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PubMed2003

Molecular epidemiology of human cancer risk. Gene-environment interactions and p53 mutation spectrum in human lung cancer.

Molecular epidemiology of cancer risk utilizes knowledge of both the genetic changes in cancer and the current hypothesis of chemical carcinogenesis when selecting possible markers for individual susceptibility, early disease, and biologically significant exposure. Polymorphisms of drug-metabolizing enzymes, especially CYP enzymes, and mutations in the p53 tumor-suppressor gene have been in the center of interest for the past decade. Both have shown promise, CYP polymorphisms as markers for individual susceptibility and p53 mutation spectrum at population level for specific exposure. However, it is probable that very few markers, if any, are sufficient alone. Future challenges for molecular epidemiology in the lung cancer field include pursuing ethically the best performance in applying that knowledge, in addition to the development of reliable and well-validated markers.

Biomarkers, Tumor↗

PubMed1997

Mutational spectrum induced by chromium(III) in shuttle vectors replicated in human cells: relationship to Cr(III)-DNA interactions.

Trivalent chromium (Cr(III)), the ultimate species of chromium (VI) intracellular reduction, can associate with DNA forming Cr(III) monoadducts and DNA-DNA cross-links. However, the mutational specificity of Cr(III) has not been determined partly because Cr(III) has difficulty entering cells. In this study, we have characterized the types of Cr(III)-induced DNA lesions in two buffer systems and the mutational spectrum of Cr(III)-treated shuttle vectors replicated in human 293 cells. Plasmids were treated with Cr(III) in buffers consisting of either 10 mM potassium phosphate, pH 7.5 (designated as KP), or 0.2 mM Tris-HCl and 20 microM EDTA, pH 7.4 (designated as TE/50). The amounts of Cr(III) bound to DNA increased as Cr(III) concentration increased in both buffers; these Cr(III)-DNA associations were stable in both buffers during a 24-h dialysis. The electrophoretic mobility of supercoiled DNA was markedly retarded in samples treated with Cr(III) in TE/50 but not KP buffer, suggesting that Cr(III)-mediated DNA-DNA cross-links were generated in TE/50 but did not form in KP. Polymerase-stop assay showed that DNA polymerases were mostly blocked at the 3' adjacent bases of guanines on templates treated with Cr(III) in TE/50 but were not observed on those treated in KP. The signals of Cr(III)-mediated cross-links generated in TE/50 buffers were reduced when they were dialyzed against KP buffers. Similarly, Cr(III)-DNA monoadducts formed in KP were converted to primer-template cross-links by dialysis against TE/50. The mutation frequency of Cr(III) in the supF gene of pSP189 or pZ189 shuttle vectors replicated in human cells increased as Cr(III) concentration increased in both buffers. DNA sequencing analysis showed that single-base substitutions (61-68%), two-base substitutions (3-5%), and deletions (21-34%) were induced in similar frequencies in plasmids treated with Cr(III) in either TE/ 50 or KP. The Cr(III)-induced base-substitution hot spots are different from those occurring spontaneously. Cr(III) enhances G.C base substitutions, particularly G.C-->C.G transversions, at 5'GA, 5'CG, and 5'AG sites. Base-substitution hot spots did not correlate with strong polymerase-stop sites, suggesting that base substitutions are derived from Cr(III) monoadducts, not from DNA-DNA cross-links.

Base Sequence↗

PubMed1998

Altered UV resistance and UV mutational spectrum in repair-proficient murine fibroblasts expressing endonuclease V.

In previously reported studies, we transfected repair-proficient murine fibroblasts with the denV gene of bacteriophage T4 and showed that expression of encoded endonuclease V markedly enhanced cyclobutane pyrimidine dimer (CPD) repair and reduced the frequency of ultraviolet radiation (UV)-induced mutations. In the present studies, we compared the spectra of UV-induced mutations at the hprt locus in denV-transfected and control cells. A significant difference in mutation types was observed. While multiple base deletions and single base insertions were found in denV-transfected but not control cells, multiple tandem and non-tandem point mutations identified in control cells were absent in denV-transfected cells. When we compared colony survival following UV exposure in the two cell lines, it appeared that endonuclease V expression did not enhance UV resistance, instead denV-transfected cells had increased susceptibility to low fluences of UV. The effects of endonuclease V expression on UV resistance and on UV mutational spectrum are likely to be due both to the removal of CPDs and to the novel enzymatic activity of endonuclease V.

