tumours.

APC

tumours


Input: The germline T-to-A transversion responsible for the APC I1307K allele converts the wild-type sequence to a homopolymer tract (A8) that is genetically unstable and prone to somatic mutation.


Input: The I1307K allele was found in 6.


Input: 1% of unselected Ashkenazi Jews and higher proportions of Ashkenazim with family or personal histories of CRC (ref. 2).

CRC


Input: To evaluate the role of I1307K in cancer, we genotyped 5, 081 Ashkenazi volunteers in a community survey.

cancer


Input: Risk of developing colorectal, breast and other cancers were compared between genotyped I1307K carriers and non-carriers and their first-degree relatives.

colorectal, breast and other cancers


Input: Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene.

Friedreich ataxia

FRDA


Input: Friedreich ataxia is usually caused by an expansion of a GAA trinucleotide repeat in intron 1 of the FRDA gene.

Friedreich ataxia

FRDA


Input: Occasionally, a fully expanded allele has been found to arise from a premutation of 100 or less triplet repeats.


Input: We have examined the sperm DNA of a premutation carrier.


Input: This mans leucocyte DNA showed one normal allele and one allele of approximately 100 repeats.


Input: His sperm showed an expanded allele in a tight range centering on a size of approximately 320 trinucleotide repeats.


Input: His affected son has repeat sizes of 1040 and 540.


Input: These data suggest that expansion occurs in two stages, the first during meiosis followed by a second mitotic expansion.


Input: We also show that in all informative carrier father to affected child transmissions, with the notable exception of the premutation carrier, the expansion size decreases..


Input: The R496H mutation of arylsulfatase A does not cause metachromatic leukodystrophy.

metachromatic leukodystrophy


Input: Deficiency of arylsulfatase A (ARSA) enzyme activity causes metachromatic leukodystrophy (MLD).

Deficiency of arylsulfatase A

metachromatic leukodystrophy

MLD


Input: A number of ARSA gene mutations responsible for MLD have been identified.

MLD


Input: Recently, the R496H mutation of ARSA was proposed to be a cause of MLD (Draghia et al., 1997).

MLD


Input: We have investigated the R496H mutation and found this mutation at a relatively high frequency in an African American population (f = 0. 09, n = 61 subjects).


Input: The ARSA enzyme activity in subjects with and without the R496H mutation was determined and found to be normal.


Input: It is therefore concluded that the R496H mutation of ARSA does not negatively influence the activity of ARSA and is not a cause of MLD


Input: Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes.

renal cell carcinoma

von Hippel-Lindau


Input: To discover genes involved in von Hippel-Lindau (VHL)-mediated carcinogenesis, we used renal cell carcinoma cell lines stably transfected with wild-type VHL-expressing transgenes.

von Hippel-Lindau

VHL

renal cell carcinoma


Input: Large-scale RNA differential display technology applied to these cell lines identified several differentially expressed genes, including an alpha carbonic anhydrase gene, termed CA12.


Input: The deduced protein sequence was classified as a one-pass transmembrane CA possessing an apparently intact catalytic domain in the extracellular CA module.


Input: Reintroduced wild-type VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines.

VHL

renal cell carcinoma


Input: Similar results were obtained with CA9, encoding another transmembrane CA with an intact catalytic domain.


Input: Although both domains of the VHL protein contribute to regulation of CA12 expression, the elongin binding domain alone could effectively regulate CA9 expression.

VHL


Input: We mapped CA12 and CA9 loci to chromosome bands 15q22 and 17q21.


Input: 2 respectively, regions prone to amplification in some human cancers.

cancers


Input: Additional experiments are needed to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth.

cancer


Input: A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).

diabetes mellitus

optic atrophy

Wolfram syndrome


Input: Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy.

Wolfram syndrome

WFS

autosomal recessive neurodegenerative disorder

insulin-dependent diabetes mellitus

optic atrophy


Input: Linkage to markers on chromosome 4p was confirmed in five families.


Input: On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb.

WFS


Input: Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype.


Input: WFS1 appears to function in survival of islet beta-cells and neurons..


Input: Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.

tumor


Input: BRCA1 and BRCA2 account for most cases of familial, early onset breast and/or ovarian cancer and encode products that each interact with hRAD51.

breast and/or ovarian cancer


Input: Results presented here show that BRCA1 and BRCA2 coexist in a biochemical complex and colocalize in subnuclear foci in somatic cells and on the axial elements of developing synaptonemal complexes.


Input: Like BRCA1 and RAD51, BRCA2 relocates to PCNA + replication sites following exposure of S phase cells to hydroxyurea or UV irradiation.


Input: Thus, BRCA1 and BRCA2 participate, together, in a pathway (s) associated with the activation of double-strand break repair and/or homologous recombination.


