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 487 records · Page 27Linked to original sources

PubMed2004

Discordant PKU phenotype in one family due to disparate genotypes and a novel mutation.

Classical phenylketonuria (PKU) and mild hyperphenylalaninaemia (MHP) are two ends of the broad diagnostic spectrum in phenylalanine hydroxylase (PAH) deficiency. We have analysed a family in which classical PKU, MHP and a normal phenotype occurred in family members with different mutations. Sequence analysis revealed three mutations segregating in the family. The individual with classical PKU had two previously reported deleterious mutations. A third novel mutation was identified in the other two individuals. This report demonstrates that when discordant phenotypes occur in a family, without protein loading or phenylalanine tolerance test, complete analysis of the PAH gene may be performed in order to support the diagnosis and assist in accurate genetic counselling and patient management.

Alleles↗

PubMed2006

Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families.

To meet the increasing demand for BRCA1 and BRCA2 mutation analysis, a robust system for selecting families who have a higher chance of a mutation has become important. Several models have been developed to help predict which samples are more likely to be mutation positive than others. We have undertaken a complete BRCA1 and BRCA2 mutation analysis in 267 Danish families with high-risk family history. We found deleterious mutations in 28% (76) of the families, 68% (52) of those in BRCA1 and 32% (24) in BRCA2. We compared our results with two popular manual models developed to estimate the chance of a positive result. One is the recently published Manchester model and the other is the Frank 2 model updated by Myriad Genetic Laboratories, Inc. Neither of the models would have suggested screening all mutation-positive samples. The Manchester model would have suggested screening 124 of the families in the cohort, thereby detecting 54 of 76 mutations (sensitivity 71%; specificity 63%), whereas the Frank 2/Myriad model would have found 60 of 76 mutations by screening 169 samples if a 10% likelihood was adapted (sensitivity 79%; specificity 43%). The updated Manchester model suggested screening 172 families whereby 64 mutations would have been detected (sensitivity 84%; specificity 44%). We conclude that although both models would have reduced the number of samples screened significantly, up to 28% of the mutations would not have been found by applying these models to this Danish cohort of families. This raises the question whether models designed for specific populations can be used in a wider setting.

BRCA1 Protein↗

PubMed2006

Genetic robustness and selection at the protein level for synonymous codons.

Synonymous codons are neutral at the protein level, therefore natural selection at the protein level should have no effect on their frequencies. Synonymous codons, however, differ in their capacity to reduce the effects of errors: after mutation, certain codons keep on coding for the same amino acid or for amino acids with similar properties, while other synonymous codons produce very different amino acids. Therefore, the impact of errors on a coding sequence (genetic robustness) can be measured by analysing its codon usage. I analyse the codon usage of sequenced nuclear and cytoplasmic genomes and I show that there is an extensive variation in genetic robustness at the DNA sequence level, both among genomes and among genes of the same genome. I also show theoretically that robustness can be adaptive, that is natural selection may lead to a preference for codons that reduce the impact of errors. If selection occurs only among the mutants of a codon (e.g. among the progeny before the adult phase), however, the codons that are more sensitive to the effects of mutations may increase in frequency because they manage to get rid more easily of deleterious mutations. I also suggest other possible explanations for the evolution of genetic robustness at the codon level.

Amino Acid Sequence↗

PubMed2002

Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing.

BACKGROUND: In hereditary non-polyposis colorectal cancer, over 90% of the identified mutations are in two genes, hMSH2 and hMLH1. A large proportion of the mutations detected in these genes are of the missense type which may be either deleterious mutations or harmless polymorphisms. AIM: To investigate whether nine missense and one splice site mutation of hMLH1 and hMSH2, in 10 kindreds with a familial history of colorectal cancer or young age of onset, could be interpreted as pathogenic. METHODS: Clinical and genetic characteristics were collected: (i) evolutionary conservation of the codon involved; (ii) type of amino acid change; (iii) occurrence of mutation in healthy controls; (iv) cosegregation of mutation with disease phenotype; (v) functional consequences of gene variant; and (vi) microssatellite instability and immunoexpression of hMSH2 and hMLH1 analysis. RESULTS: Seven different missense and one splice site mutation were identified. Only 1/8 was found in the control group, 2/7 occurred in conserved residues, and 5/7 resulted in non-conservative changes. Functional studies were available for only 2/8 mutations. Segregation of the missense variant with disease phenotype was observed in three kindreds. CONCLUSION: In the majority of families included, there was no definitive evidence that the missense or splice site alterations were causally associated with an increased risk of developing colorectal cancer. Until further evidence is available, these mutational events should be regarded and interpreted carefully and genetic diagnosis should not be offered to these kindreds.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Environmental stress and the effects of mutation.

