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PubMed2004

Mechanism of 2-aminopurine-stimulated mutagenesis in Escherichia coli.

2-Aminopurine (2AP), a base analog, causes both transition and frameshift mutations in Escherichia coli. The analog is thought to cause mutations by two mechanisms: directly, by mispairing with cytosine, and indirectly, by saturation of mismatch repair (MMR). The goal of this work was to measure the relative contribution of these two mechanisms to the occurrence of transition mutations. Our data suggest that, in contrast to 2-aminopurine-stimulated frameshift mutations, the majority of transition mutations are a direct effect of base mispairing.

2-Aminopurine↗
PubMed1999

Mutations in autosomal dominant polycystic kidney disease 2 gene: Reduced expression of PKD2 protein in lymphoblastoid cells.

The polycystic kidney disease 2 (PKD2) gene, encoding a 968-amino acid integral membrane protein with six predicted membrane-spanning domains and intracellular NH2 and COOH termini, is mutated in approximately 15% of the cases of autosomal dominant polycystic kidney disease (ADPKD), a common genetic disease frequently resulting in renal failure. For a better understanding of the cause of this disorder, we searched for mutations in the PKD2 gene in two PKD2-linked families characterized by different clinical phenotypes. A common polymorphism, a nonsense mutation, and a frameshift mutation were found. Both mutations are predicted to produce truncated proteins of 314 and 386 amino acids, arrested at the first extracellular loop of the protein. Restriction enzyme analysis of polymerase chain reaction (PCR) and reverse transcriptase (RT)-PCR products, respectively, showed that mutations cosegregated with the disease and mutated alleles were expressed at the messenger RNA level in lymphoblastoid cell lines. However, in these cells, Western blot analysis showed only PKD2 normal protein, and it was expressed at a lower level than that found in cells without the PKD2 mutation. These findings suggest that in lymphoblastoid cells, the truncated protein product of the mutant allele may not be stable.

Aged↗
PubMed2006

Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome.

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting 1 per 10,000-15,000 female births worldwide. The disease-causing gene has been identified as MECP2 (methyl-CpG-binding protein 2). In this study, we performed diagnostic mutational analysis of the MECP2 gene in RTT patients. Four exons and a putative promoter of the MECP2 gene were analyzed from the peripheral blood of 43 Korean patients with Rett syndrome by PCR-RFLP and direct sequencing. Mutations were detected in the MECP2 gene in approximately 60.5% of patients (26 cases/43 cases). The mutations consisted of 14 different types, including 9 missense mutations, 4 nonsense mutations and 1 frameshift mutation. Of these, three mutations (G161E, T311M, p385fsX409) were newly identified and were determined to be disease-causing mutations by PCR- RFLP and direct sequencing analysis. Most of the mutations were located within MBD (42.3%) and TRD (50%). T158M, R270X, and R306C mutations were identified at a high frequency. Additionally, an intronic SNP (IVS3+23C>G) was newly identified in three of the patients. IVS3+23C>G may be a disease-related and Korea-specific SNP for RTT. L100V and A201V are apparently disease-causing mutations in Korean RTT, contrary to previous studies. Disease-causing mutations and polymorphisms are important tools for diagnosing RTT in Koreans. The experimental procedures used in this study should be considered for clinical molecular biologic diagnosis.

Base Sequence↗
PubMed2006

Identifying candidate colon cancer tumor suppressor genes using inhibition of nonsense-mediated mRNA decay in colon cancer cells.

Inhibition of the nonsense-mediated decay (NMD) mechanism in cells results in stabilization of transcripts carrying premature translation termination codons. A strategy referred to as gene identification by NMD inhibition (GINI) has been proposed to identify genes carrying nonsense mutations. Genes containing frameshift mutations in colon cancer cell line have been identified using a modified version of GINI. To increase the efficiency of identifying mutant genes using GINI, we have now further improved the strategy. In this approach, inhibition of NMD with emetine is complemented with inhibiting NMD by blocking the phosphorylation of the hUpf1 protein with caffeine. In addition, to enhance the GINI strategy, comparing mRNA level alterations produced by inhibiting transcription alone or inhibiting transcription together with NMD following caffeine pretreatment were used for the efficient identification of false positives produced as a result of stress response to NMD inhibition. To demonstrate the improved efficiency of this approach, we analysed colon cancer cell lines showing microsatellite instability. Bi-allelic inactivating mutations were found in the FXR1, SEC31L1, NCOR1, BAT3, PHF14, ZNF294, C19ORF5 genes as well as genes coding for proteins with yet unknown functions.

