SEARCH · PubMed Health

Results for “deleterious mutation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 703 records · Page 39Linked to original sources

PubMed1988

Mutation in the CYP21B gene (Ile-172----Asn) causes steroid 21-hydroxylase deficiency.

Steroid 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. It results from a deficiency in a specific cytochrome P450, P450c21 (P450XXIA). The gene encoding this protein (CYP21B) and a closely linked pseudogene (CYP21A) are located in the HLA complex on chromosome 6p. Many mutant alleles are associated with deletions of CYP21B; we report the cloning and characterization of a nondeleted mutant CYP21B gene. This mutant gene is expressed on transfection into mouse Y1 adrenal cells, producing mRNA levels similar to those seen after transfection of the normal CYP21B gene. In codon 172 of the mutant gene, the normal codon ATC, encoding isoleucine, has been changed to AAC, encoding asparagine. This mutation is normally present in the CYP21A pseudogene, so that it may have been transferred to the mutant CYP21B gene by gene conversion. Hybridization of oligonucleotide probes corresponding to this and two other mutations normally present in CYP21A demonstrated that 4 out of 20 patients carried the codon 172 mutation; in one of these patients, the mutation was present as part of a larger gene conversion involving at least exons 3-6. Gene conversion may be a frequent cause of 21-hydroxylase deficiency alleles due to the presence of six chi-like sequences (GCTGGGG) in the CYP21 genes and the close proximity of the CYP21A pseudogene, which has several potentially deleterious mutations.

Adrenal Hyperplasia, Congenital↗

PubMed2003

Predictive testing for BRCA1 and 2 mutations: a male contribution.

BACKGROUND: Management strategies for women carrying BRCA1 and 2 mutations are becoming clearer and predictive testing for a known family mutation is commonly undertaken. Implications for men are not as clear and they participate less frequently. PATIENTS AND METHODS: Twenty-six men from 10 extended families underwent predictive testing. Their motivation, reaction and outcome were studied. Subjects had appropriate pre- and post-test counselling. Informed consent was obtained before predictive testing for known deleterious mutations. DNA analysis followed standard procedures. RESULTS: Eighteen tested positive and eight negative. Four had adverse psychological reactions and three reneged on their commitments to impart results. The spouse of another man had an adverse psychological reaction to the disclosure of his positive result. Two, already suffering from prostate cancer, were phenocopies and paternal lineage transmission was unexpectedly determined in another. Risk was removed from 33 offspring and confirmed for 56. CONCLUSIONS: Complex themes associated with genetic testing are confirmed and the spectrum extended. Men appear to understand the importance of participating in this process. Methods of avoiding adverse reactions merit further study along with other aspects of the process.

Adult↗

PubMed1995

Autosomal recessive lamellar ichthyosis: identification of a new mutation in transglutaminase 1 and evidence for genetic heterogeneity.

Autosomal recessive lamellar ichthyosis (ARLI) belongs to the group of congenital disorders of cornification. It is characterized by a severe and generalized ichthyosis, and other variable cutaneous signs. The human transglutaminase 1 (TGM1) gene was recently found to be the disease-causing gene. Linkage analysis in 23 families (of which 13 were consanguineous) showed that for 10 of them, the disease was linked to the TGM1 gene. A new deleterious mutation introducing a stop codon in the TGM1 reading frame was found. Nevertheless, for the 13 other ARLI families, TGM1 was found to be unlinked to the disease. The present data show that ARLI is genetically heterogeneous and confirm that TGM1 is one of the responsible genes.

Base Sequence↗

PubMed2004

Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis.

Familial tumoral calcinosis (FTC; OMIM 211900) is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Using linkage analysis, we mapped the gene underlying FTC to 2q24-q31. This region includes the gene GALNT3, which encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Sequence analysis of GALNT3 identified biallelic deleterious mutations in all individuals with FTC, suggesting that defective post-translational modification underlies the disease.

Base Sequence↗

PubMed2002

Perspective: prostate cancer susceptibility genes.