Animals↗

PubMed2005

The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI).

Generalized arterial calcification of infancy (GACI), is characterized by calcification of the internal elastic lamina of large and medium-sized arteries and stenosis due to myointimal proliferation. Although survival to adulthood has been reported, most patients die within the first six months of life. Recently, we found mutations of ENPP1 coding for ecto-nucleotide pyrophosphatase/phosphodiesterase 1 to be associated with GACI in 8 of 11 families. In this study, we analyzed ENPP1 in affected individuals of another 12 unrelated families. We identified 11 novel homozygous or compound heterozygous mutations in 10 of the 12 new families. The mutations (1 nonsense, 7 missense, 1 single amino acid deletion, and 2 frame shift mutations) were scattered over the whole coding region with a slightly more condensed distribution within the catalytic and nuclease-like domain as compared to the first survey. In this study, three mutations were found repeatedly in apparently unrelated patients, 7 x c.913C>A (p.Pro305Thr) and c.2662C [corrected]>T (p.Arg888Trp) as well as c.2320C>T (p.Arg774Cys) each twice. However, haplotype analysis suggested a founder effect of British extraction for mutation c.913C>A (p.Pro305Thr). The fact that the two other mutations c.2662C [corrected]>T (p.Arg888Trp) and c.2320C>T (p.Arg774Cys) occurred twice within a single allele also suggests a single founder. This study confirms the role of ENPP1 mutations as the main cause of GACI and adds considerably to the mutational spectrum of ENPP1.

Adolescent↗

PubMed1999

Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation.

Hyperphenylalaninemia (HPA) is a group of diseases characterized by the persistent elevation of phenylalanine levels in tissues and biological fluids. It is an autosomal recessive disorder affecting 1 in 10,000 individuals in Caucasian populations and about 1 in 6,600 in Catalonia. We report the mutational spectrum of phenylalanine hydroxylase deficiency in the population living in Catalonia and the genotype-phenotype correlation. The molecular study was performed in 383 samples corresponding to 115 patients from 99 unrelated families and 268 relatives. We have characterized 90% of the mutant alleles; there were 57 different mutations, 49 of which have previously been described, 8 being novel mutations and two being large deletions. The 57 mutations detected corresponded to: five nonsense, seven frameshift, and eight splice defects, the remainder being missense mutations. These mutations cause 72 different genotypes in the 83 families characterized, confirming the mutational heterogeneity of phenylketonuria (PKU) in the Mediterranean population. According to our biochemical classification, our HPA population is composed of 40 PKU (35%), 36 variant PKU (31%), and 39 non-PKU HPA (34%). Mutations such as IVS 10, A403 V, and E390G correlated as expected with the phenotype and the predicted residual activity in vitro. However, in four cases (165 T, V388 M, R261Q, and Y414 C), the observed metabolic phenotype was not consistent with the predicted genotypic effect. The identification of the mutations in the PAH gene and the genotype-phenotype correlation should facilitate the evaluation of metabolic phenotypes, diagnosis, implementation of optimal dietary therapy, and determination of prognosis in the patients and genetic counselling for the patient's relatives.

Alleles↗

PubMed2000

Russian mutational spectrum differs from that of their Western counterparts.

It has been previously noted that the hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutant frequency of Russian subjects is significantly higher than age-matched Western counterparts. To further explore this difference, approximately 100 mutants collected from Russian twins reported in a previous study have been sequenced and compared to an aged-matched Western mutant dataset. The mutational spectrum of the Russian subjects was significantly different (Adams and Skopek Monte Carlo test, P = 0. 004). Curiously, this younger Russian spectrum resembles that recovered from older individuals in the West. Specifically, A:T-->C:G transversions are significantly over-represented (Fisher's Exact test, P = 0.003) in the twin spectrum as compared to the young (age </= 35) Western spectrum. Even more noteworthy is the observation that 42% (23/55) of the base substitutions, almost double the expected value, have not been previously reported. These observations lead to the conclusion that this group of young Russian subjects has a mutational pattern which is distinct from the pattern of mutation observed in Western counterparts. The origin of this difference, whether related to genotoxic challenge, repair, or avoidance, cannot be distinguished, but diet and other lifestyle factors clearly may be responsible.