Input: Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and/or ovarian cancer..

hereditary breast and/or ovarian cancer


Input: A novel Arg362Ser mutation in the sterol 27-hydroxylase gene (CYP27): its effects on pre-mRNA splicing and enzyme activity.


Input: A novel C to A mutation in the sterol 27-hydroxylase gene (CYP27) was identified by sequencing amplified CYP27 gene products from a patient with cerebrotendinous xanthomatosis (CTX).

cerebrotendinous xanthomatosis

CTX


Input: The mutation changed the adrenodoxin cofactor binding residue 362Arg to 362Ser (CGT 362Arg to AGT 362Ser), and was responsible for deficiency in the sterol 27-hydroxylase activity, as confirmed by expression of mutant cDNA into COS-1 cells.


Input: Quantitative analysis showed that the expression of CYP27 gene mRNA in the patient represented 52.


Input: 5% of the normal level.


Input: As the mutation occurred at the penultimate nucleotide of exon 6 (-2 position of exon 6-intron 6 splice site) of the gene, we hypothesized that the mutation may partially affect the normal splicing efficiency in exon 6 and cause alternative splicing elsewhere, which resulted in decreased transcript in the patient.


Input: Transfection of constructed minigenes, with or without the mutation, into COS-1 cells confirmed that the mutant minigene was responsible for a mRNA species alternatively spliced at an activated cryptic 5 splice site 88 bp upstream from the 3 end of exon 6.


Input: Our data suggest that the C to A mutation at the penultimate nucleotide of exon 6 of the CYP27 gene not only causes the deficiency in the sterol 27-hydroxylase activity, but also partially leads to alternative pre-mRNA splicing of the gene.

deficiency in the sterol 27-hydroxylase activity


Input: To our knowledge, this is the first report regarding effects on pre-mRNA splicing of a mutation at the-2 position of a 5 splice site.


Input: ATM germline mutations in classical ataxia-telangiectasia patients in the Dutch population.

ataxia-telangiectasia


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

autosomal recessive disorder ataxia-telangiectasia

A-T


Input: In our study, we have determined the ATM mutation spectrum in 19 classical A-T patients, including some immigrant populations, as well as 12 of Dutch ethnic origin.

A-T


Input: Both the protein truncation test (PTT) and the restriction endonuclease fingerprinting (REF) method were used and compared for their detection efficiency, identifying 76% and 60% of the mutations, respectively.


Input: Most patients were found to be compound heterozygote.


Input: Seventeen mutations were distinct, of which 10 were not reported previously.


Input: Mutations are small deletions or point mutations frequently affecting splice sites.


Input: Moreover, a 16.


Input: 7-kb genomic deletion of the 3 end of the gene, most likely a result of recombination between two LINE elements, was identified.


Input: The most frequently found mutation, identified in three unrelated Turkish A-T individuals, was previously described to be a Turkish A-T founder mutation.

A-T

A-T


Input: The presence of a founder mutation among relatively small ethnic population groups in Western Europe could indicate a high carrier frequency in such communities.


Input: In patients of Dutch ethnic origin, however, no significant founder effect could be identified.


Input: The observed genetic heterogeneity including the relative high percentage of splice-site mutations had no reflection on the phenotype.


Input: All patients manifested classical A-T and increased cellular radioresistant DNA synthesis.

A-T


Input: Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome.

autosomal recessive Alport syndrome


Input: Autosomal recessive Alport syndrome is a progressive hematuric glomerulonephritis characterized by glomerular basement membrane abnormalities and associated with mutations in either the COL4A3 or the COL4A4 gene, which encode the alpha3 and alpha4 type IV collagen chains, respectively.

Autosomal recessive Alport syndrome

hematuric glomerulonephritis

glomerular basement membrane abnormalities


Input: To date, mutation screening in the two genes has been hampered by the lack of genomic structure information.


Input: We report here the complete characterization of the 48 exons of the COL4A4 gene, a comprehensive gene screen, and the subsequent detection of 10 novel mutations in eight patients diagnosed with autosomal recessive Alport syndrome.

autosomal recessive Alport syndrome


Input: Furthermore, we identified a glycine to alanine substitution in the collagenous domain that is apparently silent in the heterozygous carriers, in 11.


Input: 5% of all control individuals, and in one control individual homozygous for this glycine substitution.


Input: There has been no previous finding of a glycine substitution that is not associated with any obvious phenotype in homozygous individuals.


Input: Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families.

breast and ovarian cancer


Input: We have identified four mutations in each of the breast cancer-susceptibility genes, BRCA1 and BRCA2, in French Canadian breast cancer and breast/ovarian cancer families from Quebec.

breast cancer

breast cancer

breast/ovarian cancer


Input: To identify founder effects, we examined independently ascertained French Canadian cancer families for the distribution of these eight mutations.

cancer


Input: Mutations were found in 41 of 97 families.


Input: Six of eight mutations were observed at least twice.


