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At least 811 records · Page 45Linked to original sources
PubMed2005

Mutation scanning by meltMADGE: validations using BRCA1 and LDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population.

We have developed a mutation-scanning approach suitable for whole population screening for unknown mutations. The method, meltMADGE, combines thermal ramp electrophoresis with MADGE to achieve suitable cost efficiency and throughput. The sensitivity was tested in blind trials using 54 amplicons representing the BRCA1 coding region and a panel of 94 unrelated family breast cancer risk consultands previously screened in a clinical diagnostic laboratory. All 10 common polymorphisms, 15/15 previously identified disease-causing mutations, and three previously untested single base changes were identified. Assays of LDLR exons 3 and 8 were validated in 460 familial hypercholesteremics and detected 8/9 known variants. We then applied the exon 3 assay in several DNA banks representing approximately 8000 subjects with known cholesterol values and applied both assays in one DNA bank (n = 3600). In exon 3 we identified one previously reported moderate mutation, P84S (n = 1), also associated with moderate hypercholesteremia in this subject; an unreported silent variant, N76N (n = 1); and known severe hypercholesteremia splice mutation 313+1G-->A (n = 2). Around exon 8 we identified a paucimorphism (n = 35) at the splice site 1061-8T-->C (known to be in complete linkage disequilibrium with T705I) and unreported sequence variants 1186+11G-->A (n = 1) and D335N G-->A (n = 1). The cholesterol value for D335N was on the 96.2 percentile and for T705I, 2/35 carriers were above the 99th percentile. Thus, variants with predicted severe, moderate, and no effect were identified at the population level. In contrast with case collections, CpG mutations predominated. MeltMADGE will enable definition of the full population spectrum of rare, paucimorphic, severe, moderate (forme fruste), and silent mutations and effects.

Breast Neoplasms↗
PubMed2005

Acute myeloid leukaemia with FLT3 gene mutations of both internal tandem duplication and point mutation type.

FLT3 gene mutations, either internal tandem duplication or point mutation type, are common in acute myeloid leukaemia (AML). We describe 21 AML cases with both types of gene mutations, so-called dual mutations, representing approximately 1% of all cases. Most newly diagnosed AML with FLT3 dual mutations had monocytic differentiation and a normal karyotype. Over the disease course, changes in FLT3 mutation status were seen in 89% of cases, and were associated with cytogenetic changes. We conclude that FLT3 dual mutations occur rarely in AML, and appear to be related to clonal evolution.

Acute Disease↗
PubMed2006

Does the prevalence of gsp mutations in GH-secreting pituitary adenomas differ geographically or racially? Prevalence of gsp mutations in Japanese patients revisited.

OBJECTIVE: The prevalence of gsp mutations in GH-secreting pituitary adenomas was thought to differ geographically or racially, given its exceptionally lower incidence among Japanese patients (4.4-9.3%) compared to other regions (30-50%). However, this notion is now being challenged after a recent paper reported a 53.3% incidence among Japanese with acromegaly. We have since re-evaluated the prevalence of gsp mutations on a larger scale. PATIENTS: One hundred Japanese acromegaly patients with surgically confirmed GH-secreting pituitary adenomas were enrolled. METHODS: mRNAs from primary cultured adenomas were used for reverse transcriptase-polymerase chain reaction and direct sequencing of the Gsalpha subunit. Patient data were reviewed from medical charts. RESULTS: There were 53 gsp mutations (53%), consisting of 42 Arg201Cys, one Arg201His, one Arg201Ser, 8 Gln227Leu, and one Gln227Arg mutation. Age at operation, sex ratio, basal serum GH and IGF-I levels were no different with or without the mutations. In contrast, patients responded differently to most dynamic tests with statistical significance: serum GH levels in gsp-positive patients had blunted response to GHRH, were well suppressed by bromocriptine, and had higher rates of paradoxical response to TRH. Notably, paradoxical response to LHRH was observed exclusively in gsp-negative patients. Octreotide suppressed GH levels strongly regardless of gsp status. These clinical characteristics are similar to those of Caucasian patients. CONCLUSION: We conclude that the prevalence of gsp mutations in Japanese acromegaly patients is comparable to those of other reports from various regions. Therefore, Japanese patients do not stand as an example for geographical or racial difference in the prevalence of gsp mutations in GH-secreting pituitary adenomas.