Caffeine↗
PubMed1997

Glutathione synthetase: similarities of the proteins from Schizosaccharomyces pombe and Arabidopsis thaliana.

Glutathione synthetase predicted from the reported gene sequence from Schizosaccharomyces pombe is substantially smaller than the equivalent protein predicted from the cDNAs sequenced from Arabidopsis thaliana, Saccharomyces cerevisiae and other eukaryotes. Sequence alignments of the proteins encoded by the cDNA clones for glutathione synthetase from Arabidopsis and S. pombe show that the Arabidopsis protein contains 200 extra amino acids at the N-terminus. In order to test if this sequence is essential in the function of the protein, the full-length Arabidopsis protein and as two N-terminal deletions (Delta67-71 and Delta67-200) were expressed in S. pombe mutant MN101, which lacks endogenous glutathione synthetase activity. Although the wild-type plant cDNA could complement the yeast mutation, neither deletion mutant was able to restore glutathione-dependent cadmium resistance. When the three proteins were expressed as fusion proteins in Escherichia coli, they accumulated to the same level, but only the plasmid containing the full-length cDNA, pFLAG222, produced detectable enzyme activity in vitro. These results suggested that the N-terminus of the Arabidopsis glutathione synthetase is essential for its function and opened up the possibility that there was a sequencing error in the reported S. pombe sequence. Therefore the gsh2 sequence from wild-type S. pombe and the mutant strain MN101 were determined. The wild-type S. pombe gsh2 encodes a protein that is about the same length as that found in Arabidopsis, and the MN101 mutation involves a frameshift mutation early in the glutathione synthetase reading frame.

Amino Acid Sequence↗
PubMed1996

Molecular characterization of haemophilia A in southern Chinese.

41 unrelated southern Chinese haemophilia A patients were studied. The 5' promoter region, all 26 exons, their immediate 5' and 3' flanking splice junctions and the 3' untranslated region of the FVIII gene were amplified (including 16 different segments of exon 14) using GC-clamped primers. The GC-clamped PCR products were screened by denaturing gradient gel electrophoresis (DGGE) and fragments showing an abnormal migration pattern were sequenced. 17 mutations were identified, of which four were splicing defects, involving the first 1-6 nucleotide (nt) in the intervening sequences (IVS), six missense mutations, three nonsense mutations and four frameshift mutations. 14 other patients carried the type 1 inversion, affecting the distal copy of the FSA gene at the telomere of the X chromosome and the same gene in intron 22 of the FVIII gene. All the mothers studied (12/14) were carriers of the inversion. Two of these patients with inversion also have a co-existing missense mutation. In most cases the clinical severity of the disease corresponds to the genotype.

Base Sequence↗
PubMed2000

The molecular basis of dystrophic epidermolysis bullosa in Mexico.

BACKGROUND: Type VII collagen gene (COL7A1) mutations are the cause of dystrophic epidermolysis bullosa (DEB), but most mutations are specific to individual families, and there are limited data on the nature of COL7A1 mutations in certain ethnic populations. OBJECTIVE: To determine the molecular basis of DEB in Hispanic Mexican patients. METHODS: Patients were recruited through a newly established support group, Fundacion DEBRA Mexico. Molecular analysis was performed by polymerase chain reaction (PCR) of genomic DNA using COL7A1-specific primers, heteroduplex analysis, and direct nucleotide sequencing. RESULTS: Fifty-nine of a possible 67 COL7A1 mutations (88%) were identified in 36 affected individuals (31 recessive, five dominant) in 21 families. Recessive mutations included six frameshift mutations, four silent glycine substitutions, and two splice-site mutations. Dominant mutations comprised a de novo glycine substitution and an internal deletion. Conclusions This study establishes the molecular basis of DEB in a group of Mexican patients. Only two of the mutations have been identified previously in other ethnic groups; the remainder are specific to this population. These new data are helpful in facilitating the accurate diagnosis of DEB subtype, in improving genetic counseling, and in providing further insight into the pathophysiology of this mechanobullous disease.