Input: The BRCA1 C4446T mutation was the most common mutation found, followed by the BRCA2 8765delAG mutation.


Input: Together, these mutations were found in 28 of 41 families identified to have a mutation.


Input: The odds of detection of any of the four BRCA1 mutations was 18.


Input: 7x greater if one or more cases of ovarian cancer were also present in the family.

ovarian cancer


Input: The odds of detection of any of the four BRCA2 mutations was 5.


Input: 3x greater if there were at least five cases of breast cancer in the family.

breast cancer


Input: Interestingly, the presence of a breast cancer case < 36 years of age was strongly predictive of the presence of any of the eight mutations screened.

breast cancer


Input: Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population.


Input: The identification of common BRCA1 and BRCA2 mutations will facilitate carrier detection in French Canadian breast cancer and breast/ovarian cancer families.

breast cancer

breast/ovarian cancer


Input: Are Dp71 and Dp140 brain dystrophin isoforms related to cognitive impairment in Duchenne muscular dystrophy?

cognitive impairment

Duchenne muscular dystrophy


Input: Molecular study and neuropsychological analysis were performed concurrently on 49 patients with Duchenne muscular dystrophy (DMD) in order to find a molecular explanation for the cognitive impairment observed in most DMD patients.

Duchenne muscular dystrophy

DMD

cognitive impairment

DMD


Input: Complete analysis of the dystrophin gene was performed to define the localization of deletions and duplications in relation to the different DMD promoters.

DMD


Input: Qualitative analysis of the Dp71 transcript and testing for the specific first exon of Dp140 were also carried out.


Input: Neuropsychological analysis assessed verbal and visuospatial intelligence, verbal memory, and reading skills.


Input: Comparison of molecular and psychometric findings demonstrated that deletions and duplications that were localized in the distal part of the gene seemed to be preferentially associated with cognitive impairment.

cognitive impairment


Input: Two altered Dp71 transcripts and two deleted Dp140 DNA sequences were found in four patients with severe cerebral dysfunction.

cerebral dysfunction


Input: These findings suggest that some sequences located in the distal part of the gene and, in particular, some DMD isoforms expressed in the brain may be related to the cognitive impairment associated with DMD..

DMD

cognitive impairment

DMD


Input: I1307K APC and hMLH1 mutations in a non-Jewish family with hereditary non-polyposis colorectal cancer.

hereditary non-polyposis colorectal cancer


Input: We describe a French Canadian hereditary non-polyposis colorectal cancer (HNPCC) kindred which carries a novel truncating mutation in hMLH1.

hereditary non-polyposis colorectal cancer

HNPCC


Input: Interestingly, the I1307K APC polymorphism, associated with an increased risk of colorectal cancer, is also present in this family.

colorectal cancer


Input: The I1307K polymorphism has previously only been identified in individuals of self-reported Ashkenazi Jewish origins.


Input: In addition, in this family, there appears to be no relationship between the I1307K polymorphism and the presence or absence of cancer..

cancer


Input: Identification of a novel mutation of the CPO gene in a Japanese hereditary coproporphyria family.

hereditary coproporphyria


Input: Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase (CPO) caused by a mutation in the CPO gene.

Hereditary coproporphyria

HCP

autosomal dominant disease

deficiency of coproporphyrinogen oxidase


Input: Only 11 mutations of the gene have been reported in HCP patients.

HCP


Input: We report another mutation in a Japanese family.


Input: Polymerase chain reaction-single strand conformational polymorphism and direct sequence analyses demonstrated a C to T substitution in exon 1 of the CPO gene at nucleotide position 85, which lies in the putative presequence for targeting to mitochondria.


Input: This mutation changes the codon for glutamine to a termination codon at amino acid position 29.


Input: MaeI restriction analysis showed two other carriers in the family.


Input: The C-T mutation is located within a recently proposed putative alternative translation initiation codon (TIC-1), supporting that TIC-1 is the real TIC rather than TIC-2..


Input: Human complement factor H deficiency associated with hemolytic uremic syndrome.

Human complement factor H deficiency

hemolytic uremic syndrome


Input: This study reports on six cases of deficiency in the human complement regulatory protein Factor H (FH) in the context of an acute renal disease.

deficiency in the human complement regulatory protein Factor H

acute renal disease


Input: Five of the cases were observed in children presenting with idiopathic hemolytic uremic syndrome (HUS).

hemolytic uremic syndrome

HUS


Input: Two of the children exhibited a homozygous deficiency characterized by the absence of the 150-kD form of Factor H and the presence, upon immunoblotting, of the 42-kD Factor H-like protein 1 (FHL-1) and other FH-related protein (FHR) bands.


Input: Southern blot and PCR analysis of DNA of one patient with homozygous deficiency ruled out the presence of a large deletion of the FH gene as the underlying defect for the deficiency.