Acromegaly↗
PubMed2005

Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene.

Wilson disease (WD) is a copper metabolism disorder characterized by hepatic and/or neurological damage. More than 200 mutations in the ATP7B gene causing this autosomal recessive defect have been reported. In certain populations, a high prevalence of particular mutations allows rapid screening and diagnosis of the disease. We identified the ATP7B alterations in Spanish patients with WD. Mutations in the ATP7B gene were analysed in a total of 64 individuals from 40 different WD families by PCR amplification, single-strand conformation polymorphism (SSCP) analysis and sequencing. Twenty-one different ATP7B gene mutations were identified, eight of which were novel. 74% of the disease alleles were characterized among the 40 unrelated probands. We identified a prevalent mutation in our population (Met645Arg), present in 55% of this 40 patients. The frequency of the remaining ATP7B alterations was low. In addition, 17 different polymorphic variants were found. There is remarkable allele heterogeneity in WD in the Spanish population. Nevertheless, SSCP screening for the most frequent mutations in our population is feasible and leads to the detection of about 74% of the mutated chromosomes. Molecular diagnosis of WD is very useful in clinical practice to confirm or support clinical suspicion.

Adenosine Triphosphatases↗
PubMed2004

Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.

This study investigated the prevalence of insulin promoter factor-1(IPF-1) mutations in familial early-onset diabetes mellitus in Trinidad. We screened 264 unrelated subjects with type 2 diabetes diagnosed before 40 yr of age and a family history of diabetes for mutations in the minimal promoter and coding region of the IPF-1 gene (IPF1). This study population included 169 patients of East Indian descent (Indo-Trinidadians), 66 of African descent (Afro-Trinidadians), and 29 of mixed ancestry. We identified five IPF1 variants, including one new missense mutation E224K, the previously described diabetes-associated duplication P242 P243dupP, two silent mutations in the codons for Leu54 (c.162G>A) and Ala256 (c.768C>A), and a substitution in the 5'-untranslated region (c.-18C>T). The E224K mutation was found in two unrelated diabetic Indo-Trinidadians and 0 of 60 controls. It was present on the same haplotype in both patients suggesting a founder effect. The E224K mutation cosegregated with early-onset diabetes or impaired glucose tolerance in a large family, suggestive of the type 4 form of maturity-onset diabetes of the young rather than type 2 diabetes. Functional studies of E224K showed reduced transactivation activity. IPF1 mutations leading to synthesis of a mutant protein may contribute to the development of familial early-onset diabetes/maturity-onset diabetes of the young in Indo-Trinidadians.

Adult↗
PubMed2002

A novel nonstop mutation in the stop codon and a novel missense mutation in the type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing, respectively, nonclassic and classic 3beta-HSD deficiency congenital adrenal hyperplasia.

