Input: In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively.

renal lesions

HPT

JT


Input: In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease.

JT

polycystic kidney disease


Input: The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out.


Input: A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families.

primary HPT


Input: Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11.

multiple endocrine neoplasia (MEN) types 1 and 2


Input: The disease in these two kindreds was linked to five markers in the 1q21-q32 region (logarithm-of-odds scores 3. 2-4 2-4. 2), whereas linkage to the MEN1 and MEN2 regions was excluded.


Input: Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from > 60 to approximately 34 centimorgans.


Input: Loss of heterozygosity was studied in seven renal hamartomas from two affected individuals in the first family, as well as in a jaw tumor and a parathyroid tumor from the second family.

renal hamartomas

jaw tumor

parathyroid tumor


Input: All renal hamartomas showed loss of heterozygosity at the 1q21-q32 region.

renal hamartomas


Input: The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a tumor suppressor gene in this region

tumor


Input: Independent origin of single and double mutations in the human glucose 6-phosphate dehydrogenase gene.


Input: The vast majority of both polymorphic and sporadic G6PD variants are due to single missense mutations.


Input: In the four polymorphic variants that have two point mutations, one of the mutations is always 376 A--> G (126 Asn--> Asp), which on its own gives rise to the nondeficient polymorphic variant, G6PD A.


Input: In a study of G6PD deficient patients who presented with clinical favism in Spain, we have found a new polymorphic variant that we have called G6PD Malaga, whose only abnormality is a 542 A--> T (181 Asp--> Val) mutation.

G6PD deficient

favism


Input: This is the same mutation as previously found in association with the mutation of G6PD A in the double mutant, G6PD Santamaria.


Input: G6PD Malaga is associated with enzyme deficiency (class III), and the enzymic properties of G6PD Malaga and G6PD Santamaria are quite similar, indicating that in this case the effects of the two mutations are additive rather than synergistic.

enzyme deficiency


Input: G6PD Santamaria might have been produced by recombination between G6PD A and G6PD Malaga; however haplotype analysis, including the use of a new silent polymorphism, suggests that the same 542 A--> T mutation has taken place independently in a G6PD B gene to give G6PD Malaga and in a G6PD A gene to give G6PD Santamaria.


Input: These findings help to outline the relationship and evolution of mutations in the human G6PD locus..


Input: BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype.


Input: BRCA1 mutations cause increased risk for breast and ovarian cancer, frequently of early onset.

breast and ovarian cancer


Input: Many different mutations occur in BRCA1, including several examples of recurrent mutations, each of which accounts for a significant number of families with heritable cancer predisposition.

cancer


Input: These common mutations have an etiological role in many breast and ovarian cancer cases and provide the opportunity to examine genotype-phenotype correlations and genotype-environment interactions in individuals with the identical BRCA1 lesion.

breast and ovarian cancer


Input: We report a novel missense change in BRCA1, 2640 C--> T (R841W), found in 3 cases from a subject group of 305 breast and 79 ovarian cancer cases from Orange County, CA.

breast and 79 ovarian cancer


Input: These are consecutive, population-based cases not selected for age or family history.


Input: In all three cases, there is a strong family history of breast, ovarian, or other cancers possibly related to a BRCA1 defect and family members showed a high concordance of cancer incidence with the presence of R841W.

breast, ovarian, or other cancers

cancer


Input: The age of cancer onset was not always distinct from typical sporadic cases.

cancer


Input: Testing of a sample of 413 unrelated individuals to examine the hypothesis that R841W might be a rare polymorphism detected one additional instance in a woman with breast cancer diagnosed at age 77 years, and cancer in one parent.

breast cancer

cancer


Input: R841W is likely to be an etiologically significant lesion with involvement in close to 1% (95% confidence interval of 0-1. 7%) of all breast and ovarian cancers in this population.

breast and ovarian cancers


Input: Ataxia-telangiectasia: founder effect among north African Jews.

Ataxia-telangiectasia


Input: The ATM gene is responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T), characterized by cerebellar degeneration, immunodeficiency and cancer predisposition.

autosomal recessive disorder ataxia-telangiectasia

A-T

cerebellar degeneration

immunodeficiency

cancer predisposition


Input: A-T carriers were reported to be moderately cancer-prone.

A-T

cancer-prone


Input: A wide variety of A-T mutations, most of which are unique to single families, were identified in various ethnic groups, precluding carrier screening with mutation-specific assays.

A-T


Input: However, a single mutation was observed in 32/33 defective ATM alleles in Jewish A-T families of North African origin, coming from various regions of Morocco and Tunisia.

A-T


Input: This mutation, 103C--> T, results in a stop codon at position 35 of the ATM protein.


Input: In keeping with the nature of this mutation, various antibodies directed against the ATM protein failed to defect this protein in patient cells.


Input: A rapid carrier detection assay detected this mutation in three out of 488 ATM alleles of Jewish Moroccan or Tunisian origin.


Input: This founder effect provides a unique opportunity for population-based screening for A-T carriers in a large Jewish community..

A-T


Input: Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.

male breast cancer


Input: A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2.

male breast cancer

inherited breast/ovarian cancer


Input: Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative.

breast and/or ovarian cancer


Input: A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives.

breast/ovarian cancer


Input: No germ-line BRCA1 mutations were found.


Input: Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene.

male breast cancer


Input: Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative.

male breast cancer

cancer

ovarian cancer


Input: The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene..

male breast cancer

breast/ovarian cancer


Input: Molecular basis for Duarte and Los Angeles variant galactosemia.

