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Results for “deleterious mutation”

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PubMed2006

A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.

Familial tumoral calcinosis (FTC) is a rare autosomal recessive disorder characterized by the progressive deposition of calcified masses in cutaneous and subcutaneous tissues, which results in painful ulcerative lesions and severe skin and bone infections. Two major types of FTC have been recognized: hyperphosphatemic FTC (HFTC) and normophosphatemic FTC (NFTC). HFTC was recently shown to result from mutations in two different genes: GALNT3, which codes for a glycosyltransferase, and FGF23, which codes for a potent phosphaturic protein. To determine the molecular cause of NFTC, we performed homozygosity mapping in five affected families of Jewish Yemenite origin and mapped NFTC to 7q21-7q21.3. Mutation analysis revealed a homozygous mutation in the SAMD9 gene (K1495E), which was found to segregate with the disease in all families and to interfere with the protein expression. Our data suggest that SAMD9 is involved in the regulation of extraosseous calcification, a process of considerable importance in a wide range of diseases as common as atherosclerosis and autoimmune disorders.

Amino Acid Sequence↗
PubMed2003

Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.

BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene. METHODS: We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein. RESULTS: Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test). CONCLUSIONS: Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.

Adenosine Triphosphatases↗
PubMed2002

Accumulation of deleterious mutations: additional Drosophila melanogaster estimates and a simulation of the effects of selection.

We report an assay of egg-to-adult viability in full-sibling mutation accumulation (MA) lines derived from a completely homozygous population of Drosophila melanogaster and maintained for 210 generations. A simultaneous evaluation was also made of a large population derived from the same origin and maintained as a control for the same period. We also present computer simulations to explore the possible decline in viability of the control population due to mutation accumulation and the possible effect of selection within and between MA lines. For this purpose, we used two mutational models independent from the data analyzed and based on radically different assumptions. The first model implies a large number of mutations of small effect, whereas the second implies a much smaller number of mutations with much larger effects. The observed rate of decline in mean viability was very small but significant (0.077%). The rate of increase in among line variance (0.189 x 10(-3)) was similar to those obtained previously in the same lines. The simulation results indicated that a model of many mutations of small effect is incompatible with the evolution of the mean viability of the control and MA lines over generations, the distribution of line means after 210 generations of mutation accumulation, and the pattern of line extinction over generations. Basically, this model predicted a large drop in viability, both in the control and particularly the MA lines, that is not observed empirically. It also predicted a rate of line extinction too low in the early generations and too high in the later ones. In contrast, the model based on few mutations of large effect was generally consistent with all the observations.

Animals↗
PubMed2004

Deleterious mutations in SPINK5 in a patient with congenital ichthyosiform erythroderma: molecular testing as a helpful diagnostic tool for Netherton syndrome.

The congenital erythrodermas represent a heterogeneous group of inherited and acquired disorders often accompanied by systemic infections, impaired epidermal barrier function and concomitant life-threatening fluid and electrolyte imbalance. In the present report, we describe a patient who was considered to have congenital ichthyosiform erythroderma for 26 years until molecular testing led to the correct diagnosis of Netherton syndrome.

Adult↗
PubMed2004

Compensated deleterious mutations in insect genomes.

Relatively little is known about the importance of amino acid interactions in protein and phenotypic evolution. Here we examine whether mutations that are pathogenic in Drosophila melanogaster become fixed via epistasis in other Dipteran genomes. Overall divergence at pathogenic amino acid sites is reduced. However, approximately 10% of the substitutions at these sites carry the exact same pathogenic amino acid found in D. melanogaster mutants. Hence compensatory mutation(s) must have evolved. Surprisingly, the fraction 10% is not affected by phylogenetic distance. These results support a selection-driven process that allows compensated amino acid substitutions to become rapidly fixed in taxa with large populations.

Amino Acid Sequence↗
PubMed2000

No deleterious mutations in the FOXJ1 (alias HFH-4) gene in patients with primary ciliary dyskinesia (PCD).