In many developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal, and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that association of candidate genetic markers to this multifactorial malignancy is more difficult than the identification of susceptibility genes for some common cancers such as breast, ovary, and colon cancer. Several reasons may explain such a difficulty: 1) prostate cancer is diagnosed at a late age, thus often making it impossible to obtain DNA samples from living affected men for more than one generation; 2) the presence within high-risk pedigrees of phenocopies, associated with the lack of distinguishing features between hereditary and sporadic forms; and 3) the genetic heterogeneity of this complex disease along with the accompanying difficulty of developing appropriate statistical transmission models taking into account simultaneously multiple susceptibility genes, frequently showing moderate or low penetrance. Despite the localization of seven susceptibility loci, there has been limited confirmatory evidence of linkage for currently known candidate genes. Nonetheless, the discovery of the first prostate cancer susceptibility gene characterized by positional cloning, ELAC2 was achieved taking advantage of the Utah Family Resource. Moreover, common missense mutations in the ELAC2 gene were found to be significantly associated with an increased risk of diagnosis of prostate cancer in some studies. More recently, recombination map-ping and candidate gene analysis were used to map several genes, including the 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL) gene, to the critical region of HPC1. Two deleterious mutations in RNASEL segregate independently with the disease in two of the eight HPC1-linked families. Additional studies using larger cohorts are needed to fully evaluate the role of these two susceptibility genes in prostate cancer risk. Although a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, some of the familial risks may be due to shared environment and more specifically to common low-penetrance genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action, led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants, such as those found in 5alpha-reductase type 2 and AR genes.

Alleles↗

PubMed2005

Gamma interferon is dispensable for neopterin production in vivo.

Previous studies have indicated that neopterin is synthesized in vitro by human monocyte-derived macrophages and dendritic cells upon stimulation with gamma interferon (IFN-gamma). Neopterin production under specific conditions in vitro has also been obtained upon stimulation with IFN-alpha and/or IFN-beta. However, it is unknown if any IFN-gamma-independent neopterin synthesis is possible in vivo. In the present study we investigated the serum neopterin concentrations in patients affected by the syndrome of Mendelian susceptibility to mycobacterial disease (MSMD). Indeed, this syndrome is characterized by deeply impaired or absent IFN-gamma production or function due to severe mutations in molecules involved in IFN-gamma/interleukin-12 (IL-12)/IL-23-dependent pathway. Serum neopterin levels were measured by an enzyme-linked immunosorbent assay in 27 patients with MSMD. We found that serum neopterin levels are elevated in the complete absence of IFN-gamma activity due either to a complete deficiency of its receptor or to deleterious mutations of IL-12 or its receptor. These data clearly indicate that, as reported from in vitro studies, other stimuli are able to induce neopterin synthesis in vivo. Consequently, neopterin cannot be used as means of diagnosis of MSMD due to IFN-gamma-, IL-12-, and IL-23-dependent pathway defects.

Adolescent↗

PubMed2002

The origin of CD95-gene mutations in B-cell lymphoma.

CD95 (Apo-1/Fas) is crucial for the negative selection of B cells within the germinal center (GC). Impairment of CD95-mediated apoptosis results in defective affinity maturation and the persistence of autoreactive B-cell clones. CD95 was defined recently as a tumor-suppressor gene and is silenced in many tumor entities. In contrast to other malignancies, in GC-derived B-cell lymphomas, inactivation of the CD95 gene is often a result of deleterious mutations. Such mutations occur also at a low frequency in normal GC, but not naive, B cells. We propose that CD95 mutations in B-cell lymphomas originate from the GC reaction and are introduced most probably as targeting errors of the somatic hypermutation machinery, which bears--besides its physiological role--an inherent risk of malignant transformation and the persistence of autoreactive B-cell specificities.

Cell Lineage↗

PubMed2001

Germline mutations in the p73 gene do not predispose to familial prostate-brain cancer.

BACKGROUND: Analysis of high-risk prostate cancer (PC) families with at least one confirmed case of primary brain cancer (BC) has identified a region of genetic linkage on chromosome 1p36 termed CAPB. The p36 region of chromosome one has been reported to have frequent loss of heterozygosity (LOH) in brain and central nervous system (CNS) tumors and epidemiological studies have shown an increased relative risk of BC and tumors of the CNS in PC families. In 1997 a reported tumor suppressor with high homology to p53, termed p73, was mapped to the p36 region of chromosome one. Here, we examine the p73 gene as a potential candidate for CAPB. METHODS: Ninety-four members from the 12 prostate-brain cancer families in which linkage was originally found were examined. The complete coding region and intron-exon boundaries of the p73 gene were analyzed for germline mutations by Single Stranded Conformational Polymorphism analysis (SSCP) and direct DNA sequencing. RESULTS: Silent nucleotide substitutions only were detected within the coding regions of the gene in affected individuals. Nucleotide changes were detected in introns 1, 6, 8, 9, and 10, but all were located >or=16 base pairs from the splice site, and are thus unlikely to be deleterious mutations. CONCLUSIONS: Germline mutations in the p73 gene are unlikely to be critical for inherited susceptibility to PC in this specified subset of families.