Duarte and Los Angeles variant galactosemia


Input: Human orythrocytes that are homozygous for the Duarte enzyme variant of galactosemia (D/D) have a characteristic isoform on isoelectric focusing and 50% reduction in galactose-1-phosphate uridyltransferase (GALT) enzyme activity.

Duarte enzyme variant of galactosemia


Input: The Duarte biochemical phenotype has a molecular genotype of N314D/N314D.


Input: The characteristic Duarte isoform is also associated with a variant called the " Los Angeles (LA) phenotype, " which has increased GALT enzyme activity.


Input: We evaluated GALT enzyme activity and screened the GALT genes of 145 patients with one or more N314D-containing alleles.


Input: We found seven with the LA biochemical phenotype, and all had a 1721C--> T transition in exon 7 in cis with the N314D missense mutation.


Input: The 1721C--> T transition is a neutral polymorphism for leucine at amino acid 218 (L218L).


Input: In pedigree analyses, this 1721C--> T transition segregated with the LA phenotype of increased GALT activity in three different biochemical phenotypes (LA/N, LA/G, and LA/D).


Input: To determine the mechanism for increased activity of the LA variant, we compared GALT mRNA, protein abundance, and enzyme thermal stability in lymphoblast cell lines of D and LA phenotypes with comparable genotypes.


Input: GALT protein abundance was increased in LA compared to D alleles, but mRNA was similar among all genotypes.


Input: When LA/D and D/D GALT biochemical phenotypes were compared to N/N GALT phenotypes, both had 50%, as compared to 21%, reduction in GALT activity in the wild type (N/N) after exposure at identical initial enzyme activity to 50 degrees C for 15 min.


Input: We conclude that the codon change N314D in cis with the base-pair transition 1721C--> T produces the LA variant of galactosemia and that this nucleotide change increases GALT activity by increasing GALT protein abundance without increasing transcription or decreasing thermal lability.

LA variant of galactosemia


Input: A favorable codon bias for the mutated codon with consequently increased translation rates is postulated as the mechanism..


Input: The TSG101 tumor susceptibility gene is located in chromosome 11 band p15 and is mutated in human breast cancer.

tumor

breast cancer


Input: Recent work has identified a mouse gene (tsg101) whose inactivation in fibroblasts results in cellular transformation and the ability to produce metastatic tumors in nude mice.

metastatic tumors


Input: Here, we report that the human homolog, TSG101, which we isolated and mapped to chromosome 11, bands 15.


Input: 1-15 1-15.


Input: 2, a region proposed to contain tumor suppressor gene (s), is mutated at high frequency in human breast cancer.

tumor

breast cancer


Input: In 7 of 15 uncultured primary human breast carcinomas, intragenic deletions were shown in TSG101 genomic DNA and transcripts by gel and sequence analysis, and mutations affecting two TSG101 alleles were identified in four of these cancers.

breast carcinomas

cancers


Input: No TSG101 defects were found in matched normal breast tissue from the breast cancer patients.

breast cancer


Input: These findings strongly implicate TSG101 mutations in human breast cancer


Input: Moderate intergenerational and somatic instability of a 55-CTG repeat in transgenic mice.


Input: Myotonic dystrophy (DM) is associated with the expansion of a (CTG) n trinucleotide repeat in the 3 untranslated region (UTR) of the DM protein kinase gene (DMPK).

Myotonic dystrophy

DM

DM


Input: The (CTG) n repeat is polymorphic and varies in size between 5 and 37 repeats in unaffected individuals whereas in affected patients there are between 50 and 4, 000 CTGs.


Input: The size of the (CTG) n repeat, which increases through generations, generally correlates with clinical severity and age of onset.


Input: The instability of the CTG repeat appears to depend on its size as well as on the sex of the transmitting parent.


Input: Moreover, mitotic instability analysis of different human DM tissues shows length mosaicism between different cell lineages.

DM


Input: The molecular mechanisms of triplet instability remain elusive.


Input: To investigate the role of genomic sequences in instability, we produced transgenic mice containing a 45-kb genomic segment with a 55-CTG repeat cloned from a mildly affected patient.


Input: In contrast to other mouse models containing CAG repeats within cDNAs, these mice showed both intergenerational and somatic repeat instability..


Input: Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis.

autoimmune lymphoproliferative syndrome


Input: Programmed cell death (or apoptosis) is a physiological process essential to the normal development and homeostatic maintenance of the immune system.


Input: The Fas/Apo-1 receptor plays a crucial role in the regulation of apoptosis, as demonstrated by lymphoproliferation in MRL-lpr/lpr mice and by the recently described autoimmune lymphoproliferative syndrome (ALPS) in humans, both of which are due to mutations in the Fas gene.

autoimmune lymphoproliferative syndrome

ALPS


Input: We describe a novel family with ALPS in which three affected siblings carry two distinct missense mutations on both the Fas gene alleles and show lack of Fas-induced apoptosis.

ALPS


Input: The children share common clinical features including splenomegaly and lymphadenopathy, but only one developed severe autoimmune manifestations.

splenomegaly

lymphadenopathy

autoimmune manifestations


Input: In all three siblings, we demonstrated the presence of anergic CD3 + CD4-CD8-(double negative, [DN]) T cells; moreover, a chronic lymphocyte activation was found, as demonstrated by the presence of high levels of HLA-DR expression on peripheral CD3 + cells and by the presence of high levels of serum activation markers such as soluble interleukin-2 receptor (slL-2R) and soluble CD30 (sCD30)..