The transcription factor FOXJ1 (alias HFH-4 or FKHL13) of the winged-helix/forkhead family is expressed in cells with cilia or flagella, and seems to be involved in the regulation of axonemal structural proteins. The knockout mouse Foxj1(-/-) shows abnormalities of organ situs, consistent with random determination of left-right asymmetry, and a complete absence of cilia. The human FOXJ1 gene which maps to chromosome 17q, is thus an excellent candidate gene for Kartagener Syndrome (KS), a subphenotype of Primary Ciliary Dyskinesia (PCD), characterized by bronchiectasis, chronic sinusitis and situs inversus. We have collected samples from 61 PCD families, in 31 of which there are at least two affected individuals. Two families with complete aciliogenesis, and six families, in which the affected members have microsatellite alleles concordant for a locus on distal chromosome 17q, were screened for mutations in the two exons and intron-exon junctions of the FOXJ1 gene. No sequence abnormalities were observed in the DNAs of the affected individuals of the selected families. These results demonstrate that the FOXJ1 gene is not responsible for the PCD/KS phenotype in the families examined.

Alleles↗
PubMed2003

Deletion of codons 88-92 of the melanocortin-4 receptor gene: a novel deleterious mutation in an obese female.

Genetic and pharmacological studies have shown that the melanocortin-4 receptor (MC4R) is an important regulator of food intake and energy homeostasis. Consistent with these studies, several mutations of the MC4R gene have been identified as being associated with early-onset severe obesity. We report here the first in-frame deletion mutation of the MC4R gene (delta88-92) in an obese female patient with onset of obesity at less than 5 yr of age. Functional analysis revealed that the mutant receptor is expressed well on the cell surface but completely devoid of ligand binding and cAMP generation in response to agonist stimulation. We conclude that this novel mutation is the cause of obesity of this patient.

Adolescent↗
PubMed2004

Influence of dominance, leptokurtosis and pleiotropy of deleterious mutations on quantitative genetic variation at mutation-selection balance.

In models of maintenance of genetic variance (V (G)) it has often been assumed that mutant alleles act additively. However, experimental data show that the dominance coefficient varies among mutant alleles and those of large effect tend to be recessive. On the basis of empirical knowledge of mutations, a joint-effect model of pleiotropic and real stabilizing selection that includes dominance is constructed and analyzed. It is shown that dominance can dramatically alter the prediction of equilibrium V (G). Analysis indicates that for the situations where mutations are more recessive for fitness than for a quantitative trait, as supported by the available data, the joint-effect model predicts a significantly higher V (G) than does an additive model. Importantly, for what seem to be realistic distributions of mutational effects (i.e., many mutants may not affect the quantitative trait substantially but are likely to affect fitness), the observed high levels of genetic variation in the quantitative trait under strong apparent stabilizing selection can be generated. This investigation supports the hypothesis that most V (G) comes from the alleles nearly neutral for fitness in heterozygotes while apparent stabilizing selection is contributed mainly by the alleles of large effect on the quantitative trait. Thus considerations of dominance coefficients of mutations lend further support to our previous conclusion that mutation-selection balance is a plausible mechanism of the maintenance of the genetic variance in natural populations.

Genes, Dominant↗
PubMed1999

Reconciling repertoire shift with affinity maturation: the role of deleterious mutations.

The shift in Ab repertoire, from Abs dominating certain primary B cell responses to genetically unrelated Abs dominating subsequent "memory" responses, challenges the accepted paradigm of affinity maturation. We used mathematical modeling and computer simulations of the dynamics of B cell responses, hypermutation, selection, and memory cell formation to test hypotheses attempting to explain repertoire shift. We show that repertoire shift can be explained within the framework of the affinity maturation paradigm, only when we recognize the destructive nature of hypermutation: B cells with a high initial affinity for the Ag are less likely to improve through random mutations.

Antibody Affinity↗
PubMedDate not supplied

[Enzymatic mechanisms of compensation of deleterious mutations].

Mechanisms of stabilization and compensation, that occur in biochemical systems with enzymes modified by harmful mutations are considered. The compensation of such mutations can result in their evolutionary neutralism. The stabilization is considered due to kinetic signals of metabolites which form the direct and feedback connections with enzymes (temporal stabilization), and also the compensation in enzymatic aggregates determined by the changes of conformation (spatial stabilization). Examples of the stabilization in one or several steady states of enzymatic systems are presented. The neutralism of the distortion of inhibitory and catalytic properties of enzymes is shown in the region of stabilization of these properties.

Animals↗