Adolescent↗
PubMed2001

The molecular basis of X-linked spondyloepiphyseal dysplasia tarda.

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2-7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G-->A, 157-158delAT, 191-192delTG, and 271-275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.

Base Sequence↗
PubMed2002

Predictors of the risk of mortality in neurofibromatosis 2.

To evaluate clinical and molecular predictors of the risk of mortality in people with neurofibromatosis 2 (NF2), we analyzed the mortality experience of 368 patients from 261 families in the United Kingdom NF2 registry, using the Cox proportional-hazards model and the jackknife method. Age at diagnosis, intracranial meningiomas, and type of treatment center were informative predictors of the risk of mortality. In Cox models, the relative risk of mortality increased 1.13-fold per year decrease in age at diagnosis (95% confidence interval [CI] 1.08-1.18) and was 2.51-fold greater in people with meningiomas compared with those without meningiomas (95% CI 1.38-4.57). The relative risk of mortality in patients treated at specialty centers was 0.34 compared with those treated at nonspecialty centers (95% CI 0.12-0.98). In a separate model, the relative risk of mortality in people with constitutional NF2 missense mutations was very low compared with those with other types of mutations (nonsense or frameshift mutations, splice-site mutations, and large deletions), but the CI could not be well quantified because there was only one death among people with missense mutations. We conclude that age at diagnosis, the strongest single predictor of the risk of mortality, is a useful index for patient counseling and clinical management (as are intracranial meningiomas). To ensure optimal care, we recommend that people with NF2 be referred to specialty treatment centers.

Adolescent↗
PubMed2002

Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive developmental disorder characterized by congenital muscular dystrophy and complex brain and eye abnormalities. A similar combination of symptoms is presented by two other human diseases, muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Although the genes underlying FCMD (Fukutin) and MEB (POMGnT1) have been cloned, loci for WWS have remained elusive. The protein products of POMGnT1 and Fukutin have both been implicated in protein glycosylation. To unravel the genetic basis of WWS, we first performed a genomewide linkage analysis in 10 consanguineous families with WWS. The results indicated the existence of at least three WWS loci. Subsequently, we adopted a candidate-gene approach in combination with homozygosity mapping in 15 consanguineous families with WWS. Candidate genes were selected on the basis of the role of the FCMD and MEB genes. Since POMGnT1 encodes an O-mannoside N-acetylglucosaminyltransferase, we analyzed the possible implication of O-mannosyl glycan synthesis in WWS. Analysis of the locus for O-mannosyltransferase 1 (POMT1) revealed homozygosity in 5 of 15 families. Sequencing of the POMT1 gene revealed mutations in 6 of the 30 unrelated patients with WWS. Of the five mutations identified, two are nonsense mutations, two are frameshift mutations, and one is a missense mutation. Immunohistochemical analysis of muscle from patients with POMT1 mutations corroborated the O-mannosylation defect, as judged by the absence of glycosylation of alpha-dystroglycan. The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration.

Abnormalities, Multiple↗
PubMed2002

Mental retardation and abnormal skeletal development (Dyggve-Melchior-Clausen dysplasia) due to mutations in a novel, evolutionarily conserved gene.

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function.

Amino Acid Sequence↗
PubMed2006

Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.

A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q-) syndrome has been estimated to be <1 Mb and comprises the euchromatin histone methyl transferase 1 gene (EHMT1). Previous studies suggested that haploinsufficiency for EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations--a nonsense mutation and a frameshift mutation--in the EHMT1 gene in patients with a typical 9q- phenotype. These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome.

