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PubMed2006

Determination of mutation trend in hemagglutinins by means of translation probability between RNA codons and mutated amino acids.

In this study, we used the 183 translation probabilities between RNA codons and mutated amino acids to construct the theoretical distributions of mutated amino acids in hemagglutinins of influenza A virus. We then compared the actual distributions of mutated amino acids from 953 hemagglutinins with their theoretical ones. The results demonstrated that mutated amino acids generally follow the direction of the theoretical distributions governed by RNA codons. This, in turn, highlights the mutation trend of amino acids in hemagglutinins and provides a method for estimating possible mutations in a protein according to its theoretical distributions of mutated amino acids.

Algorithms↗
PubMed1997

Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation.

One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT), a tolbutamide modified frequently sampled intravenous glucose tolerance test, and a glucagon test to examine for a possible early beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues.

Adolescent↗
PubMed1998

Detection of a rare point mutation at codon 59 and relatively high incidence of H-ras mutation in Indian oral cancer.

Analysis of H-, K- and N-ras genes for point mutations by PCR-SSCP and direct sequencing of 46 oral SCCs that were previously analyzed for p53 mutations revealed that 9 (20%) had point mutations in either the H-ras or the N-ras. A novel mutation at codon 59 (GCC-ACC) of H-ras thus far reported only in v-H-ras of Harvey murine sarcoma virus was observed in a tumor of the cheek. Majority (8/9) of these mutations were observed in H-ras, one in N-ras and none in K-ras. This study indicated that the ras gene mutation was relatively high in oral cancers associated with tobacco chewing and the ras and p53 mutational events seem to be independent and mutually exclusive.

Carcinoma, Squamous Cell↗
PubMed1999

Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families.

Point mutations in the ryanodine receptor (RYR1) gene are associated with malignant hyperthermia, an autosomal dominant disorder triggered in susceptible people (MHS) by volatile anaesthetics and depolarising skeletal muscle relaxants. To date, 17 missense point mutations have been identified in the human RYR1 gene by screening of the cDNA obtained from muscle biopsies. Here we report single strand conformation polymorphism (SSCP) screening for nine of the most frequent RYR1 mutations using genomic DNA isolated from MHS patients. In addition, the Argl63Cys mutation was analysed by restriction enzyme digestion. We analysed 57 unrelated patients and detected seven of the known RYR1 point mutations. Furthermore, we found a new mutation, Arg2454His, segregating with the MHS phenotype in a large pedigree and a novel amino acid substitution at position 2436 in another patient, indicating a 15.8% frequency of these mutations in Italian patients. A new polymorphic site in intron 16 that causes the substitution of a G at position -7 with a C residue was identified.

Caffeine↗
PubMed1997

Two novel mutations in phenylalanine hydroxylase gene and in vitro expression analysis on mutation Arg252Gln.

We report novel mutations in exon 7 of human phenylalanine hydroxylase (PAH) gene of phenylketonuria (PKU) in southern Chinese, analysed by using PCR-DGGE (denaturing gradient gel electrophoresis), solid phase DNA sequencing and in vitro expression. One of the 2 novel mutations, IVS6nt-1, is an intron-exon junctional mutation which results a splicing defect in mRNA. Arg252Gln is another novel mutation with residual PAH activity only 24% compared to wild type in in vitro mutagenesis and expression in Cos-1 cell. Other 3 known mutations and polymorphism including Arg241Cys, Arg243Gln and Val245Val (GTG to GTA) together with these novel mutations composed the mutational profile of exon 7 in the PAH gene of PKUs in this populations.

Exons↗
PubMed2001

Low-rate emergence of thymidine analogue mutations and multi-drug resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus lamivudine combination therapy.

