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PubMed2003

The mutational spectrum of the HPRT gene from human T cells in vivo shares a significant concordant set of hot spots with MNNG-treated human cells.

The preponderance of G:C to A:T transitions in inherited and somatic human mutations has led to the hypothesis that some of these mutations arise as a result of formation of O(6)-methylguanine in DNA. To test this hypothesis, the fine structure map of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced mutations was determined in human lymphoblastoid cells in the human hypoxanthine-guanine-phosphoribosyltransferase (HPRT) gene and compared with HPRT mutations observed in somatic T lymphocytes from normal individuals. Human TK6 cells, which are methylguanine methyltransferase deficient (MGMT(-)), were treated with the methylating agent MNNG to create a level of O(6)-methylguanine in cellular DNA equal to that found in normal human tissues. A total of 676 bp of the HPRT gene was scanned using constant denaturing capillary electrophoresis and high-fidelity PCR. MNNG induced 14 predominant hot spots, all which were G:C to A:T transitions. Thirteen of these 14 MNNG-induced hot spots were found among the in vivo set, and 10 of the MNNG-induced hot spots were among 75 putative in vivo hot spots (mutations observed two or more times in vivo). Using a hypergeometric test for concordance, the MNNG-induced hot spots were found to be a significant subset of the putative in vivo hot spots (P < 4 x 10(-7)). The set of shared hot spots comprise some 18% of the HPRT in vivo hot spot spectrum and strongly suggest that MNNG-induced hot spots in vitro share a common mutational pathway with a significant subset of somatic mutations in vivo.

Cell Survival↗
PubMed2005

Mutation spectrum of the APC gene in 83 Korean FAP families.

Familial adenomatous polyposis (FAP) is a clinically well-defined hereditary disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP is characterized by polyposis in the large bowel and variable extracolonic manifestations. With an increase of reported APC germline mutations, many reports have investigated genotype-phenotype correlations in FAP patients. Here, we analyzed the APC gene for germline mutations in 83 unrelated Korean FAP patients and investigated genotype-phenotype correlations. We identified germline APC mutations in 59 (71%) of the cases, including 34 frameshift mutations, 19 nonsense mutations, and six splice site mutations. Among 59 patients with the identified germline mutation of the APC gene, 37 had been reported previously and were included in the genotype-phenotype analysis. In the other 22 patients, we identified seven novel mutations: c.1438C>T, c.2232_2233dupCT, c.3426delT, c.3739_3769del31, c.3931_3935delATTGG, c.4332dupA, and c.4722_4725delACTA. Desmoid tumors were identified in six of the examined FAP patients, five of whom had APC germline mutations; these mutations involved codons 849, 864, 1309, 1444 and 1464, respectively (c.2547_2548delTA, c.2592_2593insCT, c.3927_3931delAAAGA, c.4332dupA and c.4391-4394delAGAG). Four of the included FAP patients had papillary thyroid cancers; all were female and had germline APC mutations (c.1863_1865delTTAincCT, c.2805C>A, c.3183_3187delACAAA and c.3927_3931delAAAGA).

Adenomatous Polyposis Coli↗
PubMed2003

Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy.

Defects in nine sarcomeric protein genes are known to cause hypertrophic cardiomyopathy (HCM). Mutation types and frequencies in large cohorts of consecutive and unrelated patients have not yet been determined. We, therefore, screened HCM patients for mutations in six sarcomeric genes: myosin-binding protein C3 (MYBPC3), MYH7, cardiac troponin T (TNNT2), alpha-tropomyosin (TPM1), cardiac troponin I (TNNI3), and cardiac troponin C (TNNC1). HCM was diagnosed in 108 consecutive patients by echocardiography (septum >15 mm, septal/posterior wall >1.3 mm), angiography, or based on a state after myectomy. Single-strand conformation polymorphism analysis was used for mutation screening, followed by DNA-sequencing. A total of 34 different mutations were identified in 108 patients: 18 mutations in MYBPC3 in 20 patients [intervening sequence (intron) 7 + 1G > A and Q1233X were found twice], 13 missense mutations in MYH7 in 14 patients (R807H was found twice), and one amino acid change in TPM1, TNNT2, and TNNI3, respectively. No disease-causing mutation was found in TNNC1. Cosegregation with the HCM phenotype could be demonstrated for 13 mutations (eight mutations in MYBPC3 and five mutations in MYH7). Twenty-eight of the 37 mutation carriers (76%) reported a positive family history with at least one affected first-grade relative; only eight mutations occurred sporadically (22%). MYBPC3 was the gene that most frequently caused HCM in our population. Systematic mutation screening in large samples of HCM patients leads to a genetic diagnosis in about 30% of unrelated index patients and in about 57% of patients with a positive family history.