Abnormalities, Multiple↗
PubMed1992

Mutation spectra of the two guanine adducts of the carcinogen 4-nitroquinoline 1-oxide in Escherichia coli. Influence of neighbouring base sequence on mutagenesis.

When the chemical carcinogen 4-nitroquinoline 1-oxide binds to DNA in vitro, two major adducts are formed, both at guanine residues, but at different positions, i.e. the C8 or the N2 position. Well-defined adducts (either C8 or N2 guanine adducts) can be formed in vitro by reacting DNA with 4-actoxyaminoquinoline 1-oxide (Ac-4HAQO) under different reaction conditions. Forward mutations induced by each of both main 4NQO adducts in the tetracycline resistance gene of pBR322 were determined. In total, 30 independent 4NQO-induced mutations were characterized, showing mainly base-pair substitution mutations and some frameshift mutations. We have observed that the 5' neighbouring base influences the specificity of dGuo-N2-AQO induced base-pair substitutions mutagenesis; a similar effect does not occur with dGuo-C8-AQO. This study reveals the importance of the N2 guanine adduct in the mutagenesis induced by 4NQO in vivo.

4-Nitroquinoline-1-oxide↗
PubMed1996

Mutation in the p53 tumor suppressor gene in rat esophageal papillomas induced by N-nitrosomethylbenzylamine.

Mutations in the p53 tumor suppressor gene have been implicated in the pathogenesis of a wide variety of human neoplasms. The location and types of p53 gene mutation can reflect exposure of humans to certain types carcinogenic agents. Much less is known about the role of p53 mutational inactivation in rodent tumors. Using both 'Hot' (radioactive) and 'Cold' (non-radioactive) single strand conformation polymorphism (SSCP) analyses, the present study of analyzed exons 5-8 and the exon-intron junction of the p53 gene from rat esophageal papillomas induces by N- nitrosomethylbenzylamine (NMBA) for mutations. Nine of 30 (30%) esophageal papillomas contained SSCP mobility shifts, principally within exons 5 and 7. These positive SSCP findings were further validated by direct DNA sequencing analysis. Eight of the nine mutations were G:C-->A:T transitions in codons 131, 149, 153, 242 (2), 243, 248, and the 5 end of intron 7. None of these G:C-->A:T mutations occurred at the CpG sites. The other mutation was a frameshift mutation in codon 176. The G:C-A:T transitions observed in this study are consistent with the documented formation of O(6)-methylguanine adducts in DNA N-nitroso compounds. These results suggest that point mutations of the p53 gene are involved in the development of approximately one-third of NMBA-induced rat esophageal papillomas. 'Hot' and 'Cold' SSCP methods were equally sensitive for the identification of mutations in the rat p53 gene.

Animals↗
PubMed1992

Molecular characterization of mutations of nit-4, the pathway-specific regulatory gene which controls nitrate assimilation in Neurospora crassa.

The nit-4 genes of three conventional Neurospora crassa mutations and of the closely related species, Neurospora intermedia, have been isolated by amplifying the genomic DNA with the polymerase chain reaction. Nucleotide sequencing has revealed that the three nit-4 mutants, alleles 15, 1214, and 2994, are the result of a missense mutation, a nonsense mutation and a frameshift mutation, respectively. The nucleotide sequence of the NIT4 protein coding region of a nit-4 mutant (allele 2994) and of N. intermedia have been determined and compared with that of wild-type N. crassa. The molecular characteristics confirm that the mutated gene of 2994 originated from N. intermedia and was introgressed into N. crassa. The polyglutamine domains of the N. crassa wild type, the 2994 mutant, or N. intermedia cannot replace an upstream glutamine-rich domain which is essential for nit-4 function.

Amino Acid Sequence↗
PubMed1993

Genetic screening in Saccharomyces cerevisiae for large numbers of mitochondrial point mutations which affect structure and function of catalytic subunits of cytochrome-c oxidase.