Aged↗

PubMed1996

Phenotypic variation in Waardenburg syndrome: mutational heterogeneity, modifier genes or polygenic background?

We have identified 11 mutational changes in the PAX3 gene in patients with type 1 Waardenburg syndrome (WS1) including three in the paired domain, six within or immediately adjacent to the homeodomain and two previously described polymorphic variants in exons 2 and 6. The affected members of one family carried substitutions involving two base pairs separated by one unaltered codon. Two of the deleterious mutations were identical and three others were identical to previously reported mutations. A comparison of clinical findings in families carrying substitutions in the same codon failed to reveal conspicuous similarities. Although subtle mutation-specific effects may well exist, allelic heterogeneity clearly cannot account for within family variation. However, the striking concordance of a pair of monozygotic twins with Waardenburg syndrome (WS) and previous reports of similar pairs indicate that phenotypic variation in WS has a genetic basis. If the genetic effects are mediated by oligogenic epistasis, as studies in the mouse suggest, it may ultimately be possible to predict clinically relevant aspects of the Waardenburg phenotype.

Amino Acid Sequence↗

PubMed1999

A cellular assay distinguishes normal and mutant TIGR/myocilin protein.

Glaucoma is a blinding eye disease that affects approximately 70 000 000 people world-wide. Mutations in the gene TIGR / MYOC have been shown to cause the most common form of the disease, primary open angle glaucoma, in selected families. Amino acid sequence variants of the gene have been found in 2-4% of sporadic primary open angle glaucoma cases. Most variants are rare and it is often difficult to definitively distinguish between a deleterious mutation and a benign variant solely on the basis of relative frequencies in patient and control groups. The function of the TIGR/myocilin protein is unknown and an assay to functionally classify variants is lacking. We sought to develop a biochemical assay to distinguish different forms of TIGR/myocilin. We investigated the Triton X-100 detergent solubility characteristics of mutant and normal forms of the protein, expressed by transfection in cultured cells. We observed a clear difference in the behavior of the two types of TIGR/myocilin; all confirmed mutant proteins tested were substantially Triton insoluble, while normal protein and controls were completely soluble. We also tested seven ambiguous variant proteins and classified them as mutant or normal on the basis of their Triton solubility. The results in some cases validated, and in other cases contradicted, earlier classifications of these variants. To our knowledge, Triton solubility is the first example of a general difference in the properties of mutant and normal forms of TIGR/myocilin. The assay we have developed will be useful for discerning protein functional information from the location of mutations, will aid genetic counseling of individuals with TIGR/myocilin variants and may provide a clue to understanding a mechanism by which mutations in TIGR / MYOC cause glaucoma.

Amino Acid Substitution↗

PubMed1994

Invasion and maintenance of a gene duplication.

The ubiquity of multigene families is evidence for the frequent occurrence of gene duplication, but the origin of multigene families from a single gene remains a little-studied aspect of genome evolution. Although it is clear that a duplication can arise and become fixed in a population purely by random genetic drift and that the rate of fixation is accelerated if the duplication is directly advantageous, the nature of gene duplication suggests that other factors may influence the fate of a novel duplication. In the face of disadvantageous loss-of-function mutations, duplication of a functional gene may provide a buffer against such mutations. Here the conditions for invasion of a rare duplication starting from a mutation-selection balance are derived with formal population genetic models in both haploids and diploids. Recurrent duplication protects the duplicated chromosome from loss and can be very effective in increasing its frequency in a population. In the absence of recurrent duplication, one might suppose that a duplication would be favored by natural selection because it can mask the effects of deleterious mutations. However, the models show that a duplication can invade only if it provides a direct advantage to the organism. This result is closely related to recent theoretical work on the evolution of ploidy.

Diploidy↗

PubMed2025

Sexual selection, genomic evolution and population fitness in Drosophila pseudoobscura.

Sexual selection shapes the genome in unique ways. It is also likely to have significant fitness consequences, such as purging deleterious mutations from the genome or conversely maintaining genetic load in a population via sexual conflict. Here, we examined what the influence of sexual selection has on genomic variation potentially underlying population fitness using experimentally evolved Drosophila pseudoobscura populations. Sexual selection was manipulated by keeping replicate lines in elevated polyandry or strict monogamy for approximately 200 generations followed by individual-based sequencing. Using pi (π), fixation index (Fst)and recombination rate measures, we confirmed signatures of selection were not dispersed but mainly localized to the third and X chromosome. Overall mutational load was similar between lines but our analysis of the distribution of fitness effects revealed considerable variation between lines and chromosomes. Furthermore, we found that the distribution of transposable elements differs between the lines, with a higher load in monogamous lines. Our results suggest that complex interactions between purifying selection and sexual conflict are shaping the genome, particularly on chromosome 3 and the sex chromosome; sexual selection influences divergence across chromosomes but in a more complex way than proposed by simple 'purging' of deleterious loci.