Adult↗
PubMed1994

Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation.

We have characterized the disease-causing mutations in the steroid 21-hydroxylase genes of 127 patients with different clinical forms of congenital adrenal hyperplasia, representing 186 unrelated chromosomes. The gene was completely absent on 29.8% of the chromosomes, and this together with the I2 splice (27.7%), I173N (20.8%), V282L (5.4%), and R357W (3.8%) mutations constitute 87.5% of all affected chromosomes. In total, 15 different sequence aberrations combine to form 19 different disease-causing alleles. The results confirm that genotyping is an efficient means of diagnosing steroid 21-hydroxylase deficiency, although special consideration is needed to resolve genotypes when full families are not available. Clinical presentations of the different combinations of mutations indicate that genotyping is reliable for prediction of clinical outcome in patients with 21-hydroxylase deficiency. It is especially helpful in determining whether in utero treatment of affected females is indicated and in classifying the severity of 21-hydroxylase deficiency in children diagnosed through neonatal screening, before symptoms have appeared.

Adrenal Hyperplasia, Congenital↗
PubMed1991

Mutation spectrum of copper-induced DNA damage.

The ability of metal ions to damage DNA and cause mutagenesis has been analyzed with reversion and forward mutation assays using single-stranded DNA templates. We previously reported that incubation of phi X174 am3 DNA with Fe2+ in vitro results in mutagenesis when the treated DNA is transfected into Escherichia coli spheroplasts (Loeb, L. A., James, E. A., Waltersdorph, A. M., and Klebanoff, S. J. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 3918-3922, 1988). We now extend these studies to other metal ions. Of the metal ions tested, copper ions were the most mutagenic; the frequency of mutants produced was equal to or greater than that produced by Fe2+. Mutagenesis by Cu+ was diminished by catalase, mannitol, and superoxide dismutase suggesting the involvement of H2O2, hydroxyl ions, and superoxide, respectively. However, the findings that Cu+ and Cu2+ are nearly equally mutagenic and that the mutagenic activities are not completely inhibited by oxygen free radical scavengers make it unlikely that the mechanism for mutagenesis is simply the production of hydroxyl free radicals. The spectra of mutations produced by either copper ion using the lacZ gene as a target are very similar and differ from those reported with other agents. The predominant mutagenic sequence changes are single-base substitutions, the most frequent being replacement of a template C by a T. This transition presumably results from mispairing of an altered C with deoxyadenosine. Copper-induced mutations are not randomly distributed. Instead, they are found predominantly in clusters suggesting direct interaction of copper ions with specific nucleotide sequences in DNA. Evidence is considered that the high frequency of C----T transitions may be a common manifestation of DNA damage by oxygen radicals.

Bacteriophage phi X 174↗
PubMed2003

The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNALys gene.

In a case of childhood-onset myoclonus epilepsy with "ragged-red fibers" (MERRF), a hitherto unreported mutation within the mitochondrial tRNA(Lys) gene was identified as the cause of the disease. Substitution G8361A was maternally inherited, heteroplasmic in all tissues tested, and correlated with mitochondrial dysfunction in individual muscle fibers. The growing number of MERRF-associated mutations within the tRNA(Lys) gene affirms the specific role of this mitochondrial tRNA in the pathogenesis of the disease.

