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PubMed1993

Mutational specificities of environmental carcinogens in the lacI gene of Escherichia coli. VI: Analysis of methylene chloride-induced mutational distribution in Uvr+ and UvrB- strains.

To better understand the mechanisms of mutagenesis by the carcinogen, methylene chloride (DCM), we have determined the nature and distribution of forward mutations induced by DCM in the N-terminal region of the lacI gene of Escherichia coli. A total of 116 lacI-d mutations (50 from Uvr+, 66 from UvrB- strain) were characterized by DNA sequencing. Both similarities and differences were observed. Although in both strains base substitutions predominated (74-88%) the distribution among the classes differed. In the case of the Uvr+ strain, DCM substantially increased the frequency of G:C-->C:G transversion and duplication events. Direct repeats were not observed at the endpoints of the duplications, however, all endpoints were in an A:T-rich region. In contrast, in the UvrB- strain, DCM induced A:T-->G:C, A:T-->C:G, G:C-->C:G events as well as deletions. The mutational spectra presented here represent a first step in the elucidation of the mechanism(s) of DCM-induced mutation.

Base Composition↗
PubMed1993

Genome wide spontaneous mutation in human cells determined by the spectrum of mutations in hprt cDNA genes.

We have studied spontaneous mutagenesis in five hprt cDNA genes integrated at five different genomic positions in a human lymphoblastoid cell line (TK6). The spectra of 40 mutants from each position were combined to obtain a mutation spectrum of the overall genome. This collection of mutants was used to assess the contribution of several mutagenic processes to spontaneous mutagenesis. Deletions and single base pair changes account for the majority of the mutants and arise in approximately equal amounts (43 and 41%, respectively). The majority of the deletions and insertions are < 5 bp and are likely to be caused by template-directed misalignment (slippage) during replication. To account for frameshifts at non-iterated sites we propose a slightly different template-directed replication error model. A considerable amount of the observed base pair changes can also be explained by this last model, but several other processes leading to base pair changes such as depurination, deamination or spontaneously arising DNA damage are likely to contribute as well. We have compared this spectrum with mutation spectra in the endogenous hprt genes using published mutation data. It is shown that in the endogenous genes the contribution of base pair substitutions is much larger (71%) than in the hprt cDNA integrates and that deletions are less frequently observed (20%). The mutation rates of the integrated hprt cDNA genes show a mean increase of 30-fold as compared with the endogenous hprt gene. This results in a 60-fold increase of the absolute rate of deletion in the hprt cDNA genes and in a 15-fold increase of the base pair substitution rate. Replication errors such as slippage or the mechanism proposed in this study probably account to a large extent for this increase.

Adenine Phosphoribosyltransferase↗
PubMed2004

First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations.

Thirty-seven unrelated Iranian CF families were screened for the presence of seven common mutations (DeltaF508, G542X, W1282X, G551D, N1303K, 1717-1G-->A, and 621-1G-->T) using ARMS PCR and exons 4 and 7 of the CFTR gene by SSCP method. This study resulted in the identification of 26.8 per cent of all CF alleles: DeltaF508 (16.2 per cent), W1282X (4 per cent), G542X (2.7 per cent), R117H (1.3 per cent), R347H (1.3 per cent), and A120T (1.3 per cent) mutations were detected. To the best of our knowledge, it is the first report of an Asian subject carrying the A120T mutation. Our findings suggest heterogeneity in the Iranian population, stressing the need to draw attention to sequence analysis in order to find population-specific mutations.

Adolescent↗
PubMed2001

Primary congenital glaucoma: three case reports on novel mutations and combinations of mutations in the GLC3A (CYP1B1) gene.

PURPOSE: To describe three patients with congenital glaucoma homozygous and compound heterozygous for different mutations and benign sequence variants in the cytochrome P 450 1B1 (CYP1B1) gene. METHODS: All patients were examined by slit-lamp biomicroscopy, gonioscopy, measurement of the cornea and optic disc, ultrasound biometry, and automated static threshold perimetry when possible. Direct sequence analysis was performed on DNA extracted from peripheral blood from the patients and their parents. RESULTS: For patient 1, a newborn boy with buphthalmos and an opaque cornea, a novel homozygous C/T transition in codon 355 (CGA>TGA) led to a predicted nonsense codon Arg355X truncating the protein by 188 amino acids. For patient 2, a 24-year-old man, a compound heterozygous mutation 1410-1422del/1546-1555dup was found. For patient 3, a 34-year-old man, two novel heterozygous missense mutations resulting in an Ala443Gly and a Glu229Lys amino acid exchange and five benign sequence variants were found. CONCLUSION: Our results confirm the crucial role of CYP1B1 mutations for congenital glaucoma.