OBJECTIVES: Mutations usually associated with zidovudine exposure have been observed in zidovudine-naive patients treated by stavudine in combination. These mutations were named thymidine analogue mutations (TAMs). This fact, combined with phenotypical and biochemical findings provided additional evidence for cross-resistance between zidovudine and stavudine. A recent genotypic study in naive patients receiving stavudine/didanosine combination showed emergence of TAMs and a multidrug-resistance mutation (MDR), Q151M, in 36 and 10% of cases, respectively. Stavudine plus lamivudine is one of the most used binucleoside associations in the antiretroviral combinations. The objective of this study was to assess the genotypic changes in the HIV-1 reverse transcriptase (RT) gene in antiretroviral-naive patients treated by stavudine plus lamivudine. METHODS: We analysed the RT gene of 44 HIV-1 patients, naive of antiretroviral therapy, who were treated for 24 or 48 weeks with stavudine/lamivudine. RESULTS: At the end of the follow-up, all patients acquired the lamivudine-associated mutation M184V. Only two subjects (4.5%) developed a TAM (T215Y; M41L), one subject developed a V75T/A mutation and one subject developed the particular MDR pattern F116Y, Q151M. CONCLUSIONS: Our study clearly demonstrated that naive subjects treated with stavudine/lamivudine for 24-48 weeks selected a low rate of TAMs and MDR Q151M. One hypothesis explaining these results could be the development of the M184V mutation.

Acquired Immunodeficiency Syndrome↗
PubMed2001

The use of the amplification refractory mutation system (arms) in the detection of rare beta-thalassemia mutations in the Malays and Chinese in Malaysia.

Molecular characterization and prenatal diagnosis for beta-thalassemia can be carried out using the Amplification Refractory Mutation System (ARMS). The ARMS is a rapid and direct molecular technique in which beta-thalassemia mutations are visualized immediately after DNA amplification by gel electrophoresis. In the University of Malaya Medical Center, molecular characterization and prenatal diagnosis for beta-thalassemia is carried out using ARMS for about 96% of the Chinese and 84.6% of the Malay patients. The remaining 4% and 15.4% of the uncharacterized mutations in the Chinese and Malay patients respectively are detected using DNA sequencing. DNA sequencing is an accurate technique but it is more time-consuming and expensive compared with the ARMS. The ARMS for the rare Chinese beta-mutations at position -29 (A-->G) and the ATG-->AGG base substitution at the initiator codon for translation in the beta-gene was developed. In the Malays, ARMS was optimized for the beta-mutations at codon 8/9 (+G), Cap (+1) (A-->C) and the AATAAA-->AATAGA base substitution in the polyadenylation region of the beta-gene. The ARMS protocols were developed by optimization of the parameters for DNA amplification to ensure sensitivity, specificity and reproducibility. ARMS primers (sequences and concentration), magnesium chloride concentration, Taq DNA polymerase and PCR cycling parameters were optimized for the specific amplification of each rare beta-thalassemia mutation. The newly-developed ARMS for the 5 rare beta-thalassemia mutations in the Chinese and Malays in Malaysia will allow for more rapid and cost-effective molecular characterization and prenatal diagnosis for beta-thalassemia in Malaysia.

Base Sequence↗
PubMed1992

p53 mutations in human malignant gliomas: comparison of loss of heterozygosity with mutation frequency.

Mutations in the p53 gene were analyzed in 40 gliomas using the single strand conformation polymorphism assay together with restriction fragment length polymorphism analysis to assess loss of heterozygosity for 17p alleles in the same tumors. Mutations occurred in 40% of the gliomas and were found in exons 4-8 of the p53 gene. G:C to T:A transversions, which occur in high frequency in some lung (greater than 50%), liver (greater than 80%), breast (30%), and esophageal cancers (25%), were noted in greater than 25% of the gliomas studied here. These transversions were clustered in exon 5 from codons 156 to 168, a region of the p53 gene not previously associated with a high frequency of mutation, and may represent a new hot spot for mutations in certain cancers. The majority of gliomas (27 of 38) analyzed here retained both 17p alleles. The frequency of p53 mutations was 37% in this group of tumors and increased to 64% in tumors with one 17p allele. Allelic loss for chromosome 17p occurred in 4 of 11 gliomas independently of mutations in the p53 gene. Absence of p53 mutations in 36% of the tumors with one 17p allele suggests that a tumor suppressor gene other than p53 may be located on chromosome 17p and involved in progression to malignancy of some gliomas.

Adolescent↗
PubMed2006

Detection of F508del mutation in cystic fibrosis transmembrane conductance regulator gene mutation among Malays.