Mutations are the ultimate fuel for evolution, but most mutations have a negative effect on fitness. It has been widely accepted that these deleterious fitness effects are, on average, magnified in stressful environments. Recent results suggest that the effects of deleterious mutations can, instead, sometimes be ameliorated in stressful environments.

Animals↗

PubMed1997

Familial schizencephaly associated with EMX2 mutation.

We describe two brothers aged 8 and 10 affected by severe bilateral schizencephaly, carrying an identical point mutation of the homeobox gene EMX2. Both children had severe neurologic deficits and mental retardation, although they differed in the anatomic extent of the brain malformation and in the severity of the clinical picture. The present findings, together with the reported cases of schizencephaly associated with EMX2 mutations, support the hypothesis that, at least in some cases, schizencephalies are determined by deleterious mutations of this homeobox gene. The different morphoclinical pictures suggest that, besides the EMX2 mutation, other factors are relevant in determining the severity of the brain malformation and clinical picture.

Brain↗

PubMed1995

Molecular epidemiology of factor IX germline mutations in Mexican Hispanics: pattern of mutation and potential founder effects.

Germline mutations in patients with hemophilia B generally have arisen within the past 150 years. Evidence suggests that these germline mutations generally result from endogenous processes. However, a unique pattern would be expected if a population were exposed to a physiologically important germline mutagen since mutagens generally produce characteristic patterns, or "fingerprints", of mutation. To determine the pattern of mutation in Mexican Hispanics, the regions of likely functional significance in the factor IX gene were screened by dideoxy fingerprinting (ddF) in 31 families with hemophilia B. Mutations were found in 30 of these families. Haplotype analysis was performed on individuals with identical mutations to help distinguish independent, recurrent mutations from founder effects. Analysis of these 30 mutations, along with 7 mutations reported previously in Mexican Hispanic families, reveals a pattern of independent mutation that is similar to the pattern of mutation observed in 127 U.S. Caucasian families (p = 0.89). These results may reflect either an underlying pattern of germline mutation due to endogenous processes or the presence of an ubiquitous mutagen. Further analyses of the recurrent mutations revealed that two mutations, T296M and R248Q, accounted for 19% of the mutations found in the Mexicans. Haplotype data suggest that the multiple occurrences of T296M and R248Q are associated with founder effects and that screening for these mutations may allow rapid mutation detection and carrier diagnosis in a significant minority of Mexican families with hemophilia B, These two mutations also are associated with founder effects in the U.S, Caucasian population. However, the haplotypes are different in these two populations, indicating independent origins. The occurrence of identical founder mutations in distinct populations provides evidence for the previous hypothesis that the number of different mutations giving rise to mild or borderline mild/moderate hemophilia B is small compared to deleterious mutations causing more severe disease.

Factor IX↗

PubMed1996

[Causal mutation or rare polymorphism? Frequency of mutation not found in 3 chromosome is less than 3 divided by n].

The problem of distinguishing rare polymorphism from deleterious mutations is an important question in molecular medicine. In order to estimate the frequency of a sequence variation, unrelated normal individuals are usually screened for the mutation concerned. A sequence variation that is not found in non-affected individuals becomes more likely to be the cause of the disease. The aim of this paper is to provide a practical estimation of the fortuitous occurrence of a private polymorphism in one or several patients. The frequency of a sequence variation is not difficult to estimate in a population. The 95% upper frequency limit of a gene variant not observed in n chromosomes is 1-n+1 square root of 0.05. This can conveniently be approximated as 3/n. While the likelihood for finding a sequence variation only in patients is easily calculated, it is practically impossible to compute the exact probability that this variation is indeed the cause of the disease.

Confidence Intervals↗

PubMed1995

Detection of steroid 21-hydroxylase alleles using gene-specific PCR and a multiplexed ligation detection reaction.