Adult↗
PubMedDate not supplied

Improved detection of cystic fibrosis mutations in the heterogeneous U.S. population using an expanded, pan-ethnic mutation panel.

PURPOSE: To determine the comparative frequency of 93 CFTR mutations in U.S. individuals with a clinical diagnosis of cystic fibrosis (CF). METHODS: A total of 5,840 CF chromosomes from Caucasians, Ashkenazi Jews, Hispanics, African Americans, Native Americans, Asians, and individuals of mixed race were analyzed using a pooled ASO hybridization strategy. RESULTS: Sixty-four mutations provided a sensitivity of 70% to 95% in all ethnic groups except Asians, and at least 81% when the U.S. population was considered as a whole. CONCLUSIONS: For population-based carrier screening for CF in the heterogeneous U.S. population, which is characterized by increasing admixture, a pan-ethnic mutation panel of 50 to 70 CFTR mutations may provide a practical test that maximizes sensitivity.

Asian People↗
PubMed2005

Capillary morphogenesis gene-2 mutation in infantile systemic hyalinosis: ultrastructural study and mutation analysis in a Taiwanese infant.

Infantile systemic hyalinosis (ISH) is a very rare infantile stiff-skin syndrome characterized by extensive deposits of hyaline material in various organs, especially the skin and gingiva. Recent studies identified pathogenic mutations in the capillary morphogenesis gene 2 (CMG2) in both ISH and juvenile hyaline fibromatosis (JHF). Capillary morphogenesis protein-2 is an integrin-like cell surface receptor for laminins and type IV collagen, and may play a key role in cell-matrix or cell-cell interactions. We report a case of ISH in a 13-month-old Taiwanese girl who manifested progressive joint contractures, recurrent chest infections, chronic diarrhoea with severe hypoalbuminemia and ascites, gum hypertrophy, and violaceous papules and nodules over the occipital area, neck, lumbosacral and anogenital areas since birth. Skin biopsy revealed a thickened and hyalinized papillary dermis. Electron microscopy showed abundant extracellular fibrillogranular material and active fibroblasts with conspicuous Golgi complex filled with fibrillar material. Mutation analysis identified a homozygous 1073-1074insC mutation of CMG2 which had been reported in four other families and may represent a mutation hot spot.

Base Sequence↗
PubMed1998

Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site.

A 12-yr-old hypothyroid girl was diagnosed at birth as athyreotic because her thyroid gland could not be visualized by isotope scanning. Goiter development due to incomplete thyrotropin suppression, a thyroidal radioiodide uptake of < 1%, and a low saliva to plasma ratio of 2.5 suggested iodide (I-) transport defect. mRNA isolated from her thyroid gland and injected into Xenopus oocytes failed to increase I- transport. Sequencing of the entire Na+/I- symporter (NIS) cDNA revealed a C to G transversion of nucleotide (nt) 1146 in exon 6, resulting in a Gln 267 (CAG) to Glu (GAG) substitution. This missense mutation produces an NIS with undetectable I- transport activity when expressed in COS-7 cells. Although only this missense mutation was identified in thyroid and lymphocyte cDNA, genotyping revealed that the proposita and her unaffected brother and father were heterozygous for this mutation. However, amplification of cDNA with a primer specific for the wild-type nt 1146 yielded a sequence lacking 67 nt. Genomic DNA showed a C to G transversion of nt 1940, producing a stop codon as well as a new downstream cryptic 3' splice acceptor site in exon 13, responsible for the 67 nt deletion, frameshift, and premature stop predicting an NIS lacking 129 carboxy-terminal amino acids. This mutation was inherited from the mother and present in the unaffected sister. Thus, although the proposita is a compound heterozygote, because of the very low expression (< 2.5%) of one mutant allele, she is functionally hemizygous for an NIS without detectable bioactivity.

Alleles↗
PubMed2005

Heterozygous mutation of ataxia-telangiectasia mutated gene aggravates hypercholesterolemia in apoE-deficient mice.