INTRODUCTION: Cystic fibrosis (CF) is one of the common genetic disorders in the western world. It has been reported to be very rare in Asian populations. According to the Cystic Fibrosis Genetic Analysis Consortium, more than 1,000 mutations of the CF gene have been identified. The CF gene, named the cystic fibrosis transmembrane conductance regulator (CFTR), is located on chromosome 7 and composed of 27 exons. This study aims to detect possible CFTR gene mutations in Malays. METHODS: We analysed 50 blood samples from healthy Malays with no symptoms of CF. DNA was extracted from blood using commercially available extraction kits (Eppendorf, Germany). Identification of CFTR gene mutation was performed using the CF OLA (Oligonucleotide Ligation Assay) kit (Applied Biosystems, USA). The PCR-ligation products were electrophoresed on eight percent sequagel using an ABI PRISM 377 genetic analyser (Applied Biosystems, USA). Electrophoresis data was analysed using the Genotyper software and a report of the CF genotype for all loci tested was created using the CF Genotyper Template software. Out of 50, one sample (two percent) was detected to have the F508del mutation (3bp deletion at exon 10), which is one of the most common CFTR gene mutations in Caucasians. RESULTS: The F508del mutation allele was detected in one subject. This indicates that she was a CF carrier. CONCLUSION: We report the finding of a carrier of the F508del mutation of the CFTR gene in the Malay population. Our finding revealed that CF could also affect the Malay population. Larger studies are necessary to determine the exact gene frequency of this population.

Asian People↗
PubMed2005

RET mutation status in medullary thyroid cancer(MTC) patients and the significance of genetic screening for mutations in their immediate relatives--a preliminary report.

Multiple Endocrine Neoplasia (MEN) 2A is an inherited disease characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma(PHCH) and hyperparathyroidism(HPT). It has recently been shown to be associated with germline mutations in the RET proto-oncogene. Genetic testing for RET mutations will, therefore allow the identification of people with asymptomatic MEN 2 who can be offered prophylactic thyroidectomy and biochemical screening as preventive measures. No genetic study based on RET mutation detection has been available in India so far. The aim of the present study is to detect the proportion of MTC cases having inherited germline or somatic RET mutations and to identify family members at risk for MEN and, thereby the feasibility of screening for MEN. DNA extracted from the peripheral blood and somatic (tumor) tissues were subjected to PCR using primers for exons 10,11 and 16. A few samples were subjected to direct sequencing. Germline mutations were identified in 3 of 4 MEN 2A patients, 18 of 24 sporadic MTC(SMTC), 2 of 4 children of MEN2A and 8 relatives of SMTC. Common mutation was in exon 10 and 11 (c634). It is recommended that RET mutation analysis and counseling of patients and their immediate relatives be introduced on a regular basis to identify gene carriers.

Carcinoma, Medullary↗
PubMed2006

Sarcomere protein gene mutations and inherited heart disease: a beta-cardiac myosin heavy chain mutation causing endocardial fibroelastosis and heart failure.

Inherited human cardiomyopathies often lead to heart failure. A common feature of these conditions is that affected individuals can express the disease causing mutations for many years without showing clinical signs of the disease. Previous studies have demonstrated that sarcomere protein gene mutations can cause either dilated cardiomyopathy or hypertrophic cardiomyopathy. Here we demonstrate that the Arg442His missense mutation in beta-cardiac myosin heavy chain (betaMHC) causes dilated cardiomyopathy, endocardial fibroelastosis and heart failure at a very early age. Using standard genetic engineering tools we and others have made murine models by introducing human disease causing mutations into mice. The central hypothesis of these studies has been that by identifying the pathophysiological pathways activated by these mutations we can define enzymatic activities that are modified during the disease process and which may be involved in pathways that involve more common forms of cardiac disease. Murine models bearing different mutant myosins are being used to address whether each disease causing mutant betaMHC activates the same or different cellular pathways. Dissecting the molecular pathways modulated by mutations in sarcomere protein genes as well as other genes has already demonstrated that there are multiple pathways leading to cardiac remodelling and heart failure. Defining the mechanisms by which mutations in the same genes activate different cellular pathways remains an important question.

Adult↗
PubMed1991

Mutations induced by ionizing radiation in a plasmid replicated in human cells. I. Similar, nonrandom distribution of mutations in unirradiated and X-irradiated DNA.