Animals↗

PubMed2002

Molecular analysis of the anti-Müllerian hormone, the anti-Müllerian hormone receptor, and galactose-1-phosphate uridyl transferase genes in patients with the Mayer-Rokitansky-Küster-Hauser syndrome.

INTRODUCTION: Müllerian agenesis, also named the Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) or vaginal aplasia, is the second most common cause of primary amenorrhea. It is characterized by the congenital absence of the Müllerian structures including the Fallopian tubes, the uterus, and the internal portion of the vagina in an otherwise normally feminized 46,XX subject. Most cases are sporadic in inheritance, but the occurrence of some patients with chromosomal translocations or even familial aggregates suggest a genetic basis for the disease, although the etiology of the disease is still unknown. It has been suggested that activating mutations in the anti-Müllerian hormone (AMH) or in its receptor (AMHRII) are potential sources for the defect. METHODS: In this study we describe the molecular analysis of both the AMH and AMHR genes in a group of 15 patients with Müllerian agenesis. After sequencing all exons and exon/intron junctions of both genes, we were not able to detect any deleterious mutation. RESULTS: Five new polymorphisms, 2 of them in the AMHRII gene and 3 of them in the AMH gene, were identified. No significant differences between patients and controls were observed in the frequency of a given polymorphism. CONCLUSION: This work reinforces the view that molecular defects in the AMH or AMHR are unlikely sources for the MRKHS syndrome.

Anti-Mullerian Hormone↗

PubMed2003

Carriers for type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency can only be identified by HSD3B2 genotype study and not by hormone test.

OBJECTIVE: We investigated adrenal steroidogenic function relevant to 3beta-hydroxysteroid dehydrogenase (HSD3B2) activity in vivo and HSD3B2 genotype in clinically normal family members of patients with HSD3B2 genotype-proven HSD3B2 deficiency congenital adrenal hyperplasia (CAH) to determine whether genotype-proven carriers for HSD3B2 deficiency exhibit decreased enzyme activity analogous to the mildly decreased adrenal 21-hydroxylase activity in the carriers of CYP21 gene mutation. DESIGN/PATIENTS: Nineteen adult family members (ages median/range: 37/19-56 years) including 13 females and six males of six unrelated patients with HSD3B2 genotype-proven HSD3B2 deficiency were studied. MEASUREMENTS: All family members had HSD3B2 DNA analysis and an ACTH stimulation test (Cortrosyn 0.25 mg IV bolus) for determination of adrenal HSD3B activity. RESULTS: Ten of 13 females and five of six males were carriers of a proven or predictably deleterious mutation in one allele of the HSD3B2 gene, which was identified in the probands. ACTH-stimulated levels of 17-hydroxypregnenolone (delta5-17P), 17-hydroxyprogesterone (17-OHP), cortisol (F), dehydroepiandrosterone (DHEA) and androstenedione (delta4-A) and ratios of delta5-17P to 17-OHP, delta5-17P to F and DHEA to delta4-A, as well as increments of delta5-17P and DHEA values (ACTH-stimulated - baseline) in the genotype-proven female carriers (age, mean +/- SD: 36 +/- 6.7 years) and male carriers (age, mean +/- SD: 37 +/- 6.7 years) did not differ significantly from age-matched normal females (35 +/- 5.4 years, n = 20) and normal males (35 +/- 6 years, n = 10), respectively. There were no significant differences in any of the ACTH-stimulated hormonal levels or ratios between the female carriers with a seriously deleterious genotype (n = 5) and the female carriers with mildly deleterious genotypes (n = 5). These hormonal levels and ratios in three genotype-normal females and one genotype-normal male overlapped with those of the carriers. CONCLUSION: These data suggest that normal adrenal HSD3B2 activity is maintained in the genotype-proven carriers because heterodimers of mutant and wild-type HSD3B2 enzymes may be stable and exhibit similar activity compared to homodimers of wild-type enzymes, possibly by a relatively rate-unlimited effect of haplo-wild-type enzyme activity. However, we cannot preclude entirely the possibility of a limited expression of another HSD3B activity under ACTH stimulation contributing to the normal adrenal HSD3B activity in vivo in the HSD3B2 genotype-proven heterozygotes. Which mechanism plays a role in maintaining normal enzyme activity in the heterozygotes remains to be elucidated. The hormone findings in the genotypic-proven carriers for HSD3B2 deficiency also indicate that carriers for this disorder cannot be detected by a hormone test and can only be detected by HSD3B2 genotype study.