Adult↗

PubMed1999

Molecular epidemiology of human cancer risk: gene-environment interactions and p53 mutation spectrum in human lung cancer.

The p53 tumour suppressor gene is at the crossroads of a network of cellular pathways including cell cycle checkpoints, DNA repair, chromosomal segregation, and apoptosis. These pathways have evolved to maintain the stability of the genome during cellular stress from DNA damage, hypoxia, and activated oncogenes. The high frequency of p53 mutations in human cancer is a reflection of the importance of p53 involvement in this network of pathways during human carcinogenesis. An electronic database containing p53 mutations from more than 9000 cancers (http:/(/)www.iarc.fr/p53/homepage.html) can be used to generate hypotheses for further clinical, epidemiological, and laboratory investigations. For example, one can hypothesize that (a) p53 mutations vary in their pathobiological significance; (b) cellular content influences the selection of p53 mutations in clonally derived cancers; (c) the location and type of mutation within the p53 gene provide clues to functional domains in the gene product; and (d) the p53 mutation spectrum can be a molecular link between aetiological agents and human cancer. This review will focus on the role of p53 and cancer susceptibility genes in the molecular pathogenesis and epidemiology of human lung cancer.

Cocarcinogenesis↗

PubMed1999

Mutation spectrum in Salmonella induced by environmental tobacco smoke.

Environmental tobacco smoke (ETS) is a major source of indoor air pollution. Extractable-respirable particulate (ERP) from the ETS-contaminated indoor air (ERP-ETS) was collected from six passenger train cars and one control room. The mutagenicity of ERP-ETS was tested in the Ames/Salmonella test in the presence of male rat liver microsomal fraction S9. The mutation spectrum of ERP-ETS was determined by colony probe hybridization and polymerase chain reaction/DNA sequence analysis in approximately 2,370 His+ revertants. The results indicate that the majority of ERP-ETS-induced mutations were a two-base deletion of GC or CG within the hotspot sequence of CGCGCGCG at the frameshift hisD3052 allele in strain TA98. The ERP-ETS from the control room induced approximately 94.3% such deletions, while the ERP-ETS collected from the passenger cars induced approximately 89.6% such deletions. The ERP-ETS either from the control room or from the passenger cars induced approximately 74% C/G --> A/T transversions, and approximately 23% C/G --> T/A transitions within the primary target CCC at the hisG46 allele in strain TA100.

Air Pollution, Indoor↗

PubMed1993

Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients.

The UV component of sunlight is the major carcinogen involved in the etiology of skin cancers. We have studied the rare, hereditary syndrome xeroderma pigmentosum (XP), which is characterized by a very high incidence of cutaneous tumors on exposed skin at an early age, probably due to a deficiency in excision repair of UV-induced lesions. It is interesting to determine the UV mutation spectrum in XP skin tumors in order to correlate the absence of repair of specific DNA lesions and the initiation of skin tumors. The p53 gene is frequently mutated in human cancers and represents a good target for studying mutation spectra since there are > 100 potential sites for phenotypic mutations. Using reverse transcription-PCR and single-strand conformation polymorphism to analyze > 40 XP skin tumors (mainly basal and squamous cell carcinomas), we have found that 40% (17 out of 43) contained at least one point mutation on the p53 gene. All the mutations were located at dipyrimidine sites, essentially at CC sequences, which are hot spots for UV-induced DNA lesions. Sixty-one percent of these mutations were tandem CC-->TT mutations considered to be unique to UV-induced lesions; these mutations are not observed in internal human tumors. All the mutations, except two, must be due to translesion synthesis of unrepaired dipyrimidine lesions left on the nontranscribed strand. These results show the existence of preferential repair of UV lesions [either pyrimidine dimers or pyrimidine-pyrimidone (6-4) photoproducts] on the transcribed strand in human tissues.

Base Sequence↗

PubMed2005

The mutation spectrum of purified AID is similar to the mutability index in Ramos cells and in ung(-/-)msh2(-/-) mice.