Individuals with a heterozygous mutation at the ataxia-telangiectasia mutated gene (ATM) have been reported to be predisposed to ischemic heart disease. This report examined for the first time the effect of a heterozygous ATM mutation (ATM(+)(/-)) on plasma lipid levels and atherosclerosis intensity using ATM(+/-), ATM(+)(/+) (wild type), ATM(+)(/+)/LDLR(-)(/-) (low density lipoprotein receptor knockout), ATM(+)(/-)/LDLR(-)(/-), ATM(+)(/+)/ApoE(-)(/-) (apolipoprotein E knockout), and ATM(+)(/-)/ApoE(-)(/-) mice. Our data demonstrated that the plasma cholesterol and triglyceride levels in ATM(+)(/-) and ATM(+)(/-)/LDLR(-)(/-) mice were approximately the same as those in ATM(+)(/+) and ATM(+)(/+)/LDLR(-)(/-) control mice, respectively. In contrast, the plasma cholesterol level was significantly higher in ATM(+)(/-)/ApoE(-)(/-) mice than in ATM(+)(/+)/ApoE(-)(/-) control mice. In addition, the ATM(+)(/-)/ApoE(-)(/-) mice showed higher plasma apoB-48 levels, slower clearance for plasma apoB-48-carrying lipoproteins, and more advanced atherosclerotic lesions in the aorta compared with the ATM(+)(/+)/ApoE(-)(/-) mice. These novel results suggest that the product of ATM is involved in an apoE-independent pathway for catabolism of apoB-48-carrying remnants; therefore, superimposition of a heterozygous ATM mutation onto an ApoE deficiency background reduces the clearance of apoB-48-carrying lipoproteins from the blood circulation and promotes the formation of atherosclerosis.

Animals↗
PubMed2006

A new system for detecting mutations in arabidopsis thaliana and the mutational spectra resulting from ethylmethanesulfonate treatment.

A system was developed for the detection and analysis of mutations occurring on chromosomal DNA in plants. The plasmid pML4, carrying the Escherichia coli rpsL gene, a target gene for mutagenesis, was inserted into a shuttle vector, pCGN5138, to construct a plasmid which could be used for the transformation of plants. pML4 sequences were introduced into Arabidopsis thaliana mediated by Agrobacterium. The pML4 DNA was rescued from transgenic Arabidopsis plants exposed to mutagens, and the plasmids were introduced into Escherichia coli DH10B to isolate mutant clones. In this system, any form of inactivation mutation in the rpsL gene can be positively selected since it makes the E. coli cells resistant to streptomycin. Here we report that the system could detect the mutagenic effect of ethylmethanesulfonate (EMS). Further characterization of the mutants revealed that G:C to A:T transitions predominated among the EMS-induced mutations. This assay system is useful for the detection and analysis of mutations arising on chromosomal DNA in plants, and should be useful for evaluating analysis of the effects of environmental mutagens.

Arabidopsis↗
PubMed2001

Mutational screening of the CART gene in obese children: identifying a mutation (Leu34Phe) associated with reduced resting energy expenditure and cosegregating with obesity phenotype in a large family.

Cocaine- and amphetamine-regulated transcript (CART) inhibits feeding and induces the expression of c-Fos in hypothalamic areas implicated in appetite regulation. Furthermore, the CART peptide is found in neurons regulating sympathetic outflow, which in turn play an integral role in regulating body temperature and energy expenditure. The CART gene was screened by single-strand conformation polymorphism and automatic sequencing in 130 (72 girls) unrelated obese Italian children and adolescents. Their Z-scores (mean +/- SD) of relative to BMI percentiles was 3.9 +/- 1.8, and the average age at obesity onset was 4.7 +/- 2.6 years. Two previously described silent polymorphisms were found in the 3' untranslated region: an adenine deletion at position 1457 in 9 patients (allele frequency 0.035) and an A/G substitution at position 1475 in 11 patients (allele frequency 0.042). We found no difference between the obese patients heterozygous for one of these polymorphisms and those patients homozygous for the wild allele with respect to their age of obesity onset, BMI Z-scores, and leptin levels. A missense mutation of G729C resulting in the substitution of Leu with Phe at codon 34, within the NH2-terminal CART region, has been detected in the heterozygous state in a 10-year-old obese boy who has been obese since the age of 2 years. The patient belongs to a large family of obese subjects. The mutation cosegregated with the severe obesity phenotype over three generations and was not found in the control population. Resting metabolic rates were lower than expected in the propositus (-14%) and his mother (-16%), who carried the mutation. Leucine at codon 34, conserved in this position in the human and in the rat sequences, immediately precedes a couple of lysine residues that may well represent a dibasic processing site. The Leu34Phe mutation might alter the susceptibility to proteolysis of this potential processing site, likely altering the CART effect on thermogenesis and energy expenditure.