Input: The other four children presented with heterozygous deficiency and exhibited a normal immunoblotting pattern of proteins of the FH family.


Input: Factor H deficiency is the only complement deficiency associated with HUS.

Factor H deficiency

complement deficiency

HUS


Input: These observations suggest a role for FH and/or FH receptors in the pathogenesis of idiopathic HUS..

HUS


Input: Further evidence for a major ancient mutation underlying myotonic dystrophy from linkage disequilibrium studies in the Japanese population.

myotonic dystrophy


Input: The myotonic dystrophy (DM) mutation is an unstable (CTG) n repeat, present at a copy number of 5-37 repeats on normal chromosomes but amplified to 50-3000 copies on DM chromosomes.

myotonic dystrophy

DM

DM


Input: Previous findings in Caucasian populations of a DM founder chromosome raise a question about the molecular events involved in the expansion mutation.

DM


Input: To investigate whether a founder chromosome for the DM mutation exists in the Japanese population, we genotyped families using polymorphic markers near the (CTG) n repeat region and constructed haplotypes.

DM


Input: Six different haplotypes were found and DM alleles were always haplotype A.

DM


Input: To find an origin of the (CTG) n repeat mutation and to investigate the mechanism of the expansion mutation in the Japanese population we have studied 90 Japanese DM families comprising 190 affected and 130 unaffected members.

DM


Input: The results suggest that a few common ancestral mutations in both Caucasian and Japanese populations have originated by expansion of an ancestral n = 5 repeat to n = 19-37 copies.


Input: These data support multistep models of triplet repeat expansion that have been proposed for both DM and Friedreichs ataxia..

DM

Friedreichs ataxia


Input: The molecular basis of C6 deficiency in the western Cape, South Africa.

C6 deficiency


Input: Deficiency of the sixth component of human complement (C6) has been reported in a number of families from the western Cape, South Africa.

Deficiency of the sixth component of human complement


Input: Meningococcal disease is endemic in the Cape and almost all pedigrees of total C6 deficiency (C6Q0) have been ascertained because of recurrent disease.

Meningococcal disease

C6 deficiency


Input: We have sequenced the expressed exons of the C6 gene from selected cases and have found three molecular defects leading to total deficiency 879delG, which is the common defect in the Cape and hitherto unreported, and 1195delC and 1936delG, which have been previously reported in African-Americans.


Input: We also show that the 879delG and 1195delC defects are associated with characteristic C6/C7 region DNA marker haplotypes, although small variations were observed.


Input: The 1936delG defect was observed only once in the Cape, but its associated haplotype could be deduced.


Input: The data from the haplotypes indicate that these three molecular defects account for the defects in all the 38 unrelated C6Q0 individuals we have studied from the Cape.


Input: We have also observed the 879delG defect in two Dutch C6-deficient kindreds, but the 879delG defect in the Cape probably did not come from The Netherlands..


Input: Complement C7 deficiency: seven further molecular defects and their associated marker haplotypes.

Complement C7 deficiency


Input: Seven further molecular bases of C7 deficiency are described.

C7 deficiency


Input: All these new molecular defects involve single-nucleotide events, deletions and substitutions, some of which alter splice sites, and others codons.


Input: They are distributed along the C7 gene, but predominantly towards the 3 end.


Input: All were found in compound heterozygous individuals.


Input: The C6/C7 marker haplotypes associated with most C7 defects are tabulated..

C7 defects


Input: A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish.

bipolar affective disorder


Input: Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression.

Bipolar affective disorder

BPAD

manic-depressive illness

mania

hypomania

depression


Input: Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD.

BPAD


Input: To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD.

BPAD


Input: To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD.

BPAD

genetic disorders

psychiatric disorder

BPAD


Input: We have found strong evidence for a locus on chromosome 4p at D4S2949 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4. 05, P = 5. 22 x 10 (-4); SIBPAL Pempirical value < 3 x 10 (-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score = 3. 29, P = 2. 57 x 10 (-3); SIBPAL Pempirical value < 1 x 10 (-3)) that are linked to mental health wellness.


Input: These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders.

BPAD

affective disorders


Input: Segregation distortion in myotonic dystrophy.

myotonic dystrophy


Input: Myotonic dystrophy (DM) is an autosomal dominant disease which, in the typical pedigree, shows a three generation anticipation cascade.

Myotonic dystrophy

DM

autosomal dominant disease


Input: This results in infertility and congenital myotonic dystrophy (CDM) with the disappearance of DM in that pedigree.

infertility

congenital myotonic dystrophy

CDM

DM


Input: The concept of segregation distortion, where there is preferential transmission of the larger allele at the DM locus, has been put forward to explain partially the maintenance of DM in the population.

DM

DM


Input: In a survey of DM in Northern Ireland, 59 pedigrees were ascertained.