Somatic hypermutation and class switch recombination are initiated by the enzyme activation-induced cytidine deaminase (AID). Although other models exist for AID function, one model suggests that AID initiates these processes by deaminating cytidines within DNA, thereby initiating mutagenic repair pathways that involve either UNG or Msh2. Recent work shows that GST-hAID prefers to mutate WRC motifs, a motif frequently mutated in vivo. Because this is a strong argument in favor of the DNA deamination model, we sought to extend this analysis by examining the activity of purified AID with a small polyhistidine tag (His-hAID) on all 16 trinucleotide combinations (i.e., NNC). Here we show that purified His-hAID preferentially mutated cytidines within WRC (i.e., A/T, A/G, C) motifs, but poorly mutated cytidines within GYC (G, C/T, C) motifs. We next compared this mutability preference with those in hypermutating Ramos cells and in msh2(-/-)ung(-/-) mice, since both are reduced or deficient in UNG- and/or Msh2-induced mutations and are thus likely to reflect the sequence specificity of the mutator in vivo. Indeed, the mutation spectrums of purified His-hAID and GST-hAID matched the trinucleotide mutability indexes in Ramos cells and in msh2(-/-)ung(-/-) mice. Thus, the activity of AID on single-stranded DNA produces the same mutation pattern as double-stranded DNA in hypermutating cells. These data lend support to the DNA deamination model and indicate that AID does not require co-factors for its WRC specificity.

Animals↗

PubMed2005

Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.

Adenoma, Oxyphilic↗

PubMed2002

Combined DNA flow cytometry and sorting with k-ras2 mutation spectrum analysis and the prognosis of human sporadic colorectal cancer.

BACKGROUND: Activation of the k-ras2 pathways and chromosomal instability leading to aneuploidy in human sporadic colorectal cancer (sCRC) is essential to the tumor cell ability to survive, grow, and metastatize. METHODS: The study included 135 patients with sCRC who were followed up for a median of 72 months. Multiple fresh-frozen fragments obtained from superficial and invasive areas of the tumors were mixed and used to detect the degree of DNA aneuploidy (DNA index [DI]) and S-phase fraction by two scatter signals and 4,6-diamidino-2-phenylindole-2-hydrocloride (DAPI) fluorescence flow cytometry (FCM). PCR amplification and k-ras2 mutation spectrum analysis were performed using enriched epithelial nuclei after sorting DNA aneuploid nuclei and DNA diploid nuclei from which tissue-infiltrating lymphocytes were absent. RESULTS: DNA aneuploidy was detected in 98 (73%) and k-ras2 mutations in 54 cases (40%). Univariate analyses of overall survival with both Dukes' A to D or B to C series of cases showed that DNA multiple aneuploidy, k-ras2 mutations, older age, and distal site, but not increased S-phase fraction, were predictive of worse outcome. Multivariate Cox models strongly indicated that k-ras2 mutations, but neither single nor multiple DNA aneuploidy, were an independent prognostic factor in both series of patients. In particular, with B and C Dukes' stage patients (n = 110), the relative risk (RR) of death was above 2.5 with k-ras2 mutations and above 3 with the G-->C/T transversions. CONCLUSION: Combined FCM and k-ras2 analysis may be used to predict long-term increased risk of death in sCRC patients.

Age Factors↗

PubMed2003

Mutational spectrum and genotoxicity of the major lipid peroxidation product, trans-4-hydroxy-2-nonenal, induced DNA adducts in nucleotide excision repair-proficient and -deficient human cells.

trans-4-Hydroxy-2-nonenal (4-HNE), a major product of lipid peroxidation, is able to interact with DNA to form 6-(1-hydroxyhexanyl)-8-hydroxy-1,N(2)-propano-2'-deoxyguanosine (4-HNE-dG) adducts, but its genotoxicity and mutagenicity remain elusive. It has been reported that 4-HNE treatment in human cells induces a high frequency of G.C to T.A mutations at the third base of codon 249 (AGG*) of the p53 gene, a mutational hot spot in human cancers, particularly in hepatocellular carcinoma. This G.C to T.A transversion at codon 249, however, has been thought to be caused by etheno-DNA adducts induced by the endogenous metabolite of 4-HNE, 2,3-epoxy-4-hydroxynonanal. We have recently found that 4-HNE preferentially forms 4-HNE-dG adducts at the GAGG*C/A sequence in the p53 gene including codon 249 (GAGG*C). Our finding supports the possibility that G.C to T.A mutations at codon 249 may be induced by 4-HNE-dG adducts. To investigate this possibility, we determined the mutational spectrum induced by 4-HNE-dG adducts in the supF gene of shuttle vector pSP189 replicated in human cells. We have found that 4-HNE-dG adducts are mutagenic and genotoxic in human cells, and that G.C to T.A transversions are the most prevalent mutations induced by 4-HNE-dG adducts. Furthermore, 4-HNE-dG adducts induce a significantly higher level of genotoxicity and mutagenicity in nucleotide excision repair (NER)-deficient human and Escherichia coli cells than in NER-proficient cells, indicating that NER is a major pathway for repairing 4-HNE-dG adducts in both human and E. coli cells. Together, these results suggest that 4-HNE-dG adducts may contribute greatly to the G.C to T.A mutation at codon 249 of the p53 gene, and may play an important role in carcinogenesis.