Input: The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not up-regulated following genome damage.

ataxia-telangiectasia


Input: The product of the ataxia-telangiectasia gene (ATM) was identified by using an antiserum developed to a peptide corresponding to the deduced amino acid sequence.

ataxia-telangiectasia


Input: The ATM protein is a single, high-molecular weight protein predominantly confined to the nucleus of human fibroblasts, but is present in both nuclear and microsomal fractions from human lymphoblast cells and peripheral blood lymphocytes.


Input: ATM protein levels and localization remain constant throughout all stages of the cell cycle.


Input: Truncated ATM protein was not detected in lymphoblasts from ataxia-telangiectasia patients homozygous for mutations leading to premature protein termination.

ataxia-telangiectasia


Input: Exposure of normal human cells to gamma-irradiation and the radiomimetic drug neocarzinostatin had no effect on ATM protein levels, in contrast to a noted rise in p53 levels over the same time interval.


Input: These findings are consistent with a role for the ATM protein in ensuring the fidelity of DNA repair and cell cycle regulation following genome damage..


Input: Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development.


Input: Type III collagen is a fibrillar forming collagen comprising three alpha1 (III) chains and is expressed in early embryos and throughout embryogenesis.


Input: In the adult, type III collagen is a major component of the extracellular matrix in a variety of internal organs and skin.


Input: Mutations in the COL3A1 gene have been implicated as a cause of type IV Ehlers-Danlos syndrome, a disease leading to aortic rupture in early adult life.

type IV Ehlers-Danlos syndrome

aortic rupture


Input: To directly study the role of Col3a1 in development and disease, we have inactivated the Col3a1 gene in embryonic stem cells by homologous recombination.


Input: The mutated allele was transmitted through the mouse germ line and homozygous mutant animals were derived from heterozygous intercrosses.


Input: About 10% of the homozygous mutant animals survived to adulthood but have a much shorter life span compared with wild-type mice.


Input: The major cause of death of mutant mice was rupture of the major blood vessels, similar to patients with type IV Ehlers-Danlos syndrome.

type IV Ehlers-Danlos syndrome


Input: Ultrastructural analysis of tissues from mutant mice revealed that type III collagen is essential for normal collagen I fibrillogenesis in the cardiovascular system and other organs..


Input: Nonsense mutation in exon 3 of the proteolipid protein gene (PLP) in a family with an unusual form of Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease


Input: We report a G--> A transition at nucleotide 431 of the proteolipid protein gene (PLP) results in a nonsense codon in a family with an unusual form of Pelizaeus-Merzbacher disease (PMD).

Pelizaeus-Merzbacher disease

PMD


Input: The mutation, which creates a second AluI restriction site, results in a nonsense mutation in PLP.


Input: The clinical picture resembles somewhat that of X-linked spastic paraplegia (SPG).

X-linked spastic paraplegia

SPG


Input: It differs from this and both the classical and connatal forms of PMD in that it is relatively mild in form, onset is delayed beyond age 2 years, nystagmus is absent, tremors are prominent, mental retardation is not severe, some patients show dementia or personality disorders, the disease is progressive rather than static in some, and several females show signs of disease.

PMD

nystagmus

tremors

mental retardation

dementia

personality disorders


Input: The nonsense mutation, which is in exon 3B, should block the synthesis of normal PLP but spare DM20, the isoform whose persistence has been associated with mild forms of PLP-associated disease in both humans and mice..

PLP-associated disease


Input: Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.

breast and ovarian cancer


Input: Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2.

breast cancer

ovarian cancer


Input: However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence.

breast cancer


Input: A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks.

breast cancer


Input: There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions.


Input: We have examined the frequency of four of these polymorphisms Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls.

breast and ovarian cancer


Input: Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.


Input: The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.


Input: 57 and 0.


Input: 32 respectively, and these frequencies do not differ significantly between patient and control groups.


Input: Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk.

breast or ovarian cancer


Input: However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0. 01), indicating that it may be protective against breast cancer.

breast cancer

breast cancer


Input: If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.


Input: Kniest dysplasia: Dr. W.

Kniest dysplasia


Input: Kniest, his patient, the molecular defect.


Input: Kniest dysplasia is a severe chondrodysplasia caused by the defective formation of type II collagen.

Kniest dysplasia

chondrodysplasia

defective formation of type II collagen


Input: We report about Dr. Kniest, who first described the condition in 1952, and his patient, who, at the age of 50 years is severely handicapped with short stature, restricted joint mobility, and blindness but is mentally alert and leads an active life.

severely handicapped

short stature

restricted joint mobility

blindness


Input: Molecular analysis of the patients DNA showed a single base (G) deletion involving the GT dinucleotide at the start of intron 18 destroying a splice site of the COL2A1 gene.


Input: This is in accordance with molecular findings in other patients with Kniest dysplasia and confirms, in the original patient, that the disorder is caused by small inframe deletions often due to exon skipping as a result of COL2A1 splice site mutations..

Kniest dysplasia


Input: Cloning of the homogentisate 1, 2-dioxygenase gene, the key enzyme of alkaptonuria in mouse.

alkaptonuria


Input: We determined 48 amino acid residues from five peptides from the homogeneous monomer of homogentisate 1, 2-dioxygenase (HGO; E. C. 1. 13. 11. 15) of mouse liver.


Input: After digestion with trypsin, peptides were separated by reversed phase chromatography and amino acid sequenced.


Input: The deduced codon sequence of three peptides was used to derive degenerated oligomeres.


Input: By combining these oligos, we were able to amplify fragments from 100 to 300 bases (b) from mouse liver cDNA by polymerase chain reaction after reverse transcription (RT-PCR).