DM


Input: Sibships where the status of all the members had been identified were examined to determine the transmission of the DM expansion from affected parents to their offspring.

DM


Input: Where the transmitting parent was male, 58.


Input: 3% of the offspring were affected, and in the case of a female transmitting parent, 68.


Input: 7% were affected.


Input: Studies on meiotic drive in DM have shown increased transmission of the larger allele at the DM locus in non-DM heterozygotes for CTGn.

DM

DM


Input: This study provides further evidence that the DM expansion tends to be transmitted preferentially.

DM


Input: Diagnosis of hemochromatosis.

hemochromatosis


Input: If untreated, hemochromatosis can cause serious illness and early death, but the disease is still substantially under-diagnosed.

hemochromatosis

early death


Input: The cornerstone of screening and case detection is the measurement of serum transferrin saturation and the serum ferritin level.


Input: Once the diagnosis is suspected, physicians must use serum ferritin levels and hepatic iron stores on liver biopsy specimens to assess patients for the presence of iron overload.

iron overload


Input: Liver biopsy is also used to establish the presence or absence of cirrhosis, which can affect prognosis and management.

cirrhosis


Input: A DNA-based test for the HFE gene is commercially available, but its place in the diagnosis of hemochromatosis is still being evaluated.

hemochromatosis


Input: Currently, the most useful role for this test is in the detection of hemochromatosis in the family members of patients with a proven case of the disease.

hemochromatosis


Input: It is crucial to diagnose hemochromatosis before hepatic cirrhosis develops because phlebotomy therapy can avert serious chronic disease and can even lead to normal life expectancy..

hemochromatosis

hepatic cirrhosis


Input: Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer.

APC

colorectal cancer


Input: BACKGROUND & AIMS Israeli Jews of European birth, i. e., Ashkenazim, have the highest colorectal cancer incidence of any Israeli ethnic group.

colorectal cancer


Input: The I1307K APC gene variant was found in 6.

APC


Input: 1% of American Jews, 28% of their familial colorectal cancer cases, but not in non-Jews.

colorectal cancer


Input: We assessed the I1307K prevalence in Israeli Jews of differing ethnic origin and risk for colorectal cancer.

colorectal cancer


Input: METHODS DNA samples from 500 unrelated Jews of European or non-European origin, with or without a personal and/or family history of neoplasia, were examined for the I1307K variant by the allele-specific oligonucleotide (ASO) method.

neoplasia


Input: RESULTS In persons at average risk for colorectal cancer, I1307K was found in 5.

colorectal cancer


Input: 0% of 120 European and 1.


Input: 6% of 188 non-European Jews (P = 0. 08).


Input: It occurred in 15.


Input: 4% of 52 Ashkenazi Israelis with familial cancer (P = 0. 02) and was not detected in 51 non-European Jews at increased cancer risk.

cancer

cancer


Input: Colorectal neoplasia occurred personally or in the families of 13 of 20 Ashkenazi I1307K carriers, 8 of whom also had a personal or family history of noncolonic neoplasia.

Colorectal neoplasia

neoplasia


Input: CONCLUSIONS The I1307K APC variant may represent a susceptibility gene for colorectal, or other, cancers in Ashkenazi Jews, and partially explains the higher incidence of colorectal cancer in European Israelis.

colorectal, or other, cancers

colorectal cancer


Input: Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update.

hereditary coproporphyria


Input: Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase (CPO).

Hereditary coproporphyria

HC

hepatic porphyria

deficient activity of coproporphyrinogen III oxidase


Input: Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often precipitated by drugs, fasting, cyclical hormonal changes, or infectious diseases.

neurological dysfunction

infectious diseases


Input: Skin photosensitivity may also be present.


Input: The seven exons, the exon/intron boundaries and part of 3 noncoding sequence of the CPO gene were systematically analyzed by an exon-by-exon denaturing gradient gel electrophoresis (DGGE) strategy followed by direct sequencing in seven unrelated heterozygous HC patients from France, Holland, and Czech Republic.

HC


Input: Seven novel mutations and two new polymorphisms were detected.


Input: Among these mutations two are missense (G197W, W427R), two are nonsense (Q306X, Q385X), two are small deletions (662de14bp; 1168del3bp removing a glycine at position 390), and one is a splicing mutation (IVS1-15c--> g) which creates a new acceptor splice site.


Input: The pathological significance of the point mutations G197W, W427R, and the in-frame deletion 390delGly were assessed by their respective expression in a prokaryotic system using site-directed mutagenesis.


Input: These mutations resulted in the absence or a dramatic decrease of CPO activity.


Input: The two polymorphisms were localized in noncoding part of the gene 1) a C/G polymorphism in the promotor region, 142 bp upstream from the transcriptional initiation site (-142C/G), and 2) a 6 bp deletion polymorphism in the 3 noncoding part of the CPO gene, 574 bp downstream of the last base of the normal termination codon (+ 574 delATTCTT).