Aldehydes↗

PubMed2002

Mutation spectrum of 1,2-dibromo-3-chloropropane, an endocrine disruptor, in the lacI transgenic Big Blue Rat2 fibroblast cell line.

1,2-Dibromo-3-chloropropane (DBCP), a soil fumigant against nematodes, has been extensively studied for genotoxicity, carcinogenicity and damage to male reproduction-related organs, as a possible endocrine disruptor. However, the precise mechanisms involved in DBCP-induced mutagenesis and carcinogenesis are as yet unknown. Thus, in this study the mutagenicity and mutation spectrum of DBCP was determined using the lacI transgenic Big Blue Rat2 fibroblast cell line. In determining the optimal concentration of DBCP in Big Blue Rat2 fibroblast cells, the 50% inhibition concentration was calculated to be 0.75 mM. When cells were exposed to DBCP concentrations of 0.21, 0.39 and 0.75 mM, the respective relative survival rates were approximately 80, 70 and 50%. The mean mutant frequencies (MFs) (x 10(-5), +/- SEM) of the medium and 1% DMSO solvent controls were determined as 6.43 +/- 0.616 and 5.28 +/- 1.086, respectively. The MFs (x 10(-5), +/- SEM) of cells exposed to 0.21, 0.39 and 0.75 mM DBCP were 8.09 +/- 1.02, 10.86 +/- 2.17 and 12.26 +/- 0.79, respectively, with a dose-dependent effect (ANOVA, P = 0.007). Moreover, MF values for the 0.75 and 0.39 mM DBCP-treated groups were statistically significant (ANOVA, P < 0.05). The majority of recovered mutations (31/40, 77.5%) were single base pair substitutions in the DBCP-induced groups. Among 31 single base pair substitutions, 25 (62.5%) occurred at G:C base pairs, while six (15%) were at A:T base pairs. The predominant mutation was G:C-->A:T transitions (16/40, 40%), followed by G:C-->T:A transversions (9/40, 22.5%). We conclude that DBCP is a possible base substitution mutagen, especially at guanine bases.

Animals↗

PubMed1992

The 4-nitroquinoline 1-oxide mutational spectrum in single stranded DNA is characterized by guanine to pyrimidine transversions.

4-Nitroquinoline-1-oxide is a potent mutagen and carcinogen which induces two main guanine adducts at positions C8 and N2. In ds or ss damaged DNA the ratio C8/N2 adducts is 1:2 and 8-10:1, respectively. In bacteria and yeast 4NQO has been shown to be a base substitution mutagen acting at G residues inducing mainly G to A transitions. We determined the mutational spectrum induced by the 4NQO metabolite, acetoxy-4-aminoquinoline 1-oxide, in the M13lacZ'/E. coli lacZ delta M15 alpha complementation assay using ssDNA. Among 68 Ac-4HAQO induced mutants, G to Pyr transversion was the most frequent base substitution observed. By comparison with dsDNA based systems, our data suggest that dGuo-C8-AQO induces G to Pyr transversions. A mechanism to explain how this lesion may induce transversions is proposed.

4-Nitroquinoline-1-oxide↗

PubMed1997

p53 mutation spectrum in Japanese Bowen's disease suggests a role for mutagens other than ultraviolet light.