We investigated two novel point mutations in the human type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing a mild and a severe form of 3beta-HSD deficiency congenital adrenal hyperplasia. The first is a nonstop mutation in the normal stop codon 373 of the gene in exon IV [TGA (Stop) --> TGC (Cys) = Stop373C) identified from one allele of a female child with premature pubarche whose second allele had an E142K mutation. The Stop373C mutation predictably results in an open reading frame and a mutant-type (MT) II 3beta-HSD protein containing 467 amino acid residues, compared with the 372 amino acid residues of wild-type (WT) protein. The second is a homozygous missense mutation in codon 222 [CCA (Pro) --> ACT (Thr) = P222T] in the gene identified from a female neonate with salt-wasting disorder. The pcDNA vectors containing the constructs of WT II 3beta-HSD cDNA, WT cDNA with the open reading frame (WT cDNA(+)), MT Stop373C with the open reading frame (Stop373C(+)) and MT P222T cDNA were transfected in COS-I and 293T cells and expressed a similar amount of 3beta-HSD mRNA. The enzyme activity in intact cells using pregnenolone and dehydroepiandrosterone as substrate in the medium (1 micromol/liter) was identical between the WT cDNA and the WT cDNA(+), but was decreased to 27% of the WT enzymes at 6 h by MT Stop373C(+) enzyme, and was undetectable by P222T enzyme. In the homogenates of the cells, both MT Stop373C(+) and P222T enzyme activities and enzymes were undetectable despite clear detection of WT enzyme activities and WT enzymes. LH response to an LHRH analog stimulation in the pubertal female with the Stop373C/E142K genotypes and in a pubertal female with compound 273/318 frameshift genotypes were comparable to and higher than control females, respectively. In conclusion, a structurally lengthy MT II 3beta-HSD enzyme due to a nonstop mutation was relatively detrimental in intact cells causing the nonclassic phenotype of 3beta-HSD deficiency. A missense P222T mutation was seriously detrimental, causing the classic phenotype of 3beta-HSD deficiency. The undetectable Stop373C and P222T enzymes on Western blottings, together with the respective in vivo and in vitro data, suggest that a relative instability of Stop373C enzyme and a profound instability of the P222T enzyme are likely the detrimental molecular mechanisms. The increased LH in the female with the frameshift genotype and the appropriate LH response in the female with the nonstop genotype correlated with predictably severe and mild ovarian type II 3beta-HSD deficiency, respectively.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

A specific spectrum of p53 mutations in lung cancer from smokers: review of mutations compiled in the IARC p53 database.

Mutations in the p53 gene are common in lung cancer. Using data from the the International Agency for Research on Cancer p53 mutation database (R1), we have analyzed the distribution and nature of p53 mutations in 876 lung tumors described in the literature. These analyses confirm that G to T transitions are the predominant type of p53 mutation in lung cancer from smokers. The most frequently mutated codons include 157, 158, 179, 248, 249, and 273, and several of them (157, 248, and 273) have been shown to correspond to sites of in vitro DNA adduct formation by metabolites of polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene. Furthermore, most of the base changes at codons 248, 249, and 273 in lung cancer differ from those commonly observed at these codons in other cancers reported in the database. Thus, lung cancer from smokers shows a distinct, unique p53 mutation spectrum that is not observed in lung cancer from nonsmokers. These results further strengthen the association between active smoking, exposure to PAHs, and lung cancer. They also indicate that a different pattern of mutations occurs in nonsmokers, and this observation may help to identify other agents causally involved in lung cancer in nonsmokers.

Binding Sites↗
PubMed1997

Novel mutations and a mutational hotspot in the MODY3 gene.

Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) located on chromosome 12q. We have identified four novel HNF-1alpha missense mutations in MODY3 families. In four additional and unrelated families, we observed an identical insertion mutation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propose that instability of this sequence represents a general mutational mechanism in MODY3. We observed no HNF-1alpha mutations among 86 unrelated late-onset diabetic patients with relative insulin deficiency. Hence mutations in this gene appear to be most strongly associated with early-onset diabetes.

Chromosomes, Human, Pair 12↗
PubMed1998

A heterozygous frameshift mutation of the PTEN/MMAC1 gene in a patient with Lhermitte-Duclos disease - only the mutated allele was expressed in the cerebellar tumor.