Input: Five intragenic dimorphisms are now well characterized and the high degree of allelic heterogeneity in HC is demonstrated with seven new different mutations making a total of nineteen CPO gene defects reported so far..

HC

gene defects


Input: Coincidence of two novel arylsulfatase A alleles and mutation 459 + 1G > A within a family with metachromatic leukodystrophy: molecular basis of phenotypic heterogeneity.

metachromatic leukodystrophy


Input: In a family with three siblings, one developed classical late infantile metachromatic leukodystrophy (MLD), fatal at age 5 years, with deficient arylsulfatase A (ARSA) activity and increased galactosylsulfatide (GS) excretion.

metachromatic leukodystrophy

MLD


Input: The two other siblings, apparently healthy at 12 (1/2) and 15 years, respectively, and their father, apparently healthy as well, presented ARSA and GS values within the range of MLD patients.

MLD


Input: Mutation screening and sequence analysis disclosed the involvement of three different ARSA mutations being the molecular basis of intrafamilial phenotypic heterogeneity.


Input: The late infantile patient inherited from his mother the frequent 0-type mutation 459 + 1G > A, and from his father a novel, single basepair microdeletion of guanine at nucleotide 7 in exon 1 (7delG).


Input: The two clinically unaffected siblings carried the maternal mutation 459 + 1G > A and, on their paternal allele, a novel cytosine to thymidine transition at nucleotide 2435 in exon 8, resulting in substitution of alanine 464 by valine (A464V).


Input: The fathers genotype thus was 7delG/A464V.


Input: Mutation A464V was not found in 18 unrelated MLD patients and 50 controls.

MLD


Input: A464V, although clearly modifying ARSA and GS levels, apparently bears little significance for clinical manifestation of MLD, mimicking the frequent ARSA pseudodeficiency allele.

MLD


Input: Our results demonstrate that in certain genetic conditions MLD-like ARSA and GS values need not be paralleled by clinical disease, a finding with serious diagnostic and prognostic implications.

MLD


Input: Moreover, further ARSA alleles functionally similar to A464V might exist which, together with 0-type mutations, may cause pathological ARSA and GS levels, but not clinical outbreak of the disease..


Input: Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1.

hematological malignancy

neurofibromatosis type 1


Input: Heterozygous germ-line mutations in the DNA mismatch repair genes lead to hereditary nonpolyposis colorectal cancer.

hereditary nonpolyposis colorectal cancer


Input: The disease susceptibility of individuals who constitutionally lack both wild-type alleles is unknown.


Input: We have identified three offspring in a hereditary nonpolyposis colorectal cancer family who developed hematological malignancy at a very early age, and at least two of them displayed signs of neurofibromatosis type 1 (NF1).

hereditary nonpolyposis colorectal cancer

hematological malignancy

neurofibromatosis type 1


Input: DNA sequence analysis and allele-specific amplification in two siblings revealed a homozygous MLH1 mutation (C676T--> Arg226Stop).


Input: Thus, a homozygous germ-line MLH1 mutation and consequent mismatch repair deficiency results in a mutator phenotype characterized by leukemia and/or lymphoma associated with neurofibromatosis type 1..

leukemia

lymphoma

neurofibromatosis type 1


Input: Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations.

congenital eye malformations


Input: Mutations of the human PAX6 gene underlie aniridia (congenital absence of the iris), a rare dominant malformation of the eye.

aniridia

congenital absence of the iris

malformation of the eye


Input: The spectrum of PAX6 mutations in aniridia patients is highly biased, with 92% of all reported mutations leading to premature truncation of the protein (nonsense, splicing, insertions and deletions) and just 2% leading to substitution of one amino acid by another (missense).

aniridia


Input: The extraordinary conservation of the PAX6 protein at the amino acid level amongst vertebrates predicts that pathological missense mutations should in fact be common even though they are hardly ever seen in aniridia patients.

aniridia


Input: This indicates that there is a heavy ascertainment bias in the selection of patients for PAX6 mutation analysis and that the missing PAX6 missense mutations frequently may underlie phenotypes distinct from textbook aniridia.

aniridia


Input: Here we present four novel PAX6 missense mutations, two in association with atypical phenotypes ectopia pupillae (displaced pupils) and congenital nystagmus (searching gaze), and two in association with more recognizable aniridia phenotypes.

ectopia pupillae

displaced pupils

congenital nystagmus

searching gaze

aniridia


Input: Strikingly, all four mutations are located within the PAX6 paired domain and affect amino acids which are highly conserved in all known paired domain proteins.


Input: Our results support the hypothesis that the under-representation of missense mutations is caused by ascertainment bias and suggest that a substantial burden of PAX6-related disease remains to be uncovered..

