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PubMed1977

Mutator mutations in bacteriophage T4 gene 42 (dHMC hydroxymethylase).

Temperature-sensitive mutations of bacteriophage T4 gene 42 produce diverse effects upon spontaneous mutation rate. G:C vector A:T transition rates are increased, often strongly; frameshift mutation rates are weakly increased; A:T vector G:C transition rates (and perhaps also A:T vector Py:Pu transversion rates) are decreased; and one G:C vector Py:Pu transversion rate is also decreased. These results, together with certain interactions between gene-42 mutator effects and both base analogue mutagenesis and the viral error-prone repair system, suggest that the dHMC hydroxymethylase coded by gene 42 affects mutation rates in a more complex manner than by the simple regulation of the concentration of the DNA precursor dHMCTP.

Base Sequence↗
PubMed1993

Efficient 12-mutation testing in the CFTR gene: a general model for complex mutation analysis.

The identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has led to the identification of more than 225 presumed disease-causing mutations at the locus. The diagnosis of cystic fibrosis or the carrier state by direct DNA analysis is hindered by this large number. A practical assay must be able to detect enough mutations to achieve clinically significant sensitivity. The use of allele-specific oligonucleotide probes is the most promising of the available methods. However, to date this has generally involved tedious probe-by-probe hybridizations, due to variations in the oligonucleotides' denaturation temperatures caused by differences in their G-C base-pair content. We have developed a rapid, cost-effective assay that simultaneously detects 12 CFTR mutations after multiplex polymerase-chain-reaction amplification of genomic DNA. The test may be readily extended to detect additional mutations at minimal increase in the cost per test or the turnaround time. We improve specificity and avoid the need for individual hybridizations by the use of tetramethylammonium chloride to virtually eliminate the effects of G-C differences. Coupled with non-invasive sample-collection methods, this is an immediately practical assay for cystic fibrosis. More generally, it will serve as a model for the development of diagnostic tests in other genetic disorders involving complex mutation analysis.

Cystic Fibrosis↗
PubMed1993

Steroid 21-hydroxylase deficiency: two additional mutations in salt-wasting disease and rapid screening of disease-causing mutations.

A method for genetic diagnosis of steroid 21-hydroxylase deficiency was developed based on allele-specific PCR. With this approach, genotyping of fourteen mutations and diagnosis of homozygous gene deletions can be performed within hours from tissue sampling. One patient with salt-wasting disease had normal genotype at all positions screened. DNA sequencing revealed two novel mutations, a G to C transversion at the conserved splice donor site of intron 7 and a TGG to TAG nonsense mutation at Trp 406 in exon 9. Allele-specific PCR was established also for these mutations and used to screen for their presence in the pseudogene. However, the two novel mutations were not found in at least 34 pseudogenes.

Adrenal Hyperplasia, Congenital↗
PubMed1997

Modulation of disease severity of dystrophic epidermolysis bullosa by a splice site mutation in combination with a missense mutation in the COL7A1 gene.

Dystrophic epidermolysis bullosa (EBD) is a clinically heterogeneous skin disorder, characterized by abnormal anchoring fibrils (AF) and loss of dermal-epidermal adherence. EBD has been linked to the COL7A1 gene at chromosome 3p21 which encodes collagen VII, the major component of the AF. Here we investigated two unrelated EBD families with different clinical phenotypes and novel combinations of recessive and dominant COL7A1 mutations. Both families shared the same recessive heterozygous 14 bp deletion at the exon-intron 115 boundary of the COL7A1 gene. The deletion caused in-frame skipping of exon 115 and the elimination of 29 amino acid residues from the pro-alpha1(VII) polypeptide chain. As a result, procollagen VII was not converted to collagen VII and the C-terminal NC-2 propeptide which is normally removed from the procollagen VII prior to formation of the anchoring fibrils was retained in the skin. All affected individuals also carried missense mutations in exon 73 of COL7A1 which lead to different glycine-to-arginine substitutions in the triple-helical domain of collagen VII. Combination of the deletion mutation with a G2009R substitution resulted in a mild phenotype. In contrast, combination of the deletion with a G2043R substitution led to a severe phenotype. The G2043R substitution was a de novo mutation which alone caused a mild phenotype. Thus, different combinations of dominant and recessive COL7A1 mutations can modulate disease activity of EBD and alter the clinical presentation of the patients.

Adolescent↗
PubMed1997

An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection.