Lhermitte-Duclos disease is a rare disorder of the cerebellum which exhibits a focally indolent growth of the cerebellar cortex. The disease is sometimes associated with multiple hamartoma syndrome, or Cowden disease, an autosomal, dominantly inherited cancer syndrome. Germline mutations of the PTEN/MMAC1 gene, a gene recently discovered to be a tumor suppressor, have been documented in four families with Cowden disease. A family member in one of these families have had Lhermitte-Duclos disease, indicating that mutations of the gene are responsible for the development of Lhermitte-Duclos disease. However, the occurrence of Lhermitte-Duclos disease is mostly sporadic. It is unknown whether the PTEN/MMAC1 gene is involved in these cases. We performed a genetic analysis on a patient with Lhermitte-Duclos disease, as well as analyses on his family members, and found a germline mutation of the PTEN/MMAC1 gene. An insertion of A at nucleotide 83 in codon 28 was apparent in both the patient and members of his family. This mutation caused a frame shift that generated a premature stop codon in codon 43. The mutation was heterozygous, although only the mutated allele was expressed in the cerebellar tumor of the patient. A monoallelic expression of the mutated PTEN/MMAC1 gene may have been responsible for the development of a cerebellar tumor in the patient.

Adolescent↗
PubMed1999

Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.

In this study, we report further results of mutation analysis of the ATP7B gene in Wilson disease (WD) patients of Mediterranean origin. A total of 136 WD chromosomes, 73 of which were of Italian, 43 of Turkish, 18 of Sardinian, and two of Spanish origin, were analysed and the mutation characterised in 84.5% of them. We found 50 different mutations of which 19 are novel, including three nonsense, one frameshift, and 15 missense mutations. The mutations detected were rare and mostly found in the compound heterozygous state together with other mutations and only rarely in homozygosity. Most of these mutations lie in the transmembrane and ATP binding loop regions. These data expand our knowledge of both the structure-function relationships of the WD protein and the molecular pathology of WD, thus improving our capability of prevention and genetic counselling.

Adenosine Triphosphatases↗
PubMed2001

Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutations.

We sequenced the complete 16.5-kb mitochondrial genome (mtDNA) in 15 pancreatic cancer cell lines and xenografts. Homoplasmic mtDNA somatic mutations and novel variants were identified in nearly all samples. Southern blot analysis and direct sequencing of mutation sites showed that the intracellular mass of mtDNA was greatly (6-8-fold) increased in pancreatic cancer cells in relation to corresponding normal cells; this property accounted for and greatly facilitated the identification of these mutations among the dense desmoplastic host reaction characteristic of primary pancreatic cancers. Structural characteristics and mathematical modeling of the evolution of mtDNA mutations suggested that many of the mutations identified might represent a random evolution of homoplasmic variants, rather than necessarily being a product of selective pressures. Complete sequencing of the nuclear MnSOD gene, which protects cells from the mitogenic and toxic effects of oxygen radicals, did not reveal any mutations. Nevertheless, the nearly ubiquitous prevalence and high copy number of mtDNA mutations suggest that they be considered of promising clinical utility in diagnostic applications.

Adenocarcinoma↗
PubMed2002

[Possibility of using fusion proteins for detection of nonsense mutations and frame-shift mutations in BRCA1 gene].

The aim of this study was to evaluate the possibility of detecting nonsense and frame-shift mutations in exon 11 of brca1 gene by constructing fusion open reading frame (ORF) "exon 11 ORF-alpha-peptide of beta-galactosidase". The ability/inability of this newly constructed ORF to cause alpha-complementation in E. coli delta M15gal cells transformed by the plasmid with the ORF may reflect the absence/presence of nonsense and frame-shift mutations in the studied fragment. A single ORF fragment of exon 11 of brca1 gene--LacZ' gene was designed in pGEN7Zf plasmid, the plasmid was shown to cause Lac+ phenotype in E. coli delta M15gal. Four frame-shift deletion mutations were introduced into exon 11 sequence in the plasmid. Surprisingly, the frame-shift deletion mutations did not influence the ability of plasmids to induce Lac+ phenotype in E. coli delta M15gal in 3 cases and only one deletion mutation resulted in inability of the plasmid to form Lac+ phenotype in E. coli delta M15gal. We suppose that the phenomenon can be explained by the alpha-peptide translation reinitiation from inframe ATG codons situated within the exon 11 sequence. Seven inframe ATG sequences were found in exon 11, at least two in-frame ATG-containing fragments were demonstrated to cause reinitiation. On the other hand, the only deletion mutation resulted in inability of the plasmid to form Lac+ phenotype in E. coli delta M15gal did not leave LacZ' in-frame ATG in econ 11 sequence. We conclude that it is possible to detect frame-shift mutations by in-frame cloning with the LacZ' reporter gene, but this possibility is strongly impeded by the reinitiation of alpha-peptide translation from the in-frame ATG codons within the studied sequence.