The Escherichia coli supF gene encoding the suppressor tyrosine tRNA in a human shuttle plasmid, pZ189, was used as a target for molecular analysis of X-ray-induced mutations in human lymphoblastoid cells. Following replication of the in vitro-irradiated plasmid in human cells, the mutant supF-containing molecules were cloned by phenotypic screening in E. coli and the nature of the mutations was determined by direct sequencing of the tRNA gene. At 160 Gy the mutant frequency was 13 times (0.39%) that observed in unirradiated controls (0.031%). When control plasmid was replicated directly in E. coli, the mutant frequency was 16 times less than that of the plasmid passaged through the human cells. The distribution of mutations was highly nonrandom and remarkably similar in both irradiated and control DNAs. The majority of the mutations were transitions involving G.C pairs and occurred selectively at most 5'-TC (3'-AG) sequences. These mutations at C's were preferentially distributed in the nontranscribed strand. We propose that mutations in the control plasmid result from oxidative damages that occur during and/or after its incorporation into human cells and that these damages are similar to those induced by ionizing radiation. The hot spots for mutations suggest that the proximate nucleotide sequence and the overall conformation of the target DNA are important in the production and/or processing of these damages during repair and replication.

Base Composition↗
PubMed1988

Point mutations and small substitution mutations in three different upstream elements inhibit the activity of the mouse alpha 2(I) collagen promoter.

Point mutations and small substitution mutations were introduced in three different promoter segments of the mouse alpha 2(I) collagen gene that are binding sites for specific DNA-binding proteins. The first of these promoter elements contains a CCAAT motif between -80 and -84 and binds a novel factor consisting of two different components which are both needed for DNA binding (Hatamochi, A., Golumbek, P.T., Van Schaftingen, E., and de Crombrugghe, B. (1988) J. Biol. Chem. 263, 5940-5947). Four different point mutations in the CCAAT motif, which strongly inhibit binding of this heterodimeric CCAAT-binding factor, decrease the activity of the promoter at least 8-fold when assayed by DNA transfection of NIH 3T3 fibroblasts. The second cis-acting element is located around -250. Two mutations in this element, one a 3-base pair (bp), another a 4-bp substitution mutation, decrease the activity of the promoter in DNA transfection experiments by about 8- and 12-fold, respectively. The third element is located between -315 and -295 and binds nuclear factor 1 (NF1). Both 1- and 2-bp mutations which strongly inhibit binding of NF1 to this site decrease the activity of the promoter 8-10-fold in DNA transfection assays whereas another mutation in this site shows less inhibition in the activity of the promoter. Transfer of this NF1-binding site 5' to the SV40 early promoter increases the activity of this promoter more than 10-fold. These results indicate that the integrity of each of these three cis-acting elements is required for optimal activity of the alpha 2(I) collagen promoter and suggest a model whereby the factors which bind to these sequences cooperate in the formation of a transcription initiation complex.

Animals↗
PubMed1995

[Mutation of ade13-1 of the yeast Saccharomyces cerevisiae leads to the absence of growth on a complete medium with glucose and epistatically interacts with mutations in other genes for purine biosynthesis].

Saccharomyces cerevisiae gene ADE13 encodes enzyme adenylosuccinate lyase catalyzing steps 8 and 12 of the de novo purine pathway. The mutation ade13-1 induced by ethyl methanesulfonate leads to a complete loss of enzymatic activity. Stocks with this mutation cannot grow on complete organic media with glucose or fructose as a carbon source, but they can grow on media with glycerol or ethanol. The inhibiting effect of glucose is confirmed by the lack of growth on the medium with glycerol instead of glucose. Three independently obtained ade2 mutations and mutations ade1-p3, ade4, ade5, and ade5,7-33 suppress growth inhibition by glucose; i.e., they are epistatic with respect to this phenotypical expression of mutation ade13-1. The activity of adenylsuccinate lyase is not reconstituted. Mutations ade1-263, ade6, ade7-23, and ade8-21 do not manifest an epistatic effect. It was suggested that purine synthesis genes participate in the control of glycolysis or in the transduction of signal about the carbon source in the medium. The properties of ade mutations found by us were previously unknown. The results of our study contribute to the knowledge about the function of purine synthesis genes in yeasts.