Adolescent↗
PubMed2006

A novel N14Y mutation in Connexin26 in keratitis-ichthyosis-deafness syndrome: analyses of altered gap junctional communication and molecular structure of N terminus of mutated Connexin26.

Connexins (Cxs) are transmembranous proteins that connect adjacent cells via channels known as gap junctions. The N-terminal 21 amino acids of Cx26 are located at the cytoplasmic side of the channel pore and are thought to be essential for the regulation of channel selectivity. We have found a novel mutation, N14Y, in the N-terminal domain of Cx26 in a case of keratitis-ichthyosis-deafness syndrome. Reduced gap junctional intercellular communication was observed in the patient's keratinocytes by the dye transfer assay using scrape-loading methods. The effect of this mutation on molecular structure was investigated using synthetic N-terminal peptides from both wild-type and mutated Cx26. Two-dimensional (1)H nuclear magnetic resonance and circular dichroism measurements demonstrated that the secondary structures of these two model peptides are similar to each other. However, several novel nuclear Overhauser effect signals appeared in the N14Y mutant, and the secondary structure of the mutant peptide was more susceptible to induction of 2,2,2-trifluoroethanol than wild type. Thus, it is likely that the N14Y mutation induces a change in local structural flexibility of the N-terminal domain, which is important for exerting the activity of the channel function, resulting in impaired gap junctional intercellular communication.

3T3 Cells↗
PubMed2005

A novel missense mutation of doublecortin: mutation analysis of Korean patients with subcortical band heterotopia.

The neuronal migration disorders, X-linked lissencephaly syndrome (XLIS) and subcortical band heterotopia (SBH), also called "double cortex", have been linked to missense, nonsense, aberrant splicing, deletion, and insertion mutations in doublecortin (DCX) in families and sporadic cases. Most DCX mutations identified to date are located in two evolutionarily conserved domains. We performed mutation analysis of DCX in two Korean patients with SBH. The SBH patients had mild to moderate developmental delays, drug-resistant generalized seizures, and diffuse thick SBH upon brain MRI. Sequence analysis of the DCX coding region in Patient 1 revealed a c.386 C>T change in exon 3. The sequence variation results in a serine to leucine amino acid change at position 129 (S129L), which has not been found in other family members of Patient 1 or in a large panel of 120 control X-chromosomes. We report here a novel c.386 C>T mutation of DCX that is responsible for SBH.

Adolescent↗
PubMed2002

Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene.

The human DNA mismatch repair genes hMSH2 and hMLH1 are responsible for the development of hereditary nonpolyposis colorectal cancer (HNPCC). Although genetic alteration of the coding region of hMSH2 and hMLH1 has been well investigated in HNPCC patients, the regulatory regions of these genes have been poorly investigated, though recent studies have defined and characterized the core promoter regions of hMSH2 and hMLH1. Therefore, to investigate the presence of germ-line mutations, we screened the core promoter regions of hMSH2 and hMLH1 from 157 nonmalignant control individuals, 40 cases of HNPCC, 56 suspected HNPCC cases, and 45 sporadic early onset colorectal cancer patients. Three novel germ-line mutations of the hMSH2 promoter were identified in two suspected HNPCC cases and one sporadic early onset colorectal cancer patient but not in the 157 nonmalignant controls, namely, an A insertion at position -80, a G-to-A transition at position -190, and a G-to-C transversion at position -225. Tumors from patients containing the promoter mutations displayed microsatellite instability. The A insertion at -80 is within a sequence homologous to the consensus sequence for E1AF and very close to the major transcription start point. Luciferase assay demonstrated that the -80A insertion and the -190A allele decreased the transcriptional efficiency by 82 and 77%, respectively, and the -225C allele increased the transcriptional efficiency by 466%. The -80A insertion allele was detected only in affected members within the family and showed novel transcription factor binding ability. Furthermore, the loss of single nucleotide polymorphism allelic expression was identified in blood of the patient containing the -80A insertion. Our results indicate that mutations in the promoter region of hMSH2 have a limited role in development of suspected HNPCC and sporadic early onset colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2004

[Mutations in beta myosin heavy chain gene: two mutations in Chinese with familial hypertrophic cardiomyopathy and the correlation between the genotype and phenotype].