PAX6-related disease


Input: The chromosomal order of genes controlling the major histocompatibility complex, properdin factor B, and deficiency of the second component of complement.

deficiency of the second component of complement


Input: The relationship of the genes coding for HLA to those coding for properdin Factor B allotypes and for deficiency of the second component of complement (C2) was studied in families of patients with connective tissue disorders.

deficiency of the second component of complement


Input: Patients were selected because they were heterozygous or homozygous for C2 deficiency.

C2 deficiency


Input: 12 families with 15 matings informative for C2 deficiency were found.

C2 deficiency


Input: Of 57 informative meioses, two crossovers were noted between the C2 deficiency gene and the HLA-B gene, with a recombinant fraction of 0.

C2 deficiency


Input: A lod score of 13 was calculated for linkage between C2 deficiency and HLA-B at a maximum likelihood value of the recombinant fraction of 0.

C2 deficiency


Input: 18 families with 21 informative matings for both properdin Factor B allotype and HLA-B were found.


Input: Of 72 informative meioses, three recombinants were found, giving a recombinant fraction of 0.


Input: A lod score of 16 between HLA-B and Factor B allotypes was calculated at a maximum likelihood value of the recombinant fraction of 0.


Input: A crossover was shown to have occurred between genes for Factor B and HLA-D, in which HLA-D segregared with HLA-A and B.


Input: These studies suggest that the genes for Factor B and C2 deficiency are located outside those for HLA, that the order of genese is HLA-A,-B,-D, Factor B allotype, C2 deficiency, that the genes coding for C2 deficiency and Factor B allotypes are approximately 3--5 centimorgans from the HLA-A and HLA-B loci, and that the apparent lack of recombinants between the Factor B gene and C2 deficiency gene suggests that these two genes lie in close proximity to one another.

C2 deficiency

C2 deficiency

C2 deficiency

C2 deficiency


Input: Distribution of emerin and lamins in the heart and implications for Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy


Input: Emerin is a nuclear membrane protein which is missing or defective in Emery-Dreifuss muscular dystrophy (EDMD).

Emery-Dreifuss muscular dystrophy

EDMD


Input: It is one member of a family of lamina-associated proteins which includes LAP1, LAP2 and lamin B receptor (LBR).


Input: A panel of 16 monoclonal antibodies (mAbs) has been mapped to six specific sites throughout the emerin molecule using phage-displayed peptide libraries and has been used to localize emerin in human and rabbit heart.


Input: Several mAbs against different emerin epitopes did not recognize intercalated discs in the heart, though they recognized cardiomyocyte nuclei strongly, both at the rim and in intranuclear spots or channels.


Input: A polyclonal rabbit antiserum against emerin did recognize both nuclear membrane and intercalated discs but, after affinity purification against a pure-emerin band on a western blot, it stained only the nuclear membrane.


Input: These results would not be expected if immunostaining at intercalated discs were due to a product of the emerin gene and, therefore, cast some doubt upon the hypothesis that cardiac defects in EDMD are caused by absence of emerin from intercalated discs.

cardiac defects

EDMD


Input: Although emerin was abundant in the membranes of cardiomyocyte nuclei, it was absent from many non-myocyte cells in the heart.


Input: This distribution of emerin was similar to that of lamin A, a candidate gene for an autosomal form of EDMD.

EDMD


Input: In contrast, lamin B1 was absent from cardiomyocyte nuclei, showing that lamin B1 is not essential for localization of emerin to the nuclear lamina.


Input: Lamin B1 is also almost completely absent from skeletal muscle nuclei.


Input: In EDMD, the additional absence of lamin B1 from heart and skeletal muscle nuclei which already lack emerin may offer an alternative explanation of why these tissues are particularly affected..

EDMD


Input: Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2p13-p16.

copper toxicosis


Input: Abnormal hepatic copper accumulation is recognized as an inherited disorder in man, mouse, rat and dog.

hepatic copper accumulation

inherited disorder


Input: The major cause of hepatic copper accumulation in man is a dysfunctional ATP7B gene, causing Wilson disease (WD).

hepatic copper accumulation

Wilson disease

WD


Input: Mutations in the ATP7B genes have also been demonstrated in mouse and rat.


Input: The ATP7B gene has been excluded in the much rarer human copper overload disease non-Indian childhood cirrhosis, indicating genetic heterogeneity.

copper overload

non-Indian childhood cirrhosis


Input: By investigating the common autosomal recessive copper toxicosis (CT) in Bedlington terriers, we have identified a new locus involved in progressive liver disease.

copper toxicosis

CT

liver disease


Input: We examined whether the WD gene ATP7B was also causative for CT by investigating the chromosomal co-localization of ATP7B and C04107, using fluorescence in situ hybridization (FISH).

WD

CT


Input: C04107 is an anonymous microsatellite marker closely linked to CT.