Amino Acid Substitution↗
PubMed2000

Mutation spectrum and predicted function of laforin in Lafora's progressive myoclonus epilepsy.

BACKGROUND: Lafora's disease is a progressive myoclonus epilepsy with pathognomonic inclusions (polyglucosan bodies) caused by mutations in the EPM2A gene. EPM2A codes for laforin, a protein with unknown function. Mutations have been reported in the last three of the gene's exons. To date, the first exon has not been determined conclusively. It has been predicted based on genomic DNA sequence analysis including comparison with the mouse homologue. OBJECTIVES: 1) To detect new mutations in exon 1 and establish the role of this exon in Lafora's disease. 2) To generate hypotheses about the biological function of laforin based on bioinformatic analyses. METHODS: 1) PCR conditions and components were refined to allow amplification and sequencing of the first exon of EPM2A. 2) Extensive bioinformatic analyses of the primary structure of laforin were completed. RESULTS: 1) Seven new mutations were identified in the putative exon 1. 2) Laforin is predicted not to localize to the cell membrane or any of the organelles. It contains all components of the catalytic active site of the family of dual-specificity phosphatases. It contains a sequence predicted to encode a carbohydrate binding domain (coded by exon 1) and two putative glucohydrolase catalytic sites. CONCLUSIONS: The identification of mutations in exon 1 of EPM2A establishes its role in the pathogenesis of Lafora's disease. The presence of potential carbohydrate binding and cleaving domains suggest a role for laforin in the prevention of accumulation of polyglucosans in healthy neurons.

Adolescent↗
PubMed2005

Mutation spectrum leading to an attenuated phenotype in dystrophinopathies.

Although Becker muscular dystrophy (BMD; MIM 300376) is mainly caused by gross deletions of the dystrophin gene, the nature of the mutations involved in the remaining cases is of importance because of the milder clinical course of Becker. We have extensively characterized the mRNA changes associated with five novel point mutations giving rise to a Becker phenotype, which confirm that Becker arises largely due to alterations in splicing. In two cases the milder phenotype arises because of exon skipping, leading to an in-frame deletion (c.1603-2A>C and c.4250T>A). In further two cases intronic mutations (c.4519-5C>G and c.961-5925A>C) result in complex splicing changes, but with some residual normal transcripts. The last case, c.10412T>A (p.Leu3471X), results in a truncated transcript missing only part of the COOH terminal of the protein, suggesting that this region is not crucial for dystrophin function. The detection of a low amount of dystrophin in this patient could be attributable to a reduced efficiency of nonsense-mediated decay. The results emphasize that mRNA analysis is important in defining Becker mutations and will be of value in assessing various gene therapy strategies.

Adolescent↗
PubMed1995

The mutational spectrum in Waardenburg syndrome.

One hundred and thirty-four families or individuals with auditory-pigmentary syndromes such as Waardenburg syndrome (WS) or probable neurocristopathies were screened for mutations in the PAX3 and MITF genes. PAX3 mutations were found in 20/25 families with definite Type 1 WS and 1/2 with Type 3 WS, but in none of 23 with definite Type 2 WS or 36 with other neurocristopathies. The PAX3 mutations included substitutions of conserved amino acids in the paired domain or the homeodomain, splice-site mutations, nonsense mutations and frame-shifting insertions or deletions. No phenotype-genotype correlations were noted within WS1 families. With MITF, mutations likely to affect protein function were found in seven families, five of which had definite Type 2 WS. We conclude that Type 1 and Type 3 WS are allelic and are normally caused by loss of function mutations in PAX3; that Type 2 WS is heterogeneous, with about 20% of cases caused by mutations in MITF, and that individuals with auditory, pigmentary or neural crest syndromes which do not fit stringent definitions of Waardenburg syndrome are unlikely to have mutations in either the PAX3 or MITF genes. The molecular pathology of MITF/microphthalmia mutations appears to be different in humans and mice, with gene dosage having more significant effects in humans than in the mouse.

