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Results for “Mutation, Missense”

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At least 289 records · Page 16Linked to original sources
PubMed2006

Recessive dystrophic epidermolysis bullosa caused by COL7A1 hemizygosity and a missense mutation with complex effects on splicing.

Loss-of-function mutations in the gene encoding type VII collagen, COL7A1, are the molecular basis of the blistering skin disorder, recessive dystrophic epidermolysis bullosa (RDEB). COL7A1 maps to a region of the short arm of chromosome 3 that has been found to be deleted in many types of malignancies. We have characterized the first case of a large genomic deletion in chromosome 3p21.31 that removes COL7A1 entirely in an RDEB patient. This interstitial deletion spans 255 to 520 kb and encompasses 9 to 15 genes, but seems to have no pathological consequences other than RDEB. We show that the second, hemizygous allele of COL7A1 in this patient bears a base substitution within exon 94, c.7245G>A. This translates into an amino acid substitution, p.M2415I, and leads to a complex splicing abnormality that allows marginal levels of functional mRNA and protein to be synthesized. We propose that the leakiness of the splicing defect enables the partial rescue of collagen VII deficiency. This is consistent with the diagnosis of the moderately severe form of RDEB in the proband, at variance with the most severe form, RDEB Hallopeau-Siemens, that would arise from complete collagen VII deficiency.

Alleles↗
PubMed2006

In vitro analysis of genomic instability triggered by BRCA1 missense mutations.

The BRCA1 tumor suppressor gene encodes a phosphoprotein involved in many cellular key functions including DNA repair, transcription regulation, cell-cycle control and apoptosis. Most of these functions are strictly related to the ability of BRCA1 to interact with the other partners of a multimeric complex called BASC. Among these components, an important role is played by the human homolog of the bacterial MutL, MLH1. In this study, we have identified the BRCA1 binding domains to MLH1 and demonstrated that three distinct mutations in one of these interaction domains can produce, in vitro, a microsatellite instability phenotype, one of the hallmarks of an imbalance in the mismatch DNA repair machinery. These data support a model in which a structural modification in a critical domain of the BRCA1 gene product secondary to single amino acid mutations, may be able, per se, to impair the DNA damage response pathway, inducing genomic instability and eventually leading to breast carcinogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Missense mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTA) in a patient with mucolipidosis II induces changes in the size and cellular distribution of GNPTG.

Mucolipidosis type II (ML II; I-cell disease) and mucolipidosis III (ML III; pseudo Hurler polydystrophy) are autosomal recessively inherited disorders caused by a defective N-acetylglucosamine 1-phosphotransferase (phosphotransferase). The formation of mannose 6-phosphate markers in soluble lysosomal enzymes is impeded leading to their increased excretion into the serum, to cellular deficiency of multiple hydrolases, and lysosomal storage of non-digested material. Phosphotransferase deficiency is caused by mutations in GNPTA and GNPTG encoding phosphotransferase subunits. Here we report on an adolescent with progressive joint contractions and other signs of mucolipidosis II who survived to the age of 14 years. Impaired trafficking of lysosomal enzymes cathepsin D and -hexosaminidase in metabolically labeled fibroblasts was documented. Mutations in the GNPTG gene and alterations in the GNPTG mRNA level were not detected. A different electrophoretic mobility of the 97 kDa GNPTG dimer suggested posttranslational modification abrogating the compartmentalization of GNPTG in the Golgi apparatus. A nucleotide substitution in the GNPTA gene (c.3707A>T) was identified altering the predicted C-terminal transmembrane anchor of the phosphotransferase subunit. The data demonstrate that defective GNPTA not only impairs lysosomal enzyme targeting but also the availability of intact GNPTG required for phosphotransferase activity and assembly of subunits.

Adolescent↗
PubMed2003

Novel missense mutation and large deletion of GNE gene in autosomal-recessive inclusion-body myopathy.

The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene is the causative gene for autosomal-recessive hereditary inclusion-body myopathy (h-IBM). Two sisters affected with autosomal-recessive h-IBM were shown to be compound heterozygous for two novel GNE mutations: a large deletion involving exons 1-9, and a R162C amino acid change in the epimerase domain. This is the first deletion event observed in a GNE allele and expands the molecular pathogenesis of autosomal-recessive h-IBM.