Input: A fragment of 200 b was cloned and used as a probe to screen a mouse liver cDNA library.


Input: One clone from this library contained the complete cDNA-insert for HGO as determined by sequencing.


Input: The cDNA encodes for a protein of 50 kDa, as predicted.


Input: The cDNA of mouse HGO has an overall identity of 41% to the corresponding gene hmgA from Aspergillus.


Input: Sequence similarities to human expressed sequence tags (EST) clones ranged from 70% to 20%.


Input: The positions of 122 conserved amino acids could be determined by multiple sequence alignment.


Input: We identified one first intron of 928 b in the mouse gene.


Input: The gene for HGO seems to be expressed in various tissues, as shown by RT-PCR on different cDNAs.


Input: FISH experiments with the whole murine cDNA as probe clearly revealed signals at the human chromosomal band 3q13.


Input: This corresponds well to the previous assignment of the locus for the human alkaptonuria gene (AKU) to the same chromosomal region by multipoint linkage analysis.

alkaptonuria


Input: We therefore conclude that the HGO cDNA encodes the gene responsible for alkaptonuria.

alkaptonuria


Input: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

brain, breast, and prostate cancer


Input: Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers.

tumor

cancers


Input: In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas.

glioblastoma

prostate cancer

breast cancer

primary glioblastomas


Input: The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions.


Input: These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions..

tumor

tumor

metastasis


Input: Heterogeneity in Schwartz-Jampel chondrodystrophic myotonia.

Schwartz-Jampel chondrodystrophic myotonia


Input: The Schwartz-Jampel syndrome (SJS; chondrodystrophic myotonia; McK 255, 800) is a recessively inherited condition defined by myotonia, short stature, and bone dysplasia.

Schwartz-Jampel syndrome

SJS

chondrodystrophic myotonia

recessively inherited condition

myotonia

short stature

bone dysplasia


Input: Genetic linkage between SJS and chromosomal region 1q36-34 has been observed in several families, but the gene has not yet been identified.

SJS


Input: We studied the clinical and radiological features in 81 patients from the literature and 5 own patients trying to identify distinct subgroups.


Input: In addition, we tested genetic linkage to the SJS locus on chromosome 1 in one family with two affected sibs.

SJS


Input: We found that a group of patients have mild skeletal changes which may be secondary consequences of myotonia, while another group of patients appear to have primary bone dysplasia with myotonia.

myotonia

bone dysplasia

myotonia


Input: Within this latter group, there are differences in age of manifestation, clinical course and pattern of bone changes.


Input: We tentatively isolate three different types of SJS type 1A, usually recognized in childhood, with moderate bone dysplasia, corresponding to the original descriptions of Schwartz, Jampel and Aberfeld; type 1B, similar to type 1A but recognizable at birth, with more pronounced bone dysplasia resembling Kniest dysplasia; and type 2, manifest at birth, with increased mortality and bone dysplasia resembling Pyle disease.

SJS type 1A

bone dysplasia

bone dysplasia

Kniest dysplasia

bone dysplasia

Pyle disease


Input: Genetic analysis of the family with two sibs affected by SJS type 2 showed evidence against linkage to chromosome 1p36-34.

SJS type 2


Input: CONCLUSIONS SJS is clinically and radiologically heterogeneous.

SJS


Input: The causes of heterogeneity are not known yet but are likely to include both different mutations at the SJS locus on chromosome 1 and the presence of a second SJS locus.

SJS

SJS


Input: A tentative clinico-radiological classification can be useful for the characterization of patients and the development of genotype-phenotype correlations..


Input: A clinical overview of WT1 gene mutations.


Input: Mutations in the WT1 gene were anticipated to explain the genetic basis of the childhood kidney cancer, Wilms tumour (WT).

kidney cancer

Wilms tumour

WT


Input: Six years on, we review 100 reports of intragenic WT1 mutations and examine the accompanying clinical phenotypes.


Input: While only 5% of sporadic Wilms tumours have intragenic WT1 mutations, > 90% of patients with the Denys-Drash syndrome (renal nephropathy, gonadal anomaly, predisposition to WT) carry constitutional intragenic WT1 mutations.

sporadic Wilms tumours

Denys-Drash syndrome

renal nephropathy

gonadal anomaly

predisposition to WT


Input: WT1 mutations have also been reported in juvenile granulosa cell tumour, non-asbestos related mesothelioma, desmoplastic small round cell tumour and, most recently, acute myeloid leukemia..

juvenile granulosa cell tumour

non-asbestos related mesothelioma

desmoplastic small round cell tumour

acute myeloid leukemia


Input: A mutation in autosomal dominant myotonia congenita affects pore properties of the muscle chloride channel.

autosomal dominant myotonia congenita


Input: Autosomal dominant myotonia congenita is an inherited disorder of skeletal muscle caused by mutations in a voltage-gated Cl-channel gene (CLCN1, 7q35).

Autosomal dominant myotonia congenita

inherited disorder of skeletal muscle


Input: Here, we report that a mutation predicting the substitution of Gly 230 by glutamic acid (G230E) between segments D3 and D4 dramatically alters the pore properties of a recombinant human muscle Cl-channel (hCIC-1) expressed in a mammalian cell line (tsA201).


Input: The G230E mutation causes substantial changes in anion and cation selectivity as well as a fundamental change in rectification of the current-voltage relationship.


Input: Whereas wild-type channels are characterized by pronounced inward rectification and a Cl > thiocyanate > Br > NO (3) > I > CH (3) SO (3) selectivity, G230E exhibits outward rectification at positive potentials and a thiocyanate > NO (3) > I > Br > Cl > CH (3) SO (3) selectivity.