3-Hydroxysteroid Dehydrogenases↗

PubMed1999

Bcl10 is not a target for frequent mutation in human carcinomas.

The recently described Bcl10 gene has been suggested to be a major target gene for inactivation in a variety of human cancers. In order to further evaluate the role of this gene in human adult malignancies, we have analysed a series of carcinomas for mutations in the Bcl10 gene. We have screened a panel of 174 carcinoma samples in total, comprised of 47 breast, 36 epithelial ovarian, 36 endometrial, 12 cervical, 23 colorectal and 20 head/neck carcinomas, all unselected for grade or stage. This panel reflects, in part, tumours reported to have involvement of the 1p22 region of chromosome 1, the region harbouring the Bcl10 gene. No deleterious mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not a common target for inactivation in adult malignancies and that BCL10 is not the gene targeted for frequent inactivation at 1p22.

Adaptor Proteins, Signal Transducing↗

PubMed1975

Mutator factors and genetic variance components of viability in Drosophila melanogaster.

In the process of testing whether or not the independent-locus selection model holds true with previously estimated genetic parameters (cf. MUKAI and MARUYAMA 1971) in D. melanogaster collected near Raleigh, North Carolina, we found an abnormal phenomenon: an unusually large increase in dominance variance for viability in comparison with additive variance with the accumulation of mutations on 140 randomyl sampled, inversion-free second chromosomes. Mutations were accumulated only through males heterozygous for the Pm-carrying chromosome [In(2LR)bwV1] and the extracted second chromosomes, and the genetic variance components were estimated by using a partial diallel cross method.--Further investigations clarified that chromosome abberations occurred at a frequency of 0.0114 per second chromosome per generation (inversions: 0.0098; transpositions: 0.0011; translocation: 0.0004), and recessive lethal mutations occurred at an average rate of 0.031 per second chromosome per generation.--From these results and from the amount of change in the homozygous load, it was speculated that about 60--70% of the second chromosomes used had a kind of mutator which induced chromosome and/or chromatid breaks at a minimum rate of 0.18 per second chromosome per generation. These breaks resulted in recessive lethal mutations at a rate more than ten times higher than the normal rate. Also these breaks were most probably the cause of male recombination.--The above unusual increase in dominance variance can be explained by assuming that chromosome segments, introduced into the extracted "wild" chromosomes by male recombinations (double crossover) from the marker chromosomes [In(2LR)bwV1], showed heterosis and linkage disequilibria with deleterious mutations and possibly with other introduced segments.--Finally, the nature and possible significance of mutator factors are discussed.

Animals↗

PubMedDate not supplied

BRCA1 germline mutations in Cypriot breast cancer patients from 26 families with family history.

Germline mutations in the BRCA1 gene are causative for a variable number of hereditary breast/ovarian cancers. The data presented in this study are based on genetic analysis of the BRCA1 gene in 49 DNA samples from breast cancer patients with a positive family history. A combination of manual direct DNA sequencing and SSCP analysis was used to screen the entire coding region of BRCA1. Overall 13 variants were detected which included 5 missense mutations, 3 polymorphisms and 5 intronic changes. Further genetic analysis of the 13 variants was carried out using 50 control DNA samples. Our results showed that 12 out of the 13 variants detected in the DNA of the patients group, were also present in the control group. It appears that the Greek Cypriot families studied so far have an unexpectebly low frequency of deleterious mutations in the BRCA1 gene. This is the first report on BRCA1 mutation analysis in Cyprus.

Adult↗

PubMed2005

Structure-based assessment of BRCA1 and BRCA2 mutations in a small Spanish population.

Breast cancer is the most frequent cancer type among women in the world. There is abundant evidence, that alterations in the breast cancer susceptibility genes, BRCA1 and BRCA2, are present in a large proportion of families with multiple cases of breast and ovarian cancer. Our aim was to better understand the molecular and structural insights associated with the most frequent alterations, found in the BRCA1 and BRCA2 genes, within our patients. We analyzed 50 breast cancer cases. Of those, 24% were found to carry deleterious mutations, and up to 10 rare variants of unknown significance were detected. The frequency of polymorphic changes was considerably different between genes, BRCA1 (55%) and BRCA2 (19.4%). By looking at the protein level, the changes observed within the BRCA1 and BRCA2 genes could affect not only the nucleic location of the protein but also disrupt the folding and, therefore, the tumor suppressor function.

BRCA1 Protein↗