Amino Acid Sequence↗
PubMed2000

Increased mutant frequency and altered mutation spectrum of the lacI transgene in Wilson disease rats with hepatitis.

The mutant strain Long-Evans Cinnamon (LEC) rat, which accumulates copper in the liver because of a mutation in the Atp7b gene, encoding a copper-ATPase, is a model of Wilson disease. It spontaneously develops hepatitis, and subsequently hepatocellular carcinoma and cholangiofibrosis. Excess intracellular copper has been thought to induce DNA damage through reactive oxygen species produced by Cu (II)/Cu (I) redox cycling, and also by direct interaction with DNA. We have developed lacI transgenic Wilson disease (WND-B) rats by mating LEC with Big Blue F344 rats carrying a lambda shuttle vector harboring the lacI gene. lacI mutations of the livers of C-B heterozygous (Atp7b w/m, lacI) and WND-B homozygous (Atp7b m/m, lacI) rats at 6, 24, and 40 weeks of ages were analyzed. Mutant frequencies in the WND-B rats were 2.0 +/- 0.7 x 10(-5), 5.3 +/- 0.9 x 10(-5), and 5.3 +/- 1.0 x 10(-5), respectively, significantly higher than those of C-B rats. Nucleotide sequence analysis revealed that the frequency of deletion mutations of more than two nucleotides were much higher, 15% in WND-B rats, but only 2% in C-B rats. In addition, the average size of deletion was larger in the former. Loss of oligonucleotide-repeat units was specific and relatively frequent in WND-B rats. This type of mutation might be implicated in the induction of DNA strand scissions by reactive oxygen species. These findings suggest that the increase in mutant frequencies and/or the specific type of mutation according to copper accumulation play a crucial role in hepatocarcinogenesis in LEC rats.

Adenosine Triphosphatases↗
PubMed2005

Hereditary angioedema: the mutation spectrum of SERPING1/C1NH in a large Spanish cohort.

Hereditary angioedema (HAE) is a disease caused by defects in the C1 inhibitor gene (SERPING1/C1NH). We screened the entire C1NH gene for mutations in a large series of 87 Spanish families (77 with type I, and 10 with type II HAE) by SSCP, sequencing, Southern blotting, and quantitative multiplex PCR of short fluorescent fragments (QMPSF), and we characterized several defects at the mRNA level. We found large rearrangements in 13 families, and point mutations or microdeletions/insertions in 74 families. The 13 large rearrangements included nine exon deletions, of which at least eight were distinct, two were distinct exon duplications, and two were rearrangements whose precise nature could not be determined. We confirmed that exon 4 is particularly prone to rearrangements. Thirty-six mutations were unreported, and included 10 microdeletions/insertions, 10 missense, five nonsense, eight splicing, and three splicing or missense mutations. Moreover, we detected six novel uncharacterized sequence variants (USV). RT-PCR studies showed that in addition to several intronic splice site mutations tested, the exonic mutations c.882C>G and c.884T>G, located near the 3' end of exon 5, also produced exon skipping. This is the first evidence of SERPING1/C1NH mutations in coding regions that differ from the canonical splice sites that affect splicing, which suggests the presence of an exonic splicing enhancer (ESE) in exon 5.

Alternative Splicing↗
PubMed1997

The factor V Leiden mutation: spectrum of thrombotic events and laboratory evaluation.