Input: Furthermore, the cation-to-anion permeability ratio of the mutant is much greater than that of the wild-type channel.


Input: Voltage-dependent blocks by intracellular and extracellular iodide help to distinguish two distinct ion binding sites within the hClC-1 conduction pathway.


Input: Both binding sites are preserved in the mutant but have decreased affinities for iodide.


Input: These findings suggest that Gly 230 is critical for normal ion conductance in hClC-1 and that this residue resides within the channel pore..


Input: The incidence of PAX6 mutation in patients with simple aniridia: an evaluation of mutation detection in 12 cases.

aniridia


Input: Twelve aniridia patients, five with a family history and seven presumed to be sporadic, were exhaustively screened in order to test what proportion of people with aniridia, uncomplicated by associated anomalies, carry mutations in the human PAX6 gene.

aniridia

aniridia


Input: Mutations were detected in 90% of the cases.


Input: Three mutation detection techniques were used to determine if one method was superior for this gene.


Input: The protein truncation test (PTT) was used on RT-PCR products, SSCP on genomic PCR amplifications, and chemical cleavage of mismatch on both RT-PCR and genomic amplifications.


Input: For RT-PCR products, only the translated portion of the gene was screened.


Input: On genomic products exons 1 to 13 (including 740 bp of the 3 untranslated sequence and all intron/exon boundaries) were screened, as was a neuroretina specific enhancer in intron 4.


Input: Ten of the possible 12 mutations in the five familial cases and five of the sporadic patients were found, all of which conformed to a functional outcome of haploinsufficiency.


Input: Five were splice site mutations (one in the donor site of intron 4, two in the donor site of intron 6, one in each of the acceptor sites of introns 8 and 9) and five were nonsense mutations in exons 8, 9, 10, 11, and 12.


Input: SSCP analysis of individually amplified exons, with which nine of the 10 mutations were seen, was the most useful detection method for PAX6..


Input: Insulin gene region contributes to genetic susceptibility to, but may not to low incidence of, insulin-dependent diabetes mellitus in Japanese.

insulin-dependent diabetes mellitus


Input: In the Caucasian population, it has been demonstrated that the insulin gene (INS) region contains the insulin-dependent diabetes mellitus locus (IDDM2).

insulin-dependent diabetes mellitus


Input: In the Japanese population, however, there has been no report demonstrating the contribution of IDDM2 to the pathogenesis of IDDM.


Input: We conducted an association study of IDDM in a large number of Japanese subjects with multiple polymorphisms in INS region.

IDDM


Input: We found a significant association of the INS region with IDDM.

IDDM


Input: Alleles positively associated with IDDM in INS region were the same as those positively-associated with IDDM in Caucasian population, although positively-associated alleles are very common (allele frequencies > 0. 9) in the Japanese general population.

IDDM

IDDM


Input: These data suggest that IDDM2 is involved in the genetic susceptibility to IDDM in Japanese.


Input: The high frequencies of disease-associated alleles in the general population suggest that IDDM2 locus is not responsible for the low incidence of IDDM in Japanese.


Input: The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure.


Input: The ninth component of human complement (C9) is the last of the terminal complement components creating the membrane attack complex.


Input: C9 is a single-chain serum protein that is encoded by a gene located on chromosome 5p.


Input: Deficiency of terminal complement components is generally associated with recurrent neisseria infections.

Deficiency of terminal complement components

neisseria infections


Input: We studied a previously described Swiss family with inherited C9 deficiency.

inherited C9 deficiency


Input: To identify the genetic basis of C9 deficiency, we developed an approach using exon-specific PCR and direct DNA sequencing.

C9 deficiency


Input: As a cause of C9 deficiency, we found two different point mutations, both generating TGA stop codons in the coding sequence.

C9 deficiency


Input: One mutation, a C to A exchange, was detected in exon 2 at cDNA position 166, the other, a C to T exchange, was located in exon 4 (cDNA position 464).


Input: In family studies of three first-degree relatives with heterozygous C9 deficiency, we demonstrated that the two mutations are segregating independently.

C9 deficiency


Input: Therefore, these mutations are sufficient to explain the complete deficiency of both the probands studied.


Input: DNA sequencing of the exon-intron junctions revealed a number of revisions regarding the boundaries between exons 4, 5, and 6 as well as between exons 10 and 11.


Input: No additional introns were detected in exons 6 and 10.


Input: Furthermore, DNA marker studies were conducted using known polymorphisms of the C6, C7, and C9 genes, confirming the linkage of the observed C9 mutations with defined haplotypes..


Input: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer.

breast cancer


Input: BACKGROUND To define the incidence of BRCA1 mutations among patients seen in clinics that evaluate the risk of breast cancer, we analyzed DNA samples from women seen in this setting and constructed probability tables to provide estimates of the likelihood of finding a BRCA1 mutation in individual families.

breast cancer


Input: METHODS Clinical information, family histories, and blood for DNA analysis were obtained from 263 women with breast cancer.

breast cancer


Input: Conformation-sensitive gel electrophoresis and DNA sequencing were used to identify BRCA1 mutations.