BRCA1 Protein↗
PubMed2003

Common CYP21 gene mutations in Czech patients and statistical analysis of worldwide mutation distribution.

CYP21 gene molecular analysis was performed to determine the mutational analysis of 87 unrelated Czech patients with different forms of steroid 21-hydroxylase deficiency. Eight of the most common point mutations (intron 2 splice, P30L, 8 bp deletion in exon 3, I172N, V281L, Q318X, R356W, P453S) were analyzed using Amplification-created restriction site method. Cluster in exon 6 mutation was analyzed using allele-specific oligonucleotide hybridisation. Deletions and conversions were screened by modification of an sequence specific oligonucleotides hybridisation. The most frequent mutation in Czech patients was intron 2 splice mutation (45.4%). The comparison of mutation frequencies was made among Czech and European population (high frequency of intron 2 splice, 8bp deletion, P30L, P453S and low frequency of deletions/conversions in Czech population) and among Czech and different regions worldwide (low frequency of deletions/large gene conversions, V281L, R356W, high frequency of intron2, 8bp deletion, P30L and P453S in Czech population). We compared common mutation frequencies of different regions worldwide (North and South America, Asia, North Africa, Europe). Significant differencies in selected regions were determined by ANOVA statistical analysis (One-sample t-test, confidence interval) at value of p<0.05.

Adolescent↗
PubMed1993

Four new mutations in the apolipoprotein B gene causing hypobetalipoproteinemia, including two different frameshift mutations that yield truncated apolipoprotein B proteins of identical length.

Familial hypobetalipoproteinemia can be caused by mutations in the apolipoprotein (apo)B gene that interfere with the translation of a full-length apoB molecule. Frequently, a truncated apoB molecule can be detected in the plasma lipoproteins of affected subjects. In this report, we characterize four different apoB gene mutations causing hypobetalipoproteinemia that are associated with the synthesis of truncated apoB proteins. Two of the mutations are nonsense mutations caused by single nucleotide substitutions; these mutations are associated with the production of apoB-32.5 (1473 amino acids) and apoB-82 (3733 amino acids). The other two mutations are single nucleotide deletions (of apoB cDNA nucleotides 7295 and 7359, respectively). The altered reading frames created by these different frameshift mutations terminated with the same stop codon, and both therefore yielded a truncated protein of identical size: apoB-52.8 (2395 amino acids). The two apoB-52.8 proteins differ, however, in the number of novel carboxyl-terminal amino acids introduced by the frameshift. The buoyant density of lipoproteins containing the truncated apoBs was inversely related to the length of the truncated apoB. ApoB-32.5 was present only in high density lipoproteins (HDL) and the d > 1.21 g/ml fraction, whereas apoB-82 was present almost exclusively in very low density lipoproteins (VLDL). ApoB-52.8 was present primarily in VLDL, intermediate density lipoproteins (IDL), and low density lipoproteins (LDL); trace amounts were observed in the HDL.

Adult↗
PubMed1996

Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability.

Adolescent↗
PubMed1996

[Screening for mutations in the PAH gene in Chinese: a new splice and a novel polymorphic mutation].