Actin Cytoskeleton↗
PubMed1998

Three novel integrin beta3 subunit missense mutations (H280P, C560F, and G579S) in thrombasthenia, including one (H280P) prevalent in Japanese patients.

We analyzed three unrelated Japanese patients with type II Glanzmann thrombasthenia (GT) for associated mutations. Polymerase chain reaction and subsequent direct sequencing of platelet RNA and genomic DNA revealed three single nucleotide substitutions of the integrin beta3 subunit gene (His (CAT)-280 to Pro (CCT), Cys (TGT)-560 to Phe (TTT), and Gly(GGC)-579 to Ser(AGC)). Interestingly, the three unrelated patients all had the H280P mutation; one was homozygous and the other two heterozygous for this mutation. Ectopic expression of wild type and mutant complexes in Chinese hamster ovary cells revealed decreased surface expression of the mutated alphaIIbbeta3 complexes, thus demonstrating that these mutations may result in the mild GT phenotypes. The identification of three unrelated patients having the same mutation (H280P) suggests that this mutation might be prevalent in the Japanese thrombasthenic population.

Aged↗
PubMed1999

Effects of missense mutations and deletions on membrane anchoring and enzyme function of human steroid 21-hydroxylase (P450c21).

We studied membrane binding and enzyme function of six variant forms of human steroid 21-hydroxylase (P450c21), a mutant (P30Q) from a patient with congenital adrenal hyperplasia, four artificial deletions in the amino terminal region (delS1 and del S2; the first and second hydrophobic segment, delS3; the region in between, delS4; the combination of these), and one naturally ocurring polymorphism in a region implicated to be critical for membrane integration (delL10). Enzyme function was assayed after transient expression in COS-1 cells, and membrane binding was studied by coupled in vitro transcription-translation in the presence of microsomal membranes. P450c21(delS1) retained some enzyme activity but showed severely reduced membrane binding. P450c21(P30Q), P450c21 (delS2), P450c21(delS3), and P450c21(delS4) had abolished enzyme function. P450c21(P30Q) and P450c21 (delS2) did not affect membrane binding, P450c21 (delS3) had slightly reduced binding with a qualitative difference suggested by the absence of a glycosylated form of the protein, and P450c21(delS4) had abolished membrane integration. No significant differences could be identified for the delL10 variant. These data support that P450c21 spans the membrane through its first hydrophobic domain only, and that the protein lacking this segment retains sufficiently normal structure to enable catalysis. They also confirm that P30Q is responsible for the severe phenotype of the patient in which it was found, and indicate that the common delL10 polymorphism does not have a major effect on enzyme function.

17-alpha-Hydroxyprogesterone↗
PubMed2000

A missense mutation in the RING finger motif of PEX2 protein disturbs the import of peroxisome targeting signal 1 (PTS1)-containing protein but not the PTS2-containing protein.

SK24 and PT54 mutant cells, which are peroxisome-deficient Chinese hamster ovary (CHO) cells isolated using peroxisomal forms of green fluorescent protein (GFP), were found to be defective in the PEX2 gene. The nucleotide sequences of PEX2 cDNA from the mutant cells were determined to identify mutation sites in the mutant cells. The mutation in SK24 cells changed cysteine to tyrosine at amino acid position 258, which is a component of the RING finger (C(3)HC(4)) motif in the carboxyl terminus of the protein. PT54 cells contained a nonsense mutation in the codon for glutamine at position 101, resulting in premature termination. The immunocytochemical analyses revealed distinct phenotypes between mutant cells defective in the PEX2 gene. Both mutant cells exhibited cytosolic mislocalizations on catalase and urate oxidase containing PTS1. On the other hand, on 3-ketoacyl-CoA thiolase containing PTS2, PT54 cells exhibited cytosolic mislocalization, but SK24 cells exhibited peroxisomal localization. When wild-type or mutant-type PEX2 cDNA was transfected into both mutant cells, the stable transformants restored the phenotype in accordance with the transfected cDNA. These observations indicate that an amino acid substitution, cysteine-258 to tyrosine, in the RING finger motif of PEX2 protein, whose function is required for peroxisomal localizations of both PTS1- and PTS2-containing proteins, results in a complete defect in the PTS1 pathway but not in the PTS2 pathway.