A new search for mitochondrial respiratory deficient mutants (Mit-) has been undertaken in order to accumulate a large number of point mutations in the coding portions of cytochrome-c-oxidase catalytic subunits and cytochrome b. Therefore, a mitochondrial DNA which retains the exons and lacks all the introns of the cytochrome oxidase subunit I and of the cytochrome-b split genes has been introduced into a strain carrying a nuclear recessive mutation affecting the adenine-nucleotide translocator, the op1 mutation, which is known to prevent the accumulation of large deletion petite mutants and this was used as the parental strain. After a moderate MnCl2 mutagenesis in order to limit multiple mutations, 105 Mit- mutants were isolated from 15,000 mutagenised clones in Saccharomyces cerevisiae. Mutations were mapped to the three catalytic subunits encoding genes (COX1, COX2 and COX3) of the cytochrome-c oxidase (70 mutations) and to the cytochrome-b gene (15 mutations). More than 50% of the mutants tested still exhibited mitochondrial translation products (subunits I, II and III), suggesting that they carry a missense mutation, rather than a nonsense mutation which would normally have led to a truncated protein. Mutations in the COX1 gene were allocated to four different subregions corresponding to exons 4 and 8 or to groups of exons, exons 1, 2, 3 or exons 5, 6, 7. Seven missense monosubstitution mutations and two frameshift mutations were also identified. The amino acid changes of the missense mutations were located in the vicinity of the CuB-heme alpha 3 binuclear centre ligands.

Amino Acid Sequence↗
PubMed1992

Cloning, sequencing, expression, and functional studies of a 15,000-molecular-weight Haemophilus somnus antigen similar to Escherichia coli ribosomal protein S9.

Haemophilus somnus is a gram-negative bacterium capable of causing a number of disease syndromes in cattle. This article describes the cloning and characterization of a gene coding for a 15,000-molecular-weight (15K) polypeptide which reacts strongly with antiserum against H. somnus. Analysis of plasmid-encoded polypeptides by polyacrylamide gel electrophoresis showed that the corresponding gene is the second in a transcriptional unit. The first gene codes for a protein with a molecular weight of approximately 17,000. Using antiserum against the two recombinant proteins, we could show that the natural proteins are predominantly present in purified ribosomes from H. somnus. The nucleotide sequence of both genes and flanking regions has been determined, and the deduced amino acid sequence of the two polypeptides was used to search for sequence homology in the GenBank data base. The 15K polypeptide showed 89% similarity to the Escherichia coli ribosomal protein S9, and the 17K polypeptide showed 94% similarity to the E. coli ribosomal protein L13. In E. coli, the corresponding genes constitute a bicistronic operon, with the same gene order as that found in H. somnus. A plasmid expressing the 15K protein was found to complement an E. coli rpsI mutation. When a frameshift mutation was introduced into the 15K protein gene, the resulting plasmid failed to complement this rpsI mutation, demonstrating functional homology between the 15K protein and S9 from E. coli. Downstream from the 15K protein gene is located another open reading frame, which could code for a polypeptide with a predicted molecular weight of 24,427. A protein with a similar molecular weight was detected in minicells containing the recombinant clone. This polypeptide is 69% similar to the stringent starvation protein (Ssp) of E. coli.

Amino Acid Sequence↗
PubMed2004

Influence of MECP2 gene mutation and X-chromosome inactivation on the Rett syndrome phenotype.

To date, approximately 200 different mutations in the MECP2 gene have been identified. We analyzed the entire coding sequence of the MECP2 gene and the X-chromosome inactivation pattern in 42 sporadic cases of Rett syndrome. Of the 42 patients, 30 had pathogenic mutations, including 14 different mutations: 9 missense mutations, 4 nonsense mutations, and 1 frameshift mutation. One was a novel mutation (S134P). There was a tendency for patients who had a nonsense mutation in the transcriptional repression domain region to show earlier onset of regression and more severe language retardation than patients with a mutation in the methyl-CpG binding domain region. However, the parameters of clinical severity were variable among patients with the same type of mutation, depending on the pattern of X-chromosome inactivation. This study suggests that the X-chromosome inactivation pattern can modify the phenotype of Rett syndrome, which is primarily determined by the type and site of MECP2 gene mutation.

Age of Onset↗