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One Missense Mutation (one + missense_mutation)
Selected AbstractsGenetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease,HUMAN MUTATION, Issue 6 2008Veerle Bogaerts Abstract In one genetic study, the high temperature requirement A2 (HTRA2) mitochondrial protein has been associated with increased risk for sporadic Parkinson disease (PD). One missense mutation, p.Gly399Ser, in its C-terminal PDZ domain (from the initial letters of the postsynaptic density 95, PSD-95; discs large; and zonula occludens-1, ZO-1 proteins [Kennedy, 1995]) resulted in defective protease activation, and induced mitochondrial dysfunction when overexpressed in stably transfected cells. Here we examined the contribution of genetic variability in HTRA2 to PD risk in an extended series of 266 Belgian PD patients and 273 control individuals. Mutation analysis identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. Moreover, we identified six patient-specific variants in 5, and 3, regulatory regions that might affect HTRA2 expression as supported by data of luciferase reporter gene analyses. Our study confirms a role of the HTRA2 mitochondrial protein in PD susceptibility through mutations in its functional PDZ domain. In addition, it extends the HTRA2 mutation spectrum to functional variants possibly affecting transcriptional activity. The latter underpins a previously unrecognized role for altered HTRA2 expression as a risk factor relevant to parkinsonian neurodegeneration. Hum Mutat 29(6), 832,840, 2008. © 2008 Wiley-Liss, Inc. [source] Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations,,HUMAN MUTATION, Issue 5 2002Kathrin Rommel Abstract Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and other related connective tissue disorders. In this study we performed SSCP to analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical MFS or related phenotypes. We report 7 missense mutations, 3 splice site alterations, one indel mutation, one nonsense mutation and two mutations causing frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55, respectively. One missense mutation (V449I) substitutes a valine residue in the non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One missense mutation (G880S) affects the "hybrid" motif in exon 21 by replacing glycine to serine. The 3 splice site mutations detected are: IVS1,1G>A in intron 1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was identified in exon 15 leading to the substitution of a conserved cysteine residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon 17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and R429X have been reported before. © 2002 Wiley-Liss, Inc. [source] Characterization of the porcine Kisspeptins receptor gene and evaluation as candidate for timing of puberty in sowsJOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 4 2008S. Li Summary Kisspeptins receptor (KISS1R), also called GPR54, is a key regulator of puberty in many species. KISS1R and its genetics in pigs remain unexplored. The objective of this study was to characterize the porcine KISS1R gene and evaluate the association of KISS1R mutations with age at puberty in sows. KISS1R was assigned to pig chromosome 2q21-24 by radiation hybrid mapping. It has a 1438 bp full-length cDNA and spans 3349 bp genomic sequence consisting of five exons and four introns. Semi-quantitative RT-PCR showed that KISS1R transcripts was particularly abundant in the adrenal, prostate, testis, thymus, pituary and hypothalamus. KISS1R mRNA content in the hypothalamus was determined by real-time quantitative RT-PCR, and it fluctuated during the oestrous cycle with the highest level in the luteal phase. Anoestrus sows had markedly lower hypothalamic KISS1R mRNA content than cyclic animals. Seven KISS1R SNPs were identified in the founder animals of a White Duroc × Erhualian intercross. One missense mutation (T/C245) showed quite different allele distribution in Chinese and Western breeds. All F0, F1 animals and 367 detailed phenotyped cyclic F2 sows in the White Duroc × Erhualian intercross were genotyped for three KISS1R polymorphisms. No significant association of KISS1R haplotypes and haplotype pairs with age at puberty was observed in the resource population, indicating that mutations in KISS1R are not responsible for divergent age at puberty in White Duroc and Erhualian pigs. [source] Biochemical and functional analysis of CTR1, a protein kinase that negatively regulates ethylene signaling in ArabidopsisTHE PLANT JOURNAL, Issue 2 2003Yafan Huang Summary CTR1 encodes a negative regulator of the ethylene response pathway in Arabidopsis thaliana. The C-terminal domain of CTR1 is similar to the Raf family of protein kinases, but its first two-thirds encodes a novel protein domain. We used a variety of approaches to investigate the function of these two CTR1 domains. Recombinant CTR1 protein was purified from a baculoviral expression system, and shown to possess intrinsic Ser/Thr protein kinase activity with enzymatic properties similar to Raf-1. Deletion of the N-terminal domain did not elevate the kinase activity of CTR1, indicating that, at least in vitro, this domain does not autoinhibit kinase function. Molecular analysis of loss-of-function ctr1 alleles indicated that several mutations disrupt the kinase catalytic domain, and in vitro studies confirmed that at least one of these eliminates kinase activity, which indicates that kinase activity is required for CTR1 function. One missense mutation, ctr1,8, was found to result from an amino acid substitution within a new conserved motif within the N-terminal domain. Ctr1,8 has no detectable effect on the kinase activity of CTR1 in vitro, but rather disrupts the interaction with the ethylene receptor ETR1. This mutation also disrupts the dominant negative effect that results from overexpression of the CTR1 amino-terminal domain in transgenic Arabidopsis. These results suggest that CTR1 interacts with ETR1 in vivo, and that this association is required to turn off the ethylene-signaling pathway. [source] Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors,,HUMAN MUTATION, Issue 5 2003Lan Kluwe Abstract Neurofibromatosis type 1 (NF1) patients have 10% of lifetime risk for developing malignant peripheral nerve sheath tumors (MPNST), one of the most aggressive cancers. We examined the spectrum of constitutional NF1 mutations among 24 NF1 patients with MPNST. We found mutations in 18 patients: four megabase deletions involving the NF1 gene, 13 truncating mutations, and only one missense mutation. One deletion included both exonic and intronic sequences. No typical splicing mutation was found. Five of these mutations were novel: c.3686delA, c.197_204+9del17, c.3044T>C (p.Leu1015Pro), c.2497delT, and c.6020_6027dup. The proportion of megabase deletions of the NF1 gene found in patients with MPNST (17%=4/24) was higher than that in a group of unselected NF1 patients (5.4%=27/500). © 2003 Wiley-Liss, Inc. [source] How much phenotypic variation can be attributed to parkin genotype?ANNALS OF NEUROLOGY, Issue 2 2003Ebba Lohmann MD To establish phenotype,genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations. Ann Neurol 2003 [source] | |||||||||||||