The gene for the most common and severe form of autosomal dominant polycystic kidney disease, PKD1, encodes a 14 kb mRNA that is predicted to result in an integral membrane protein of 4302 amino acids. The major challenge faced by researchers attempting to complete mutation analysis of the PKD1 gene has been the presence of several homologous loci also located on chromosome 16. Because the sequence of PKD1 and its homologs is nearly identical in the 5' region of the gene, most traditional approaches to mutation analysis cannot distinguish sequence variants occurring uniquely in PKD1. Therefore, only a small number of mutations have been identified to date and these have all been found in the 3', unique portion of the gene. In order to begin analysis of the duplicated region of PKD1, we have devised a novel strategy that depends on long-range PCR and a single gene-specific primer from the unique region of the gene to amplify a PKD1-specific template that spans exons 23-34. This 10 kb template, amplified from genomic DNA, can be employed for mutation analysis using a wide variety of sequence-based approaches. We have used our long-range PCR strategy to begin screening for sequence variants with heteroduplex analysis, and several affected individuals were discovered to have clusters of base pair substitutions in exons 23 and 25. In two patients, these changes, identified in exon 23, would be predicted to result in multiple amino acid substitutions in a short stretch of the protein. This clustering of base pair substitutions is unusual and suggests that mutation may result from unique structural features of the PKD1 gene.

Amino Acid Sequence↗
PubMed1990

Conserved cysteine to serine mutation in tyrosinase is responsible for the classical albino mutation in laboratory mice.

Albinism, due to a lack of melanin pigment, is one of the oldest known mutations in mice. Tyrosinase (monophenol oxygenase, EC 1.14.18.1) is the first enzyme in the pathway for melanin synthesis, and the gene encoding this enzyme has been mapped to the mouse albino (c) locus. We have used mouse tyrosinase cDNA clones and genomic sequencing to study the albino mutation in laboratory mice. Within the tyrosinase gene coding sequences, a G to C transversion at nucleotide 308, causing a cysteine to serine mutation at amino acid 103, is sufficient to abrogate pigment production in transgenic mice. This same base pair change is fully conserved in classical albino strains of laboratory mice. These results indicate that a conserved mutation in the tyrosinase coding sequences is responsible for the classical albino mutation in laboratory mice, and also that most albino laboratory mouse strains have been derived from a common ancestor.

Albinism↗
PubMed1996

Dominant negative mutator mutations in the mutL gene of Escherichia coli.

The mutL gene product is part of the dam-directed mismatch repair system of Escherichia coli but has no known enzymatic function. It forms a complex on heteroduplex DNA with the mismatch recognition MutS protein and with MutH, which has latent endonuclease activity. An N-terminal hexahistidine-tagged MutL was constructed which was active in vivo. As a first stop to determine the functional domains of MutL, we have isolated 72 hydroxylamine-induced plasmid-borne mutations which impart a dominant-negative phenotype to the wild-type strain for increased spontaneous mutagenesis. None of the mutations complement a mutL deletion mutant, indicating that the mutant proteins by themselves are inactive. All the dominant mutations but one could be complemented by the wild-type mutL at about the same gene dosage. DNA sequencing indicated that the mutations affected 22 amino acid residues located between positions 16 and 549 of the 615 amino acid protein. In the N-terminal half of the protein, 12 out of 15 amino acid replacements occur at positions conserved in various eukaryotic MutL homologs. All but one of the sequence changes affecting the C-terminal end of the protein are nonsense mutations.

Adenosine Triphosphatases↗
PubMed2000

Japanese individuals do not harbor the T594M mutation but do have the P592S mutation in the C-terminus of the beta-subunit of the epithelial sodium channel: the Ohasama study.

OBJECTIVE: To assess the implications of polymorphisms of the amiloride-sensitive epithelial sodium channel in essential hypertension in the Japanese population by determining the incidence of the T594M mutation in the , subunit of the epithelial sodium channel, and by screening the C-terminus of the epithelial sodium channel. METHODS: Single-strand confirmational polymorphism (SSCP) analysis using two sets of primers which cover the last two-thirds of the last exon coding the B epithelial sodium channel and modification of a specific enzyme restriction site (NlaIII) for the T594M mutation were performed on 803 Japanese subjects. They were randomly selected from the study participants representative of a general population of Ohasama, Japan, who measured their home blood pressure. Polymerase chain reaction (PCR) products presenting a shift in SSCP gel, as well as controls, were directly sequenced by autoanalyser to identify the mutation. RESULTS: SSCP analysis identified altered migration in five subjects. Four SSCP variants found by sequencing were heterogeneous for the P592S (CCT to TCT) mutation conserving the PY motif, although it was not significantly associated with either home or casual blood pressure values. The resting polymorphism was at codon Thr 594, leading to no change in the amino acid sequence (ACG to ACA). None of the PCR products were modified by NlaIII, indicating the absence of the T594M mutation. CONCLUSIONS: The epithelial sodium channel variants at the C-terminus are not involved in the common form of essential hypertension in Japanese.