Input: RESULTS BRCA1 mutations were identified in 16 percent of women with a family history of breast cancer.

breast cancer


Input: Only 7 percent of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations.

breast cancer

ovarian cancer


Input: The rates were higher among women from families with a history of both breast and ovarian cancer.

breast and ovarian cancer


Input: Among family members, an average age of less than 55 years at the diagnosis of breast cancer, the presence of ovarian cancer, the presence of breast and ovarian cancer in the same woman, and Ashkenazi Jewish ancestry were all associated with an increased risk of detecting a BRCA1 mutation.

breast cancer

ovarian cancer

breast and ovarian cancer


Input: No association was found between the presence of bilateral breast cancer or the number of breast cancers in a family and the detection of a BRCA1 mutation, or between the position of the mutation in the BRCA1 gene and the presence of ovarian cancer in a family.

breast cancer

breast cancers

ovarian cancer


Input: CONCLUSIONS Among women with breast cancer and a family history of the disease, the percentage with BRCA1 coding-region mutations is less than the 45 percent predicted by genetic-linkage analysis.

breast cancer


Input: These results suggest that even in a referral clinic specializing in screening women from high-risk families, the majority of tests for BRCA1 mutations will be negative and therefore uninformative..


Input: Mutations in the arginine-rich protein gene (ARP) in pancreatic cancer.

pancreatic cancer


Input: The ARP gene encodes a highly conserved arginine-rich protein from chromosomal band 3p21.


Input: 1 1.


Input: At the cytogenetic level this region is frequently deleted in a variety of different solid tumors, although not in pancreatic cancer.

solid tumors

pancreatic cancer


Input: We have reported the presence of a specific mutation (ATG50--> AGG) or deletion of codon 50 of the ARP gene in different tumor types (Shridhar et al., 1996, 1996a).

tumor types


Input: In the present study, we have observed mutations involving codon 50 in 11 of 37 pancreatic tumors.

pancreatic tumors


Input: The frequency of codon 50 mutation is roughly the same in pancreatic tumors as in the other types of tumors previously examined.

pancreatic tumors

tumors


Input: In addition, we have detected mutations at codon 51 in multiple PCR subclones in two other pancreatic tumors.

pancreatic tumors


Input: Mutations in the ARP gene are thus commonly observed in pancreatic cancer, as well as many other cancers.

pancreatic cancer

cancers


Input: Difficulties in the ascertainment of C9 deficiency: lessons to be drawn from a compound heterozygote C9-deficient subject.

C9 deficiency


Input: A group of patients with long-surviving mismatched kidney allografts were investigated for complement function using haemolytic assays in agarose gels.


Input: One patient was found to have no alternative pathway activity but a low normal classical pathway.


Input: Surprisingly, investigation revealed that the patients complement was normal for all components except C9, which was functionally absent.


Input: The patient was shown to be heterozygous for DNA markers in the C6, C7 and C9 region of chromosome 5 and therefore appears to be a compound heterozygote for two uncharacterized C9 deficiency genes.

C9 deficiency


Input: Serological analysis by ELISA revealed that he has trace concentrations of a non-functional C9 molecule.


Input: Western blot analysis was not sufficiently sensitive to permit detection of this molecule.


Input: We hypothesize that the patient is heterozygous for a complete deficiency of C9 and for a gene directing hyposynthesis of a defective C9.

complete deficiency of C9


Input: We also suggest that C9 deficiency may be more common among Caucasians than has been reported..

C9 deficiency


Input: Screening for ESR mutations in breast and ovarian cancer patients.

breast and ovarian cancer


Input: In the present study, leukocyte DNA from 143 patients with familial clustering of breast and/or ovarian cancer and tumour DNA from 96 breast carcinomas were screened for base mutations in the estrogen receptor gene (ESR).

breast and/or ovarian cancer

tumour

breast carcinomas


Input: Three patients with a family history of cancer were carrying a Gly160Cys germline substitution.

cancer


Input: This alteration was also detected in eight (four females and four males) of 729 controls (366 female, 363 males), indicating that the substitution probably represents a polymorphism.


Input: However, in the 229 female controls in whom family history of cancer was known, one of two who had a sister with breast cancer was carrying the variant allele.

cancer

breast cancer


Input: Hence, a possible clinical significance of the glycine into cysteine cannot be completely ruled out and should be further investigated.


Input: Somatic mutations were not detected in any of the tumours studied, and the present data do not provide support for somatic ESR base mutations as an important mechanism for hormonal therapy resistance in estrogen receptor-positive breast carcinomas..

tumours

estrogen receptor-positive breast carcinomas


Input: Molecular bases of C7 deficiency: three different defects.

C7 deficiency


Input: The molecular basis of C7 deficiency has been investigated in two Irish families and a number of Israeli families of Moroccan Sephardic Jewish origin.

C7 deficiency


Input: Exon PCR and sequencing revealed a heterozygous point mutation at the 3 splice acceptor site of intron 1 in one Irish family.


Input: In the other Irish family, exons 7 and 8 failed to amplify and they were shown to be deleted.


Input: Marker haplotype studies of the C6 and C7 gene region and Southern blots show that the Irish family with the splice defect also segregate for the deletion, which is not easily detected in heterozygotes.


Input: The Israeli C7-deficient cases all share a C7 haplotype and are homozygous for a mis-sense mutation in exon 9.


Input: However, one individual is heterozygous for markers at adjacent C6 loci, showing that there has been an intergenic recombination and suggesting that the deficiency mutation is of appreciable antiquity..


Input: Molecular heterogeneity of classical and Duarte galactosemia: mutation analysis by denaturing gradient gel electrophoresis.

classical and Duarte galactosemia


Input: Classical galactosemia is caused by one common missense mutation (Q188R) and by several rare mutations in the galactose-1-phosphate uridyltransferase (GALT) gene.

Classical galactosemia


Input: The most common variant of GALT, the Duarte variant, occurs as two types, Duarte-1 (D-1) and Duarte-2 (D-2), both of which carry the sequence change N314D.