Amino Acid Sequence↗
PubMed1999

Familial hypertrophic cardiomyopathy associated with a novel missense mutation affecting the ATP-binding region of the cardiac beta-myosin heavy chain.

Mutations in the cardiac beta -myosin heavy chain gene (MYH7), and other genes encoding cardiac sarcomere proteins may cause familial hypertrophic cardiomyopathy (F-HCM), an autosomal dominant disease, characterized by myocardial hypertrophy. We analysed the MYH7 gene in three generations of a family with one borderline and four clinically verified cases of hypertrophic cardiomyopathy, and identified a mutation in exon 7 changing the 190 arginine residue into a threonine residue. The mutation is located in the ATP-binding region of the myosin head and alters the charge in the F-helix close to the phosphate-binding P-loop. The mutation may thus interfere with the coupling between ATP-hydrolysis and the transition into mechanical energy. In conclusion, the novel Arg190Thr mutation in exon 7 of the MYH7 gene is associated with the development of symptomatic myocardial hypertrophy in adults.

Adenosine Triphosphate↗
PubMed2001

A novel missense mutation in human lactate dehydrogenase B-subunit gene.

Reduced activity of serum lactate dehydrogenase (LDH; EC 1.1.1.27) was found in a male medical student during practical examinations of his own blood. Serum LDH isoenzyme pattern showed reductions in activities of the isoenzymes with lower subunit A/B ratios such as LDH1 and LDH2. These findings were indicative of a partial LDH-B subunit deficiency, which was confirmed in erythrocyte hemolysates by Western blotting. Polymerase chain reaction (PCR)-based DNA sequence analysis of the LDH-B subunit gene revealed a heterozygous nucleotide change: a guanine to adenine substitution in codon 69 (GGG --> GAG) at the third exon of the LDH-B subunit gene that resulted in a glycine to glutamic acid substitution (G69E). The mutation was confirmed by PCR-restriction fragment length polymorphism (RFLP) analysis using a mismatched primer to introduce a new NcoI restriction site. The same heterozygous mutation was found in his mother but not in other family members. This mutation involves a residue belonging to alphaC helix in LDH-B subunit protein molecule that functions as an interface for other subunits.

Adult↗
PubMed2001

One missense mutation in the factor X gene causing factor X deficiency--factor X Kanazawa.

We investigated the molecular basis of factor X deficiency in a Japanese patient whose factor X activity and antigen level were 45% and 50% of normal control values, respectively. All exons and intron/exon junctions of the factor X gene were studied using a strategy combining polymerase chain reaction (PCR) amplification and nonradioactive single-strand conformational polymorphism (SSCP) analysis. Exon 5, containing the DNA fragment of the proband, showed aberrant migration by SSCP analysis. All exon-containing DNA fragments amplified by PCR were sequenced, and it was revealed that the proband was a heterozygote for a G --> A substitution in exon 5 of the factor X gene of the proband. This mutation predicts an amino acid replacement of arginine (Arg) for glycine (Gly) at codon 114 in the second EGF-like domain.

Aged↗
PubMed2004

Missense mutations in the human insulin promoter factor-1 gene are not a common cause of type 2 diabetes mellitus in Taiwan.

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder characterized by a hyperglycemia resulting from defect in insulin secretion and insulin action. Recent studies showed that dominant negative mutations in the insulin promoter factor-1 (IPF-1), a pancreatic beta-cell specific transcription factor, cause maturity-onset diabetes of the young (MODY), a subtype of T2DM with early onset and monogenic autosomal inheritance. In addition to MODY, IPF-1 mutations are suggested to predispose to common late-onset T2DM with different penetration of the mutations reflected in their in vitro activity. Thus, we investigated IPF-1 C18R, Q59L, D76N and R197H mutations in Taiwanese patients with common late-onset T2DM, because research into IPF-1 variants in Taiwanese diabetic patients--a population with the lowest range of diabetic incidence--has never been documented. Peripheral blood samples were collected and genomic DNA was extracted from 434 patients with T2DM and 194 non-diabetes control study subjects. IPF-1 genetic variations were analyzed by PCR and restriction fragment length polymorphism (RFLP) analysis. We did not find any of these four IPF-1 mutations in our patients. Our results suggested that IPF-1 mutations were not a common cause associated with Taiwanese T2DM.

Age of Onset↗
PubMed1998

Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians.