OBJECTIVE: to screening for novel mutations in the phenylalanine hydroxylase (PAH) genes in Chines as to investigate the molecular basis of phenylketonuria and to raise its diagnosis rate. METHODS: We applied the polymorase chain reaction (PCR) on amplified DNA fragment harboring exon 4 of the PAH gene. For novel mutations detected, the amplified fragments were sequenced by using ds-DNA cycle-sequencing method. RESULTS: Seven out of 24 cases of PKU had different kinds of band-shifting, which are subjected to two patterns of polymorphism. The first one, only in one case, has one mutation band migrating before the normal bands, while, the second one, which was common among the cases, had both the mutation bands running ahead of the normal bands. By sequence analysis, these polymorphic patterns corresponded to two noval mutations. One was a GT-->AT substitution at the 5' splice donor site of intron 4, and the other is an A to C transversion at position-11 of intron 3. CONCLUSION: The two mutations are both first reported. The 5' donor splicing mutation may result in skipping of the preceeding exon during RNA processing. The A to C transversion, which accounted for about 20% of the Chinese PKU alleles is a polymorphism changes.

DNA Mutational Analysis↗
PubMed1997

Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype.

An exacerbated genomic instability characterizes hereditary and sporadic gastrointestinal cancer of the microsatellite mutator phenotype (MMP), generating somatic frameshift mutations in genes containing mononucleotide repeats. We have recently shown that approximately 50, 40, and 30% of MMP+ colon tumors harbor frameshift mutations in (G)8, (A)8, and (C)8 tracks within the proapoptotic gene BAX and the hMSH3 and hMSH6 DNA mismatch repair genes, respectively. Here we report a higher incidence of frameshift mutations in these 3 genes in a panel of 25 MMP+ gastric adenocarcinomas: 64% in BAX and hMSH3, and 52% in hMSH6. These results support a multiple mutator gene model for the stepwise unfolding of the MMP and further illustrate the importance of the escape from apoptosis in gastrointestinal cancer. The tumor suppressor role played by BAX is also supported by the finding of other somatic BAX mutations, including recurrent missense mutations, not only in gastrointestinal cancer of the MMP but also in gastrointestinal cancer without the MMP.

Apoptosis↗
PubMed1997

Detection of Ki-ras mutations by PCR and differential hybridization and of p53 mutations by SSCP analysis in endoscopically obtained lavage solution from patients with long-standing ulcerative colitis.

OBJECTIVES: The goal of this study was the early detection of malignant transformation in patients with long-standing ulcerative colitis; therefore, mutations of the Ki-ras and p53 gene were analyzed in lavage solution and biopsies obtained at surveillance colonoscopy. METHODS: DNA was isolated from 14 patients (nine female, five male) with a history of pancolitis for more than 10 yr. Exon 1 of the Ki-ras gene and exons 5-8 of the p53 gene were amplified via polymerase chain reaction. Mutations of the p53 gene were detected via single-strand conformation polymorphism analysis; point mutations of the Ki-ras gene were hybridized on dot blots with oligonucleotides marked with digoxigenin. RESULTS: Wild-type Ki-ras and wild-type p53 were detected in all cases of ulcerative colitis and in four of seven control patients. In two ulcerative colitis patients, a mutation was found in the Ki-ras gene (Gly --> Asp 12 and Gly --> Val 12), and in one patient, a mutation in exon 5 of the p53 gene. Mutations were found only in the lavage fluid, whereas random biopsies were negative. CONCLUSIONS: From colonic lavage fluid, it is possible to extract DNA of sufficient quantity and quality for polymerase chain reaction-based amplification and subsequent analysis via single-strand conformation polymorphism or hybridization. Mutations were found in three of 14 patients with long-standing ulcerative colitis but were not found in controls. The method may be useful for the screening of such patients.

Aspartic Acid↗