Input: D-1 increases, whereas D-2 decreases GALT activity.


Input: To study the molecular genetics of classical and Duarte galactosemia, we analyzed the GALT mutations in 30 families with classical galactosemia, in 10 families with the D-2 variant and in 3 individuals carrying the D-1 allele by denaturing gradient gel electrophoresis (DGGE).

classical and Duarte galactosemia

classical galactosemia


Input: DGGE detected 59 of the 60 classical galactosemia alleles.

galactosemia


Input: Q188R accounted for 60%, K285N accounted for 28% of these alleles.


Input: Eight novel candidate galactosemia mutations were found.

galactosemia


Input: On all D-2 alleles N314D occurred in cis with two intronic sequence changes, on the D-1 alleles in cis with a neutral mutation in exon 7.


Input: We conclude that the mutations causing galactosemia are highly heterogeneous and that K285N is a second common galactosemia mutation in our population..

galactosemia

galactosemia


Input: Isolation of full-length ATM cDNA and correction of the ataxia-telangiectasia cellular phenotype.

ataxia-telangiectasia


Input: A gene mutated in the human genetic disorder ataxia-telangiectasia (A-T), ATM, was recently identified by positional cloning.

genetic disorder ataxia-telangiectasia

A-T


Input: ATM is a member of the phosphatidylinositol-3-kinase superfamily, some of which are protein kinases and appear to have important roles in cell cycle control and radiation signal transduction.


Input: We describe herein, to our knowledge, for the first time, the cloning of a full-length cDNA for ATM and correction of multiple aspects of the radio-sensitive phenotype of A-T cells by transfection with this cDNA.

A-T


Input: Overexpression of ATM cDNA in A-T cells enhanced the survival of these cells in response to radiation exposure, decreased radiation-induced chromosome aberrations, reduced radio-resistant DNA synthesis, and partially corrected defective cell cycle checkpoints and induction of stress-activated protein kinase.

A-T


Input: This correction of the defects in A-T cells provides further evidence of the multiplicity of effector functions of the ATM protein and suggests possible approaches to gene therapy..

A-T


Input: Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma.

alveolar rhabdomyosarcoma


Input: Chromosomal translocations identified in hematopoietic and solid tumors result in deregulated expression of protooncogenes or creation of chimeric proteins with tumorigenic potential.

hematopoietic and solid tumors


Input: In the pediatric solid tumor alveolar rhabdomyosarcoma, a consistent t (2; 13) (q35; q14) or variant t (1; 13) (p36; q14) translocation generates PAX3-FKHR or PAX7-FKHR fusion proteins, respectively.

solid tumor alveolar rhabdomyosarcoma


Input: In this report, we demonstrate that in addition to functional alterations these translocations are associated with fusion product overexpression.


Input: Furthermore, PAX3-FKHR and PAX7-FKHR overexpression occurs by distinct mechanisms.


Input: Transcription of PAX3-FKHR is increased relative to wild-type PAX3 by a copy number-independent process.


Input: In contrast, PAX7-FKHR overexpression results from fusion gene amplification.


Input: Thus, gene-specific mechanisms were selected to overexpress PAX3-FKHR and PAX7-FKHR in alveolar rhabdomyosarcoma, presumably due to differences in regulation between the wild-type loci.

alveolar rhabdomyosarcoma


Input: We postulate that these overexpression mechanisms ensure a critical level of gene product for the oncogenic effects of these fusions..


Input: atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity.

acute radiation toxicity


Input: Mutations in atm and p53 cause the human cancer-associated diseases ataxia-telangiectasia and Li-Fraumeni syndrome, respectively.

cancer-associated diseases ataxia-telangiectasia

Li-Fraumeni syndrome


Input: The two genes are believed to interact in a number of pathways, including regulation of DNA damage-induced cell-cycle checkpoints, apoptosis and radiation sensitivity, and cellular proliferation.


Input: Atm-null mice, as well as those null for p53, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development.

T-cell lymphomas


Input: To study the interactions of these two genes on an organismal level, we bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations.


Input: Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumour formation relative to singly null mice, indicating that both genes collaborate in a significant manner to prevent tumorigenesis.

tumour


Input: With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance.


Input: This implies that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent.


Input: Finally-and in contrast to prior predictions-atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumours..

acute radiation toxicity

tumours


Input: Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP.

myotonic dystrophy


Input: Myotonic dystrophy, or dystrophia myotonica (DM), is an autosomal dominant multisystem disorder caused by the expansion of a CTG trinucleotide repeat in the 3 untranslated region of the DMPK protein kinase gene on chromosome 19q13.

Myotonic dystrophy

dystrophia myotonica

DM

autosomal dominant multisystem disorder


Input: 3 (refs 1-3).


Input: Although the DM mutation was identified more than five years ago, the pathogenic mechanisms underlying this most prevalent form of hereditary adult neuromuscular disease remain elusive.

DM

neuromuscular disease


Input: Previous work from our laboratory demonstrated that a DNase l-hypersensitive site located adjacent to the repeats on the wild-type allele is eliminated by repeat expansion, indicating that large CTG-repeat arrays may be associated with a local chromatin environment that represses gene expression.


Input: Here we report that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene.


Input: Analysis of DMAHP expression in the cells of DM patients with loss of the hypersensitive site revealed a two-to fourfold reduction in steady-state DMAHP transcript levels relative to wild-type controls.

DMAHP


Input: Allele-specific analysis of DMAHP expression showed that steady-state transcript levels from the expanded allele were greatly reduced in comparison to those from the wild-type allele.