Adenylosuccinate Lyase↗
PubMed1994

Cancers beget mutations versus mutations beget cancers.

Despite the plethora of "oncogenes" and "tumor suppressor genes," the hypothesis that cancer is usually the result of genomic mutations may be wrong. We should at least examine the alternative hypothesis, for which there is considerable evidence, that mutations do not commonly beget cancer, but rather that cancer phenotypes result from confused or aberrant patterns of normal-gene expression; the abnormal patterns are postulated to result from epigenetic mechanisms rather than from mutations. The epigenetic hypothesis that I am proposing suggests that cancers may exhibit mutations primarily because replicative errors at inactive sites in the cancer genome may be repaired slowly or not at all, but the mutations so produced, occurring at already inactivated sites in the genome, may have limited biological significance. Thus, it may be more correct to say that cancers beget mutations than it is to say that mutations beget cancers.

Animals↗
PubMed1996

Use of the single strand conformation polymorphism method for rapid screening for mutations in the low density lipoprotein receptor gene in patients with familial hypercholesterolemia: effect on plasma lipid levels of different classes of mutations.

The single strand conformational polymorphism (SSCP) method was used to screen patients with familial hypercholesterolemia (FH) for mutations in the 3' part of exon 4 of the low density lipoprotein receptor (LDLR) gene. In 311 patients, six previously described mutations were identified in 29 apparently unrelated individuals (9.3%); three of the mutations are null alleles producing no protein, while the other three lead to production of a defective protein. In the patients where no mutation was detected mean total plasma cholesterol levels were 9.4 mmol/l, compared to 11.3 mmol/l in those individuals with a mutation creating a null allele, and 11.2 mmol/l in those with a mutation that resulted in the production of a defective protein (p < 0.001). These data reinforce observations of others that specific mutations in the LDL receptor gene are associated with different effects on plasma lipids, and indicate that the phenotype is influenced by the genotype.

Adult↗
PubMed1997

Compound heterozygosity for a nonsense mutation and a splice site mutation in the type VII collagen gene (COL7A1) in recessive dystrophic epidermolysis bullosa.

Mutations in the type VII collagen gene (COL7A1) have recently been established as the molecular basis of the inherited blistering skin disorder, dystrophic epidermolysis bullosa. We report a novel combination of COL7A1 mutations in a Japanese patient with an autosomal recessive form of dystrophic epidermolysis bullosa. Clinically, the patient had suffered from generalized trauma-induced blistering since the first week of life loss of most finger- and toenails, esophageal stenosis and partial fusion of the fingers and toes. Immunofluorescence microscopy of the dermal-epidermal junction in the patient's skin revealed reduced intensity of staining with an anti-type VII collagen antibody. Transmission electron microscopy showed only a few thin, poorly formed anchoring fibrils. The patient was a compound heterozygote for a nonsense mutation on one COL7A1 allele and a donor splice site mutation on the other allele. The mutations were identified by PCR amplification of genomic DNA, heteroduplex analysis, and nucleotide sequencing, and verified by restriction endonuclease digestion. Reverse transcriptase-PCR and sequencing of cDNA from the patient's cultured keratinocyte mRNA showed evidence of aberrant splicing resulting from the donor splice site mutation, due to activation of a cryptic intronic splice site that leads to a frameshift and a downstream premature termination codon. Knowledge of the genetic lesions in this patient is helpful in elucidating the molecular consequences of COL7A1 mutations in dystrophic epidermolysis bullosa and in providing information about the fundamental mechanisms involved in maintaining adhesion between the epidermis and the dermis.

Adult↗
PubMed2000

Detection of mutations in the ALD gene (ABCD1) in seven Italian families: description of four novel mutations.

The study describes the mutations causing adrenoleukodystrophy in seven Italian families. Four missense mutations leading to amino acid substitutions, two frameshift mutations leading to a premature termination signal, and a splicing mutation were identified. Mutations 2014C>T (P543L), 2053A>G (Q556A), 673-674insCC, and 1874+1G>A are described for the first time in this report. Mutations 1638C>T (R418W), 1588G>A(R401Q), and 1801-1802delAG are already known to be link to ALD.

ATP Binding Cassette Transporter, Subfamily D, Mem↗