PURPOSE: This study aims to describe the spectrum of clinical thrombotic events and to compare the methods of laboratory evaluation for the newly described prothrombotic factor V Leiden mutation. METHODS: Specimens from 1376 patients with thrombotic events or their relatives were tested for the factor V Leiden mutation by polymerase chain reaction plus restriction digest from Jan. 1, 1995, to Mar. 31, 1996. Activated protein C (APC) resistance test data was available for 554 of these patients. Clinical information was available for 166 patients with the mutation. RESULTS: Of 1376 patients tested for factor V Leiden mutation, 270 (19.6%) were positive, with 12 homozygotes and 258 heterozygotes. Of 554 patients for whom APC resistance data was available, 221 (39.9%) had low APC resistance ratios (< or = 2.4); of these only 97 (43.9%) were factor V Leiden-positive. Among 333 samples with normal or elevated APC resistance ratios, 19 (5.7%) were later identified with the factor V Leiden mutation, despite the normal screening test. One hundred fourteen of 166 patients (68.7%) with the mutation had at least one thrombotic event, most commonly deep venous thrombosis and pulmonary embolus. Arterial cerebrovascular thrombotic events occurred in 11 patients (10%), and myocardial infarctions in eight (7%). The mean age of all patients with arterial thrombotic events was 45.4 years. CONCLUSIONS: The factor V mutation is a common cause of venous thromboses but may also be associated with the early presentation of arterial thrombotic events. The APC resistance test is a sensitive screening assay but has limitations of its specificity in clinical practice.

Adolescent↗
PubMed2002

The mutation spectrum of hyperphenylalaninaemia in the Republic of Ireland: the population history of the Irish revisited.

Phenylketonuric and hyperphenylalaninaemic patients in the population of the Republic of Ireland were screened for mutations at the human phenylalanine hydroxylase (PAH) locus. A composite data set for the island of Ireland was generated by merging the findings of this study with extant data for Northern Ireland. Analysis of this data on the basis of the four historic provinces (Munster, Leinster, Connacht and Ulster) revealed genetic diversity that is informative in terms of demographic forces that shaped the Irish population. R408W, the predominant Irish PAH mutation associated with haplotype 1.8, reached its highest relative frequency in the most westerly province, Connacht. This suggests that the gradient of R408W-1.8 observed across north-western Europe continues into Ireland and peaks in Connacht. Spatial autocorrelation analysis demonstrated that the gradient is consistent with a localised cline of R408W-1.8 likely to have been established by human migration. This and parallel allele frequency clines may represent the genetic traces of the Palaeolithic colonisation of Europe, a pattern not substantially altered in north-western Europe by subsequent Neolithic migrations. An analysis of mutant allele distributions in Ulster, Scotland and the rest of Ireland confirmed that Ulster has been a zone of considerable admixture between the Irish and Scottish populations, indicating a proportion of Scottish admixture in Ulster approaching 46%. Mutations primarily associated with Scandinavia accounted for 6.1% of mutations overall, illustrating the influence of Viking incursions on Irish population history.

Amino Acid Substitution↗
PubMed2002

The mutational spectrum of brachydactyly type C.

Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.

Animals↗
PubMed2006

An updated mutation spectrum in an Australian series of PJS patients provides further evidence for only one gene locus.

The genetic predisposition Peutz-Jeghers Syndrome (PJS) has been shown to be associated with mutations in the serine threonine kinase 11 (STK11) gene but only a proportion of probands have been shown to harbour changes in the gene. The remaining patients were proposed to be either associated with a second PJS gene or they harboured more cryptic mutations within the STK11 gene itself. With the introduction of the multiplex ligation probe amplification (MLPA) assay, large sequence losses or gains can be more readily identified. In this report we have screened 33 PJS patients from unrelated families, employing a combination of denaturing high-performance liquid chromatography, direct DNA sequencing and the MLPA assay to identify deleterious changes in the STK11 gene. The results revealed that 24 (73%) of patients diagnosed with PJS-harboured pathogenic mutations in the STK11 gene, including 10 (36%) with exonic or whole-gene deletions. No phenotypic differences were identified in patients harbouring large deletions in the STK11 gene compared to patients harbouring missense or nonsense mutations. Mutation analysis in PJS should include techniques such as MLPA to identify large exonic or whole-gene deletions and rearrangements. The high proportion of families with identifiable mutations in the STK11 gene using this range of techniques suggests that most, if not all PJS, is attributable to mutations in the STK11 gene, perhaps including as yet undiscovered changes in promoter or enhancer sequences or other cryptic changes.

AMP-Activated Protein Kinase Kinases↗
PubMed2005

Clinical and mutational spectrum of Mowat-Wilson syndrome.

Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.

Abnormalities, Multiple↗