Input: Together, these results demonstrate that CTG-repeat expansions can suppress local gene expression and implicate DMAHP in DM pathogenesis.

DMAHP


Input: Constitutively methylated CpG dinucleotides as mutation hot spots in the retinoblastoma gene (RB1).

retinoblastoma


Input: A wide spectrum of mutations, ranging from point mutations to large deletions, have been described in the retinoblastoma gene (RB1).

retinoblastoma


Input: Mutations have been found throughout the gene; however, these genetic alterations do not appear to be homogeneously distributed.


Input: In particular, a significant proportion of disease-causing mutations results in the premature termination of protein synthesis, and the majority of these mutations occur as C--> T transitions at CpG dinucleotides (CpGs).


Input: Such recurrent CpG mutations, including those found in RB1, are likely the result of the deamination of 5-methylcytosine within these CpGs.


Input: In the present study, we used the sodiumbisulfite conversion method to detect cytosine methylation in representative exons of RB1.


Input: We analyzed DNA from a variety of tissues and specifically targeted CGA codons in RB1, where recurrent premature termination mutations have been reported.


Input: We found that DNA methylation within RB1 exons 8, 14, 25, and 27 appeared to be restricted to CpGs, including six CGA codons.


Input: Other codons containing methylated cytosines have not been reported to be mutated.


Input: Therefore, disease-causing mutations at CpGs in RB1 appear to be determined by several factors, including the constitutive presence of DNA methylation at cytosines within CpGs, the specific codon within which the methylated cytosine is located, and the particular region of the gene within which that codon resides..


Input: The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.

von Hippel-Lindau tumor


Input: The von Hippel-Lindau tumor suppressor gene (VHL) has a critical role in the pathogenesis of clear-cell renal cell carcinoma (RCC), as VHL mutations have been found in both von Hippel-Lindau disease-associated and sporadic RCCs.

von Hippel-Lindau tumor

clear-cell renal cell carcinoma

RCC

von Hippel-Lindau disease-associated and sporadic RCCs


Input: Recent studies suggest that vascular endothelial growth factor (VEGF) mRNA is upregulated in RCC-and von Hippel-Lindau disease-associated tumors.

RCC-and von Hippel-Lindau disease-associated tumors


Input: We have therefore assessed the effect of the VHL gene product on VEGF expression.


Input: VEGF promoter-luciferase constructs were transiently cotransfected with a wild-type VHL (wt-VHL) vector in several cell lines, including 293 embryonic kidney and RCC cell lines.

RCC


Input: wt-VHL protein inhibited VEGF promoter activity in a dose-dependent manner up to 5-to 10-fold.


Input: Deletion analysis defined a 144-bp region of the VEGF promoter necessary for VHL repression.


Input: This VHL-responsive element is GC rich and specifically binds the transcription factor Sp1 in crude nuclear extracts.


Input: In Drosophila cells, cotransfected VHL represses Sp1-mediated activation but not basal activity of the VEGF promoter.


Input: We next demonstrated in coimmunoprecipitates that VHL and Sp1 were part of the same complex and, by using a glutathione-S-transferase-VHL fusion protein and purified Sp1, that VHL and Sp1 directly interact.


Input: Furthermore, endogenous VEGF mRNA levels were suppressed in permanent RCC cell lines expressing wt-VHL, and nuclear run-on studies indicated that VHL regulation of VEGF occurs at least partly at the transcriptional level.

RCC


Input: These observations support a new mechanism for VHL-mediated transcriptional repression via a direct inhibitory action on Sp1 and suggest that loss of Sp1 inhibition may be important in the pathogenesis of von Hippel-Lindau disease and RCC..

von Hippel-Lindau disease

RCC


Input: Adult onset globoid cell leukodystrophy (Krabbe disease): analysis of galactosylceramidase cDNA from four Japanese patients.

Adult onset globoid cell leukodystrophy

Krabbe disease


Input: We examined galactosylceramidase (GALC) cDNA in four Japanese patients with adult onset globoid cell leukodystrophy (Krabbe disease; AO-GLD) by polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) analysis, subsequent sequence determination, and restriction enzyme digestion of PCR products, initial symptoms were the onset of slowly progressive spastic paraplegia from the middle of the second decade, and all patients had diminished GALC activity in their leukocytes.

adult onset globoid cell leukodystrophy

Krabbe disease

AO-GLD

spastic paraplegia

diminished GALC activity


Input: We identified three missense mutations (I66M, G270D, L618S) and one exon-6 skipping (535-573del).


Input: Two of the patients had only the I66M mutant mRNA, and one only the G27OD mutant mRNA.


Input: The fourth patient carried a compound heterozygous mutation of 535-573del and L618S.


Input: To determine the enzymatic activities produced by these mutations, we constructed mutated GALC cDNAs and expressed them in COS-1 cells.


Input: Three mutations, viz., G270D, L618S, and exon-6 skipping (535-573del), produced diminished GALC activity as expected.

diminished GALC activity


Input: The I66M mutation in the wild-type GALC cDNA (I289) had normal activity, but when this mutation and the V289 polymorphism were introduced into the same allele, it had decreased activity.


Input: Thus, the combination of a unique mutation and polymorphism causes conformational change in the GALC enzyme, resulting in low enzymatic activity.


Input: AO-GLD mutations, including those found here, are located in the N-terminus (I66M, G270D, 535-573del) or C-terminus (L618S) of the GALC enzyme, whereas the reported mutations in the infantile form (IF-GLD) are in the central domain.

AO-GLD

IF-GLD


Input: This difference in mutation sites may affect the clinical features of GLD.

GLD