CT


Input: However, BAC clones containing ATP7B and C04107 mapped to the canine chromosome regions CFA22q11 and CFA10q26, respectively, demonstrating that WD cannot be homologous to CT.

WD

CT


Input: The copper transport genes CTR1 and CTR2 were also excluded as candidate genes for CT since they both mapped to canine chromosome region CFA11q22.


Input: A transcribed sequence identified from the C04107-containing BAC was found to be homologous to a gene expressed from human chromosome 2p13-p16, a region devoid of any positional candidate genes.


Input: Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition.

APC

FAP

APC

colorectal cancer


Input: BACKGROUND/AIMS The development of colorectal cancer and a variable range of extracolonic manifestations in familial adenomatous polyposis (FAP) is the result of the dominant inheritance of adenomatous polyposis coli (APC) gene mutations.

colorectal cancer

familial adenomatous polyposis

FAP

adenomatous polyposis coli

APC


Input: In this study, direct mutation analysis of the APC gene was performed to determine genotype-phenotype correlations for nine extracolonic manifestations and to investigate the incidence of APC mutations in non-FAP colorectal cancer.

APC

APC

colorectal cancer


Input: METHODS The APC gene was analysed in 190 unrelated FAP and 15 non-FAP colorectal cancer patients using denaturing gradient gel electrophoresis, the protein truncation test, and direct sequencing.

APC

FAP

colorectal cancer


Input: RESULTS Chain terminating signals were only identified in patients belonging to the FAP group (105 patients).

FAP


Input: Amino acid changes were identified in four patients, three of whom belonged to the non-FAP group of colorectal cancer patients.

colorectal cancer


Input: Genotype-phenotype correlations identified significant differences in the nature of certain extracolonic manifestations in FAP patients belonging to three mutation subgroups.

FAP


Input: CONCLUSIONS Extended genotype-phenotype correlations made in this study may have the potential to determine the most appropriate surveillance and prophylactic treatment regimens for those patients with mutations associated with life threatening conditions.


Input: This study also provided evidence for the pathological nature of amino acid changes in APC associated with both FAP and non-FAP colorectal cancer patients..

FAP

colorectal cancer


Input: Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism.

Inherited colorectal polyposis

cancer


Input: Germ-line and somatic truncating mutations of the APC gene are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis, respectively.

APC

colorectal tumor

familial adenomatous polyposis syndrome


Input: Recently, an isoleucine--> lysine polymorphism at codon 1307 (I1307K) of the APC gene has been identified in 6%-7% of the Ashkenazi Jewish population.

APC


Input: To assess the risk of this common APC allelic variant in colorectal carcinogenesis, we have analyzed a large cohort of unselected Ashkenazi Jewish subjects with adenomatous polyps and. or colorectal cancer, for the APC I1307K polymorphism.

APC

adenomatous polyps

colorectal cancer,


Input: The APC I1307K allele was identified in 48 (10. 1%) of 476 patients.


Input: Compared with the frequency in two separate population control groups, the APC I1307K allele is associated with an estimated relative risk of 1.


Input: 7 for colorectal neoplasia (both P =. 01).

colorectal neoplasia


Input: Furthermore, compared with noncarriers, APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient (P =. 03), as well as a younger age at diagnosis.

adenomas

colorectal cancers


Input: We conclude that the APC I1307K variant leads to increased adenoma formation and directly contributes to 3%-4% of all Ashkenazi Jewish colorectal cancer.

adenoma

colorectal cancer


Input: The estimated relative risk for carriers may justify specific clinical screening for the 360, 000 Americans expected to harbor this allele, and genetic testing in the setting of long-term-outcome studies may impact significantly on colorectal cancer prevention in this population.

colorectal cancer


Input: Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas.

non-inherited breast carcinomas


Input: Although the link between the BRCA1 tumour-suppressor gene and hereditary breast and ovarian cancer is established, the role, if any, of BRCA1 in non-familial cancers is unclear.

tumour

hereditary breast and ovarian cancer

non-familial cancers


Input: BRCA1 mutations are rare in sporadic cancers, but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization is postulated to be important in non-familial breast and ovarian cancers.

sporadic cancers

non-familial breast and ovarian cancers


Input: Epigenetic loss, however, has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins, reports of which have ranged from exclusively nuclear, to conditionally nuclear, to the ER/golgi, to cytoplasmic invaginations into the nucleus.


Input: In an attempt to resolve this issue, we have comprehensively characterized 19 anti-BRCA1 antibodies.


Input: These reagents detect a 220-kD protein localized in discrete nuclear foci in all epithelial cell lines, including those derived from breast malignancies.

breast malignancies


Input: Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast, invasive lobular cancers and low-grade ductal carcinomas.

invasive lobular cancers

low-grade ductal carcinomas


Input: Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers..

ductal carcinomas

sporadic breast cancers