OBJECTIVE: To study the disease-causing gene mutation in Chinese with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype. METHODS: Samples of peripheral blood were collected from five Chinese patients with HCM in whose families at least 2 HCM patients existed. The exon in the functional regions of the beta myosin heavy chain gene (beta-MHC) were amplified with PCR and the products were sequenced. The relation between the genotype and phenotype was analyzed. RESULTS: Two mutations were first identified. Eighty controls were normal in the genetic test. CONCLUSION: beta-MHC may be the main disease-causing gene. Two mutations have different phenotypes. In one family, the identical mutation has different phenotypes and prognoses. The heterogeneity of phenotype suggests that multiple factors be involved in the pathogenesis.

Adolescent↗
PubMedDate not supplied

Ki-ras mutations in codon 12 and p53 mutations (biomarkers) and cytology in bile in patients with hepatobiliary-pancreatic carcinoma.

BACKGROUND/AIMS: The differentiation between benign and malignant jaundice is sometimes difficult even with modern diagnostic modalities. With recent advances in molecular biology, Ki-ras point mutation in codon 12 and p53 mutation have been reported as novel biomarkers of hepatobiliary and pancreatic carcinoma. The purpose of this study was to compare exfoliative bile cytology and biomarkers of the bile in patients with hepatobiliary and pancreatic diseases. METHODOLOGY: Cytologic examination and novel biomarkers, point mutations of codon 12 of Ki-ras and p53 mutations, were examined in the biliary tract bile aspirated through percutaneous transhepatic biliary drainage (PTBD) tube in 30 Japanese patients with benign and malignant hepatobiliary and pancreatic diseases. RESULTS: Sensitivity of the exfoliative bile cytology for malignant conditions was 31% and specificity 100%, while sensitivity of molecular markers of the bile was 25% and specificity 93%. When the cytologic examination and genetic study were in conjunction, sensitivity increased to 50% and specificity remained 93%. CONCLUSIONS: These findings suggest that genetic examinations of the bile, when used in conjunction with cytology, may improve the diagnostic yield for suspected malignant tumors of the hepatobiliary and pancreatic system.

Adult↗
PubMed1994

Mutation profiles of phenylketonuria in Quebec populations: evidence of stratification and novel mutations.

Independent phenylketonuria (PKU) chromosomes (n = 109) representing 80% of a proband cohort in Quebec province carry 18 different identified mutations in 20 different mutation/haplotype combinations. The study reported here, the third in a series on Quebec populations, was done in the Montreal region and predominantly on French Canadians. It has identified three novel mutations (A309D, D338Y, and 1054/1055delG[352fs]) and one unusual mutation/RFLP haplotype combination (E280K on Hp 2). The relative frequencies and distribution of PKU mutations were then compared in three regions and population subsets (eastern Quebec, French Canadian; western Quebec, French Canadian; and Montreal, non-French Canadian). The distributions of the prevalent and rare mutations are nonrandom and provide evidence for genetic stratification. The latter and the presence of eight unusual mutation/haplotype combinations in Quebec families with European ancestries (the aforementioned four and M1V, I65T, S349P, and R408W on Hp 1) corroborate demographic and anthropologic evidence, from elsewhere, for different origins of French Canadians in eastern and western Quebec.

DNA Mutational Analysis↗
PubMed1995

A quantitative protein S deficiency associated with a novel nonsense mutation and markedly reduced levels of mutated mRNA.

A 50-year-old Japanese man who had experienced recurrent episodes of venous thrombosis was found to have a hereditary protein S deficiency. The amount of total protein S antigen in plasma was reduced by approximately 50% in the patient and his two sons. DNA sequence analysis revealed a novel nonsense mutation, TAG for Gln 522 (CAG), in exon 14 of the protein S gene. Family studies performed by mutagenic PCR followed by restriction enzyme digestion showed that the proband and his two sons were heterozygous for this mutation. An mRNA-based analysis indicated that transcripts of the mutated allele were markedly reduced in the platelets of the affected individuals. Immunoblot analysis failed to detect the truncated mutant of protein S in the plasma or platelets of affected members. Our results demonstrated that this novel nonsense mutation was responsible for the quantitative deficiency of protein S.

Amino Acid Sequence↗