The Japanese have a much lower incidence of nonmelanoma skin cancers (NMSCs) than Caucasians, presumably due in part to their skin type conferring relative protection from ultraviolet light radiation (UVR). To examine the contribution of environmental or endogenous mutagens other than UVR, which are expected to be relatively more important to the overall burden of NMSCs in the Japanese, we directly sequenced exons 5-8 of the p53 tumour suppressor gene in 29 Japanese patients with Bowen's disease, an in situ squamous-cell carcinoma of the skin. We found 9 mutations, including two CC:GG to TT:AA tandem transitions (presumably related to UVR), 3 transversions and 4 frameshift mutations. The mutational spectrum seen in our study contrasts with that we previously found in Bowen's disease from a Caucasian population, in keeping with a different aetiology for Bowen's disease in the respective populations. The unexpectedly high prevalence of frameshift mutations suggests that environmental mutagens other than UVR that preferentially induce deletion or insertion mutations may play an important role in the tumorigenesis of Japanese Bowen's disease, and warrants further investigation.

Aged↗

PubMed2000

The influence of combined Fpg- and MutY-deficiency on the spontaneous and gamma-radiation-induced mutation spectrum in the lacZalpha gene of m13mp10.

One of the most predominating oxidative DNA damages, both spontaneously formed and after gamma-radiation is 7, 8-dihydro-8-oxoguanine (8oxoG). This 8oxoG is a mutagenic lesion because it can mispair with adenine instead of the correct cytosine leading to G:C to T:A transversions. In Escherichia coli (E. Coli) base excision repair (BER) is one of the most important repair systems for the repair of 8oxoG and other oxidative DNA damage. An important part of BER in E. coli is the so-called GO system which consists of three repair enzymes, MutM (Fpg), MutY and MutT which are all involved in repair of 8oxoG or 8oxoG mispairs. The aim of this study is to determine the effect of combined Fpg- and MutY-deficiency on the spontaneous and gamma-radiation-induced mutation spectrum of the lacZalpha gene. For that purpose, non-irradiated or gamma-irradiated double-stranded (ds) M13mp10 DNA, with the lacZalpha gene inserted as mutational target sequence was transfected into an E. coli strain which is deficient in both Fpg and MutY (BH1040). The resulting mutation spectra were compared with the mutation spectra of a fpg(-) E. coli strain (BH410) and a wild type E. coli strain (JM105) which were determined in an earlier study. The results of the present study indicate that combined Fpg- and MutY-deficiency induces a large increase in G:C to T:A transversions in both the spontaneous and gamma-radiation-induced mutation spectra of BH1040 (fpg(-)mutY(-)) as compared to the fpg(-) and the wild type strain. Besides the increased levels of G:C to T:A transversions, there is also an increase in G:C to C:G transversions and frameshift mutations in both the spontaneous and gamma-radiation-induced mutation spectra of BH1040 (fpg(-)mutY(-)).

Bacteriophage M13↗

PubMed2000

An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA).

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons in the spinal cord, causing progressive weakness of the limbs and trunk, followed by muscle atrophy. SMA is one of the most frequent autosomal recessive diseases, with a carrier frequency of 1 in 50 and the most common genetic cause of childhood mortality. The phenotype is extremely variable, and patients have been classified in type I-III SMA based on age at onset and clinical course. All three types of SMA are caused by mutations in the survival motor neuron gene (SMN1). There are two almost identical copies, SMN1 and SMN2, present on chromosome 5q13. Only homozygous absence of SMN1 is responsible for SMA, while homozygous absence of SMN2, found in about 5% of controls, has no clinical phenotype. Ninety-six percent of SMA patients display mutations in SMN1, while 4% are unlinked to 5q13. Of the 5q13-linked SMA patients, 96.4% show homozygous absence of SMN1 exons 7 and 8 or exon 7 only, whereas 3. 6% present a compound heterozygosity with a subtle mutation on one chromosome and a deletion/gene conversion on the other chromosome. Among the 23 different subtle mutations described so far, the Y272C missense mutation is the most frequent one, at 20%. Given this uniform mutation spectrum, direct molecular genetic testing is an easy and rapid analysis for most of the SMA patients. Direct testing of heterozygotes, while not trivial, is compromised by the presence of two SMN1 copies per chromosome in about 4% of individuals. The number of SMN2 copies modulates the SMA phenotype. Nevertheless, it should not be used for prediction of severity of the SMA.

Amino Acid Sequence↗