Adult↗
PubMed1999

Molecular pathology of multiple endocrine neoplasia type I: two novel germline mutations and updated classification of mutations affecting MEN1 gene.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined development of tumors in several endocrine glands and other tissues. The MEN1 gene was recently identified and isolated by positional cloning. This gene was screened in two unrelated MEN1 Spanish kindreds (with four affected members and seven asymptomatic members) using single-strand conformation polymorphism, DNA sequencing, and restriction enzyme analysis. Two novel germline mutations were identified: a missense in exon 2 (H139R) and a splice-site in intron 9 (1461-2A>C). These findings allowed us to identify the MEN1 carriers among the seven asymptomatic members analyzed. An updated review of the mutations and polymorphisms found in the analysis of the MEN1 gene is provided. The report of all germline mutations causing MEN1 and easy access to this updated information are both of special diagnostic interest, because this greatly facilitates the task of attributing the disorder to a specific mutation found in a given MEN1 family. This is especially helpful in the critical differentiation of missense mutations from nonsynonymous polymorphisms that fit the pattern of segregation of the disease, but do not cause it.

Adolescent↗
PubMed1997

Effects of a frequent double-nucleotide basal core promoter mutation and its putative single-nucleotide precursor mutations on hepatitis B virus gene expression and replication.

The basal core promoter (BCP) of hepatitis B virus (HBV) directs the transcription of both precore RNA and core RNA which code for e antigen (HBeAg) and core antigen, respectively. A double mutation in the BCP which converts nucleotide (nt) 1762 from A to T and nt 1764 from G to A is frequently observed in patients with chronic hepatitis B. We recently demonstrated that this double mutation prevented the binding of a liver-enriched factor (LEF) to the BCP, suppressed only precore RNA transcription (and hence HBeAg expression), and enhanced progeny virus production. In order to understand the mechanism for the selection of this frequent double mutation, we have extended our previous studies to further characterize LEF and to compare the effects of this double-nucleotide mutation (M1) with each single-nucleotide mutation at nt 1762 (M2) and nt 1764 (M3). Our results indicate that LEF is likely composed of a heterodimer formed between the transcription factor chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and an unidentified liver-enriched factor. Further studies reveal that both M1 and M2 prevent the binding of LEF to the BCP, suppress only precore RNA transcription, and increase the efficiency of progeny virus synthesis. In contrast, M3 retains some LEF binding activity, does not suppress HBV RNA transcription, and reduces slightly the efficiency of virus progeny synthesis. The reduced ability of M3 to replicate indicates that it has no selection advantage in itself at the level of the infected hepatocyte. In spite of its enhanced replication rate, M2 is rarely detected in HBV patients. This indicates the involvement of factors other than intracellular replication rates in the selection of these virus variants in the infected individual.

Adenine↗
PubMed1999

Mutational analysis of beta-catenin gene in Japanese ovarian carcinomas: frequent mutations in endometrioid carcinomas.

To investigate the contribution of the beta-catenin gene to the development of ovarian carcinomas, mutational analysis of exon 3 of the beta-catenin gene was conducted. We analyzed 61 primary ovarian carcinomas, consisting of 49 non-endometrioid-type and 12 endometrioid-type tumors, for genetic alteration of the beta-catenin gene. Five carcinomas showed beta-catenin mutations (S37C, T41I, T41A), including 4 (33%) of 12 endometrioid-type tumors and 1 (14%) of 7 mucinous-type tumors. All of these mutations altered at the serine/threonine residues that are potential sites of GSK3-beta phosphorylation. We detected no carcinomas with interstitial deletion involving exon 3 of beta-catenin. Furthermore, we immunohistochemically studied 27 of the 61 ovarian carcinomas. Both nuclear and cytoplasmic beta-catenin expressions were demonstrated in 4 of the 27 ovarian carcinomas for which tissue samples were available for examination. All 4 cases exhibited mutations in exon 3 of beta-catenin, including a mucinous carcinoma. Our results suggested that beta-catenin gene mutation at potential GSK3-beta phosphorylation sites results in accumulation of beta-catenin protein within the cells and its translocation to nuclei. Accumulated beta-catenin protein may be involved in the development of endometrioid-type ovarian carcinomas, and some mucinous-type ovarian carcinomas.

Adult↗
PubMed1989

N-RAS mutations in T-cell acute lymphocytic leukaemia: analysis by direct sequencing detects a novel mutation.