The K+ inwardly rectifier channel (KIR) is one of the two sub-units of the pancreatic islet ATP-sensitive potassium channel complex (I(KATP)), which has a key role in glucose-stimulated insulin secretion and thus is a potential candidate for a genetic defect in Type II (non-insulin-dependent) diabetes mellitus. We did a molecular screening of the KIR6.2 gene by single strand conformational polymorphism (SSCP) and direct sequencing in 72 French Caucasian Type II diabetic families. We identified three nucleotide substitutions resulting in three amino acid changes (E23K, L270V and 1337V), that have also been identified in other Caucasian Type II diabetic subjects. These variants were genotyped in French cohorts of 191 unrelated Type II diabetic probands and 119 normoglycaemic control subjects and association studies were done. The genotype frequencies of the L270V and 1337V variants were not very different between Type II diabetic subjects and control groups. In contrast, analysis of the E23K variant showed that the KK homozygocity was more frequent in Type II diabetic than in control subjects (27 vs 14%, p = 0.015). Analyses in a recessive model (KK vs EK/EE) tended to show a stronger association of the K allele with diabetes (p = 0.0097, corrected p-value for multiple testing < 0.02). The data for the E23K variant obtained here and those obtained from three other Caucasian groups studied so far were combined and investigated by meta-analysis. Overall, the E23K variant was found to be significantly associated with Type II diabetes (0.001 < or = p < or = .00106, corrected p-values for multiple testing p < or = 0.01). This study shows that KIR6.2 polymorphisms are frequently associated with Type II diabetes in French Caucasians. Furthermore, a meta-analysis combining different Caucasian groups suggests an significant role of KIR6.2 in the polygenic context of Type II diabetes.

Aged↗
PubMed1999

Cloning of bovine LYST gene and identification of a missense mutation associated with Chediak-Higashi syndrome of cattle.

An inheritable bleeding disorder with light coat color caused by an autosomal recessive gene has been reported in a population of Japanese black cattle. The disease has been diagnosed as Chediak-Higashi Syndrome (CHS) of cattle which correspond to a human inheritable disorder caused by mutation in LYST gene. To characterize the molecular lesion causing CHS in cattle, cDNAs encoding bovine LYST were isolated from a bovine brain cDNA library. The nucleotide and deduced amino acid sequences of bovine LYST had 89.6 and 90.2% identity with those of the human LYST gene, respectively. In order to identify the mutation within the LYST gene causing CHS in cattle, cDNA fragments of the LYST gene were amplified from an affected animal by RT-PCR and their nucleotide sequences were completely determined. Notably, a nucleotide substitution of A to G transition, resulting in an amino acid substitution of histidine to arginine (H2015R) was identified in the affected animal. The presence of the substitution was completely corresponding with the occurrence of the CHS phenotype among 105 members of pedigrees of the Japanese black cattle and no cattle of other populations had this substitution. These findings strongly suggested that H2015R is the causative mutation in CHS of Japanese black cattle.

Amino Acid Sequence↗
PubMed2002

Dejerine-Sottas neuropathy with multiple nerve roots enlargement and hypomyelination associated with a missense mutation of the transmembrane domain of MPZ/P0.

In a patient affected with a slowly progressive, severe form of Dejerine-Sottas syndrome, symmetric enlargement of cranial nerves and focal hypertrophy of cervical and caudal roots were detected following MRI. Neuropathological features of the sural nerve disclosed a dramatic loss of myelinated fibres, with skewed-to-the-left, unimodal distribution of the few residual fibres, consistent with the diagnosis of congenital hypomyelination neuropathy. Genetic analysis revealed this condition to be associated with a heterozygous G to A transition at codon 167 in the exon 4 of the MPZ/P0 gene causing a Gly138Arg substitution in the transmembrane domain of the mature MPZ/P0 protein. Focal enlargement of the nerve trunks in demyelinating, hereditary motor and sensory neuropathies (HMSN) was previously reported in both asymptomatic and symptomatic cases with root compression, but peculiar to this case is the diffuse involvement of both cranial and spinal nerves. We believe that the relevance of nerve trunk hypertrophy in HMSN is probably underevaluated: therefore MRI investigation of the head and spine should be included in the diagnostic study of selected HMSN patients. Molecular analysis of peripheral myelin genes will help to rule out misdiagnosed cases.

Adult↗