Steroid 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia, an inherited inability to synthesize cortisol that occurs in 1 in 10,000-15,000 births. Affected females are born with ambiguous genitalia, a condition that can be ameliorated by administering dexamethasone to the mother for most of gestation. Prenatal diagnosis is required for accurate treatment of affected females as well as for genetic counseling purposes. Approximately 95% of mutations causing this disorder result from recombinations between the gene encoding the 21-hydroxylase enzyme (CYP21) and a linked, highly homologous pseudogene (CYP21P). Approximately 20% of these mutations are gene deletions, and the remainder are gene conversions that transfer any of nine deleterious mutations from the CYP21P pseudogene to CYP21. We describe a methodology for genetic diagnosis of 21-hydroxylase deficiency that utilizes gene-specific PCR amplification in conjunction with thermostable DNA ligase to discriminate single nucleotide variations in a multiplexed ligation detection assay. The assay has been designed to be used with either fluorescent or radioactive detection of ligation products by electrophoresis on denaturing acrylamide gels and is readily adaptable for use in other disease systems.

Adrenal Hyperplasia, Congenital↗

PubMed2000

The conserved motif in hydrophilic loop 2/3 and loop 8/9 of the lactose permease of Escherichia coli. Analysis of suppressor mutations.

The major facilitator superfamily (MFS) of transport proteins, which includes the lactose permease of Escherichia coli, contains a conserved motif G-X-X-X-D/E-R/K-X-G-R/K-R/K in the loops that connect transmembrane segments 2 and 3, and transmembrane segments 8 and 9. In three previous studies (Jessen-Marshall, A.E., & Brooker, R.J. 1996. J. Biol. Chem. 271:1400-1404; Jessen-Marshall, A.E., Parker, N., & Brooker, R.J. 1997. J. Bacteriol. 179:2616-2622; and Pazdernik, N., Cain, S.M., & Brooker, R.J. 1997. J. Biol. Chem. 272:26110-26116), suppressor mutations at twenty different sites were identified which restore function to mutant permeases that have deleterious mutations in the conserved loop 2/3 or loop 8/9 motif. In the current study, several of these second-site suppressor mutations have been separated from the original mutation in the conserved motif. The loop 2/3 suppressors were then coupled to a loop 8/9 mutation (P280L) and the loop 8/9 suppressors were coupled to a loop 2/3 mutation (i.e., G64S) to determine if the suppressors could restore function only to a loop 2/3 mutation, a loop 8/9 mutation, or both. The single parent mutations changing the first position in loop 2/3 (i.e., G64S) and loop 8/9 (i.e., P280L) had less than 4% lactose transport activity. Interestingly, most of the suppressors were very inhibitory when separated from the parent mutation. Two suppressors, A50T and G370V, restored substantial transport activity when individually coupled to the mutation in loop 2/3 and also when coupled to the corresponding mutation in loop 8/9. In other words, these suppressors could alleviate a defect imposed by mutations in either half of the permease. From a kinetic analysis, these suppressors were shown to exert their effects by increasing the V(max) values for lactose transport compared with the single G64S and P280L strains. These results are discussed within the context of our model in which the two halves of the lactose permease interact at a rotationally symmetrical interface, and that lactose transport is mediated by conformational changes at the interface.

Amino Acid Motifs↗

PubMed2006

A hemizygous SCO2 mutation in an early onset rapidly progressive, fatal cardiomyopathy.

Mutations in SCO2, a metallochaperone involved in mitochondrial copper delivery, are associated with early onset, fatal hypertrophic cardiomyopathy. All reported patients carry at least one copy of the common 1541G>A (E140K) mutation. Whereas patients with one copy of the E140K allele, in combination with a more deleterious mutation, follow a severe clinical course, patients homozygous for the E140K mutation have a delayed onset of disease and a more prolonged survival. Here, we have investigated a patient who appeared homozygous for the common 1541G>A mutation based on DNA sequencing and restriction enzyme analysis of a PCR product, yet presented with early onset, severe cardiomyopathy. Restriction enzyme analysis of parental DNA revealed that the mother was heterozygous for 1541G>A, while the father was homozygous wild-type. The patient showed biparental inheritance for microsatellite markers spanning the length of chromosome 22, making isodisomy unlikely. Sequencing of several single nucleotide polymorphisms within the 5'-UTR, intron and single exon of the SCO2 gene was uninformative; however, a 16 bp deletion within the intron was present in the patient and the mother, but not the father. Restriction enzyme analysis confirmed that the mother was heterozygous and that the patient was hemizygous for the deletion. Southern blot, Northern blot, and FISH analyses were consistent with the de novo deletion of one allele of SCO2 in the patient. This is the first report of hemizygosity in a SCO2 patient. The patient phenotype underscores the strikingly similar clinical course in all patients with one copy of the E140K allele. Examination of both patient and parental genotypes by thorough molecular analyses can reveal information with important implications for genetic counseling.