A novel mutation of the N-RAS gene of T-ALL blast cells was detected by a direct sequencing of in vitro amplified exon-1 of the N-RAS gene. Threonine (ACA) was substituted for alanine (GCA) at codon 11. This mutation would have been overlooked by conventional probe hybridization techniques. A search for other mutations in N-RAS exon-1 in T-ALL revealed a codon 13 mutation substituting aspartic acid (GAT) for glycine (GGT) in one of 18 patients. No mutations at codon 12 were detected.

Base Sequence↗
PubMed1997

Discordance between malignant hyperthermia susceptibility and RYR1 mutation C1840T in two Scandinavian MH families exhibiting this mutation.

The ryanodine receptor 1 (RYR1) mutation C1840T has been reported to segregate with malignant hyperthermia (MH) susceptibility in several families. We have investigated several Scandinavian MH families with respect to five different RYR1 mutations reported to cause predisposition to MH, and we here report on two of the families in which the C1840T mutation was detected. In these two families there was recombination between MH susceptibility and this mutation in one and three individuals, respectively. These findings may suggest that it is necessary to reconsider the specificity of the IVCT and the role of C1840T as a cause of MH susceptibility in some families exhibiting this mutation.

Anesthesia↗
PubMed2001

Cardiac troponin T mutations: correlation between the type of mutation and the nature of myofilament dysfunction in transgenic mice.

1. The heterogenic nature of familial hypertrophic cardiomyopathy (FHC) in humans suggests a link between the type of mutation and the nature of patho-physiological alterations in cardiac myocytes. Exactly how FHC-associated mutations in cardiac troponin T (cTnT) lead to impaired cardiac function is unclear. 2. We measured steady-state isometric force and ATPase activity in detergent-skinned cardiac fibre bundles from three transgenic (TG) mouse hearts in which 50, 92 and 6 % of the native cTnT was replaced by the wild type (WT) cTnT, R92Q mutant cTnT (R92Q) and the C-terminal deletion mutant of cTnT (cTnT(DEL)), respectively. 3. Normalized pCa-tension relationships of R92Q and cTnT(DEL) fibres demonstrated a significant increase in sensitivity to Ca2+ at short (2.0 microm) and long (2.3 microm) sarcomere lengths (SL). At short SL, the pCa50 values, representing the midpoint of the pCa-tension relationship, were 5.69 +/- 0.01, 5.96 +/- 0.01 and 5.81 +/- 0.01 for WT, R92Q and cTnT(DEL) fibres, respectively. At long SL, the pCa50 values were 5.81 +/- 0.01, 6.08 +/- 0.01 and 5.95 +/- 0.01 for WT, R92Q and cTnT(DEL) fibres, respectively. 4. The difference in pCa required for half-maximal activation (DeltapCa50) at short and long SL was 0.12 +/- 0.01 for the R92Q (92 %) TG fibres, which is significantly less than the previously reported DeltapCa50 value of 0.29 +/- 0.02 for R92Q (67 %) TG fibres. 5. At short SL, Ca2+-activated maximal tension in both R92Q and cTnT(DEL) fibres decreased significantly (24 and 21 %, respectively; P < 0.005), with no corresponding decrease in Ca2+-activated maximal ATPase activity. Therefore, at short SL, the tension cost in R92Q and cTnT(DEL) fibres increased by 35 and 29 %, respectively (P < 0.001). 6. The fibre bundles reconstituted with the recombinant mutant cTnT(DEL) protein developed only 37 % of the Ca2+-activated maximal force developed by recombinant WT cTnT reconstituted fibre bundles, with no apparent changes in Ca2+ sensitivity. 7. Our data indicate that an important mutation-linked effect on cardiac function is the result of an inefficient use of ATP at the myofilament level. Furthermore, the extent of the mutation-induced dysfunction depends not only on the nature of the mutation, but also on the concentration of the mutant protein in the sarcomere.

Actin Cytoskeleton↗
PubMed2005

Double heterozygosity for a novel missense mutation of Ile304 to Asn in addition to the missense mutation His280 to Pro in the integrin beta3 gene as a cause of the absence of platelet alphaIIbbeta3 in Glanzmann's thrombasthenia.