Cardiomyopathies↗

PubMed2002

A single olfactory receptor specifically binds a set of odorant molecules.

The sense of smell is mediated by the initiation of action potential in olfactory sensory neurons during odor stimulation. However, little is known about odorant-olfactory receptor (OR) recognition mechanisms. In the present work, we identified the structural motifs of odorant molecules required to activate mouse OR912-93 by detection of the odorant response using calcium measurement in cells transfected with OR and G(alpha)q and G(alpha)15 proteins. The use of sets of odorants led to the identification of ketones with an aliphatic carbon chain length >or= four carbon atoms and a carbonyl group preferentially located in position C2 or C3. The threshold of detection of these odorants is as low as 10(-6)-10(-8)m. No other odorant ligand, out of 70 representatives of the odorant world, was active. The human ortholog of OR912-93 is not functional, suggesting that apart from a stop-mutation located at the 5'-end that was corrected in the construct, it incurred other deleterious mutations during evolution.

Animals↗

PubMed2000

Local drift load and the heterosis of interconnected populations.

We use Wright's distribution of equilibrium allele frequency to demonstrate that hybrids between populations interconnected by low to moderate levels of migration can have large positive heterosis, especially if the populations are small in size. Beneficial alleles neither fix in all populations nor equilibrate at the same frequency. Instead, populations reach a mutation-selection-drift-migration balance with sufficient among-population variance that some partially recessive, deleterious mutations can be masked upon crossbreeding. This heterosis is greatest with intermediate mutation rates, intermediate selection coefficients, low migration rates and recessive alleles. Hybrid vigour should not be taken as evidence for the complete isolation of populations. Moreover, we show that heterosis in crosses between populations has a different genetic basis than inbreeding depression within populations and is much more likely to result from alleles of intermediate effect.

Alleles↗

PubMed2004

Heterozygosity for Tay-Sachs and Sandhoff diseases in non-Jewish Americans with ancestry from Ireland, Great Britain, or Italy.

Previous reports have found that non-Jewish Americans with ancestry from Ireland have an increased frequency of heterozygosity for Tay-Sachs disease (TSD), although frequency estimates are substantially different. Our goal in this study was to determine the frequency of heterozygosity for TSD and Sandhoff diseases (SD) among Irish Americans, as well as in persons of English, Scottish, and/or Welsh ancestry and in individuals with Italian heritage, who were referred for determination of their heterozygosity status and who had no known family history of TSD or SD or of heterozygosity for these conditions. Of 610 nonpregnant subjects with Irish background, 24 TSD heterozygotes were identified by biochemical testing, corresponding to a heterozygote frequency of 1 in 25 (4%; 95% CI, 1/39-1/17). In comparison, of 322 nonpregnant individuals with ancestry from England, Scotland, or Wales, two TSD heterozygotes were identified (1 in 161 or 0.62%; 95% CI, 1/328-1/45), and three TSD heterozygotes were ascertained from 436 nonpregnant individuals with Italian heritage (1 in 145 or 0.69%; 95% CI, 1/714-1/50). Samples from 21 Irish heterozygotes were analyzed for HEXA gene mutations. Two (9.5%) Irish heterozygotes had the lethal + 1 IVS-9 G --> A mutation, whereas 9 (42.8%) had a benign pseudodeficiency mutation. No mutation was found in 10 (47.6%) heterozygotes. These data allow for a frequency estimate of deleterious alleles for TSD among Irish Americans of 1 in 305 (95% CI, 1/2517-1/85) to 1 in 41 (95% CI, 1/72-1/35), depending on whether one, respectively, excludes or includes enzyme-defined heterozygotes lacking a defined deleterious mutation. Pseudodeficiency mutations were identified in both of the heterozygotes with ancestry from other countries in the British Isles, suggesting that individuals with ancestry from these countries do not have an increased rate of TSD heterozygosity. Four SD heterozygotes were found among individuals of Italian descent, a frequency of 1 in 109 (0.92%; 95% CI, 1/400-1/43). This frequency was higher than those for other populations, including those with Irish (1 in 305 or 0.33%; 95% CI, 1/252-1/85), English, Scottish, or Welsh (1 in 161 or 0.62%; 95% CI, 1/1328-1/45), or Ashkenazi Jewish (1 in 281 or 0.36%; 95% CI, 1/1361-1/96) ancestry. Individuals of Irish or Italian heritage might benefit from genetic counseling for TSD and SD, respectively.