BACKGROUND: Glanzmann's thrombasthenia (GT) is a hereditary bleeding disorder characterized by a defect in the expression or the function of alphaIIbbeta3. OBJECTIVES: The purpose of the present study was to identify genetic defects in a GT patient. METHODS: The expression of alphaIIbbeta3 was determined by flow cytometric analysis and Western blotting. We analyzed the cDNA sequences of both alphaIIb and beta3, and performed transfection experiments using COS7 cells to confirm that a specific mutation was responsible for the GT case. RESULTS: Flow cytometric analysis and Western blotting showed remarkably reduced expression of alphaIIbbeta3. Sequence analysis of the patient's cDNA indicated a new missense mutation that led to the amino acid substitution of Ile304 (ATC) with Asn (AAC) in exon 6 of the beta3 gene. This was in addition to the missense mutation of His280 (CAT) to Pro (CCT) in exon 5, which had been previously reported. The missense mutation of Ile304 (ATC) to Asn (AAC) in beta3 was found to be responsible for this GT case. This was because transfection experiments using COS7 cells indicated that alphaIIbbeta3 possessing Asn304 in beta3 was not expressed on the surface of the transfected cells. In addition, immunoprecipitation analysis demonstrated that alphaIIbbeta3 was absent inside the transfected COS7 cells possessing Asn304 in beta(3). CONCLUSION: In this study, we describe a new missense mutation (ATC to AAC) at position 1009 in exon 6 that leads to an amino acid substitution (Ile304 to Asn) in beta3, which is responsible for this GT case.

Adult↗
PubMed1999

Identification of sporadic mutations in the helix initiation motif of keratin 6 in two pachyonychia congenita patients: further evidence for a mutational hot spot.

Pachyonychia congenita (PC) is a rare, autosomal dominant, ectodermal dysplasia characterized most distinctly by the presence of symmetric nail hypertrophy. In the Jadassohn-Lewandowsky form, or PC-1, additional cutaneous manifestations may include palmoplantar hyperkeratosis, hyperhidrosis, follicular keratoses, and oral leukokeratosis. Mutations have previously been identified in the 1A helix initiation motif of either keratin 6 or keratin 16 in patients with PC-1. In the current study, we have identified 2 sporadic, heterozygous mutations in the 1A helix region of the K6 isoform (K6a). The first mutation identified was a 3 base pair deletion (K6adelta N171). The second mutation was a C-to-A transversion resulting in an amino acid substitution (K6a N171K). These data, in combination with previous reports, provide further evidence that this location is a mutational hot spot.

Amino Acid Sequence↗
PubMed2001

Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester.

PROBLEM: Thrombophilic predisposition may be one of the underlying causes of recurrent spontaneous abortions (RSA). We studied the prevalence of five thrombophilic gene mutations in patients with RSA. METHOD OF STUDY: 102 patients with two or more consecutive abortions and 128 women without miscarriage were analyzed for factor V Leiden mutation (FVL), prothrombin G20210A mutation (PTM), C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, glycoprotein IIIa (GPIIIa) C1565T polymorphism, and beta-fibrinogen G-455A polymorphism by polymerase chain reaction (PCR) techniques. RESULTS: No differences in the prevalence of FVL, MTHFR T/T, GPIIIa and 1-fibrinogen polymorphism were detected. Heterozygous PTM occurred more often in patients with RSA. This effect was significant in a subgroup with abortions exclusively in the first trimester (6.7%, vs. 0.8%, P = 0.027, OR 8.5). CONCLUSIONS: In contrast to the other mutations and polymorphisms, heterozygous PTM is more common in patients with abortions in the first trimester. This might reflect an influence of PTM on pathogenesis of early pregnancy loss.

Abortion, Habitual↗
PubMed1999

Sparfloxacin selects gyrase mutations in first-step Mycoplasma hominis mutants, whereas ofloxacin selects topoisomerase IV mutations.

The role of mutations in the genes for GyrA and ParC in quinolone resistance in Mycoplasma hominis was studied. Selection with sparfloxacin gave mutations at GyrA83 (Ser-->Leu; Escherichia coli numbering) or GyrA87 (Glu-->Lys), and mutants had increased levels of resistance to sparfloxacin (8- to 16-fold) but not to ofloxacin. Selection with ofloxacin gave changes at ParC80 (Ser-->Ile) or ParC84 (Glu-->Lys), and mutants were four- to eightfold more resistant to ofloxacin but not to sparfloxacin. Selection of second-step mutants from strains with ParC mutations with either quinolone yielded double mutants with additional mutations at GyrA83 (Ser-->Trp or Ser-->Leu) or GyrA87 (Glu-->Lys). Second-step selection of GyrA mutants gave additional mutations at ParC80 (Ser-->Ile) or ParC84 (Glu-->Lys). Two-step mutants showed high levels of resistance to ofloxacin (MICs, 64 to 128 microg/ml) and moderate levels of resistance to sparfloxacin (MICs, 2 to 8 microg/ml). The primary target of ofloxacin in first-step mutants of Mycoplasma hominis was ParC, whereas that for sparfloxacin was GyrA.

Anti-Infective Agents↗