England↗

PubMed1993

An RT-PCR-SSCP screening strategy for detection of mutations in the gene encoding the alpha 1 chain of type I collagen: application to four patients with osteogenesis imperfecta.

A strategy has been developed to allow the screening for mutations in the cDNA of the type I collagen alpha 1 chain. The method involves polymerase chain reaction amplification of four overlapping segments covering the majority of the sequence coding for alpha 1(I) collagen. Four or five restriction endonuclease digestions are performed for each segment and digested samples subjected to single strand conformation polymorphism analysis. Mutations are finally defined by DNA sequence analysis. The application to the detection of mutations in four patients with lethal and non-lethal forms of osteogenesis imperfecta is described. In each of these patients, the heterozygous mutation identified resulted in substitution of different glycine residues with serines. In addition to these deleterious mutations, several novel silent variants were characterised. The strategy provides a rapid approach to screening for mutations and polymorphisms in alpha 1(I) collagen cDNA and is of general interest in scanning large regions of DNA for sequence changes.

Adult↗

PubMed2001

Does nonneutral evolution shape observed patterns of DNA variation in animal mitochondrial genomes?

Early studies of animal mitochondrial DNA (mtDNA) assumed that nucleotide sequence variation was neutral. Recent analyses of sequences from a variety of taxa have brought the validity of this assumption into question. Here we review analytical methods used to test for neutrality and evidence for nonneutral evolution of animal mtDNA. Evaluations of mitochondrial haplotypes in different nuclear backgrounds identified differences in performance, typically favoring coevolved mitochondrial and nuclear genomes. Experimental manipulations also indicated that certain haplotypes have an advantage over others; however, biotic and historical effects and cyto-nuclear interactions make it difficult to assess the relative importance of nonneutral factors. Statistical analyses of sequences have been used to argue for nonneutrality of mtDNA; however, rejection of neutral patterns in the published literature is common but not predominant. Patterns of replacement and synonymous substitutions within and between species identified a trend toward an excess of replacement mutations within species. This pattern has been viewed as support for the existence of mildly deleterious mutations within species; however, other alternative explanations that can produce similar patterns cannot be eliminated.

Animals↗

PubMed1994

Mutation load depending on variance in reproductive success and mating system.

Equalization of reproductive success of individuals, although it results in an increase of effective population size, leads also to an increase of the mutation load. The magnitude of this increase depends highly on the mode of fitness interactions between deleterious mutations, and is higher in the case of inbreeding. Recommended practices in conservation genetics must be evaluated in regards to these differing consequences of an increase of effective population size. To keep a balance between retaining genetic variability and minimizing the increase of the mutation load, equalization of reproductive success of a set of individuals rather than of every individual might be more advantageous.

Animals↗

PubMed2002

Fitness versus longevity in age-structured population dynamics.

We examine the dynamics of an age-structured population model in which the life expectancy of an offspring may be mutated with respect to that of the parent. While the total population of the system always reaches a steady state, the fitness and age characteristics exhibit counter-intuitive behavior as a function of the mutational bias. By analytical and numerical study of the underlying rate equations, we show that if deleterious mutations are favored, the average fitness of the population reaches a steady state, while the average population age is a decreasing function of the average fitness. When advantageous mutations are favored, the average population fitness grows linearly with time t, while the average age is independent of the average fitness. For no mutational bias, the average fitness grows as t2/3.

Life Expectancy↗