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PubMed1981

Relationship between benzo(a)pyrene-induced DNA base modification and frequency of reverse mutations in mutant strains of Salmonella typhimurium.

Salmonella typhimurium cells (TA98 and TA100) were incubated with [3H]benzo(a)pyrene ([3H]BP) and induced rat liver microsomes. The BP-induced cytotoxicity and His+ reverse-mutation frequencies were determined, and bacterial DNA hydrolysates were chromatographed on Sephadex LH-20. Analysis indicated three principal DNA adducts formed from two diastereoisomeric BP diol-epoxides and a 9-hydroxy-benzo(a)pyrene metabolite. An 8.6-fold increase in TA100 cell concentration in the microsome incubation was paralleled by a 7.2-fold decrease in total adducts per cell and a 7.4-fold decrease in mutation frequency. Separate TA98 incubations were titrated with increasing concentrations of [3H](+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene ([3H]anti BP diol-epoxide), [3H](+/-)-7 beta, 8 alpha-dihydroxy-9 beta, 10 beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene [3H]syn BP diol-epoxide), or [3H]9-hydroxybenzo(a)pyrene. Linear, nonsaturated increases in DNA adduct levels were seen up to the highest observed concentrations of 4.00 microM BP diol-epoxide or 6.00 microM 9-hydroxybenzo(a)pyrene in both TA98 and TA100 cells. The increasing adduct levels were accompanied by linearly increasing mutation frequencies. At equivalent concentrations of the two DP diol-epoxides, an average of 8.2-fold more base substitution mutations (TA100) were seen than frameshift mutations (TA98). The results also indicate significant differences in absolute mutagenic efficiency (mutation frequency/unit modified DNA) between these three covalent DNA ligands (TA98, syn BP diolepoxide greater than 9-hydroxy-4,5-epoxy-benzo(a)pyrene greater than anti BP diol-epoxide; TA100, 9-hydroxy-4,5-epoxy-benzo(a)pyrene greater than syn BP diol-epoxide greater than anti BP diol-epoxide).

Animals↗
PubMed1995

Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-->Asp and Leu380-->His) and eight rare mutations of the LDL receptor gene.

Two deletions of the low-density lipoprotein (LDL) receptor gene were previously shown to account for about two thirds of all mutations causing familial hypercholesterolemia (FH) in Finland. We screened the DNA samples from a cohort representing the remaining 30% of Finnish heterozygous FH patients by amplifying all the 18 exons of the receptor gene by PCR and searching for DNA variations with the SSCP technique. Ten novel mutations were identified, comprising two nonsense and seven missense mutations as well as one frameshift mutation caused by a 13-bp deletion. A single nucleotide change, substituting adenine for guanidine at position 2533 and resulting in an amino acid change of glycine to aspartic acid at codon 823, was found in DNA samples from 14 unrelated FH probands. This mutation (FH-Turku) affects the sequence encoding the putative basolateral sorting signal of the LDL receptor protein; however, the exact functional consequences of this mutation are yet to be examined. The FH-Turku gene and another point mutation (Leu380-->His or FH-Pori) together account for approximately 8% of the FH-causing genes in Finland and are particularly common among FH patients from the southwestern part of the country (combined, 30%). Primer-introduced restriction analysis was applied for convenient assay of the FH-Turku and FH-Pori point mutations. In conclusion, this paper demonstrates the unique genetic background of FH in Finland and describes a commonly occurring FH gene with a missense mutation closest to the C terminus thus far reported.

Base Sequence↗
PubMed1996

[Liddle syndrome].

In 1963 Liddle et al. described a disorder that simulated primary aldosteronism, characterized by severe hypertension and hypokalemia but with negligible secretion of aldosterone. They theoried that this was a disorder in which the renal tubules transport ions with such abnormal facility that the end result simulates that of a mineralcorticoid excess. Later, it was postulated that this disorder could be related to the abnormality of amiloride sensitive Na channel. The activity of amiloride-sensitive Na channels constitutes the rate limiting step for Na reabsorption in Na transporting epithelia. Recently, the primary sequence of the rat amiloride-sensitive epithelial Na+ channel (rENaC) was determined by functional expression cloning and shown to be composed of three homologous subunits: alpha, beta, and gamma. Its expression of all three subunits in Xenopus oocytes markedly increased the magnitude of these currents. Analysis of subjects with Liddle's syndrome demonstrates the mutation of carboxy-terminal domain in alpha, beta, and gamma subunits. The mutations are either premature termination, frameshift mutation, or missense mutations.

Alkalosis↗
PubMed2001

Chloroplast lysates support directed mutagenesis via modified DNA and chimeric RNA/DNA oligonucleotides.

Chimeric RNA/DNA and modified DNA oligonucleotides have been shown to direct gene-conversion events in vitro through a process involving proteins from several DNA-repair pathways. Recent experiments have extended the utility of these molecules to plants, and we previously demonstrated that plant cell-free extracts are competent to support oligonucleotide-directed genetic repair. Using this system, we are studying Arabidopsis DNA-repair mutants and the role of plant proteins in the DNA-repair process. Here we describe a method for investigating mechanisms of plastid DNA-repair pathways. Using a genetic readout system in bacteria and chimeric or modified DNA oligonucleotides designed to direct the conversion of mutations in antibiotic resistance genes, we have developed an assay for genetic repair of mutations in a spinach chloroplast lysate system. We report genetic repair of point and frameshift mutations directed by both types of modified oligonucleotides. This system enables the mechanistic study of plastid gene repair and facilitates the direct comparison between plant nuclear and organelle DNA-repair pathways.

Arabidopsis↗
PubMed2000

Genetic alterations in gastric cancer cell lines and their original tissues.

To investigate the genetic changes that occur during establishment of gastric cancer cell lines, 4 gastric cancer cell lines and their original tumor tissues were examined for microsatellite instability (MSI), loss of heterozygosity (LOH), and p53 mutation. MSI status did not change during the establishment, though the cell lines gained frameshift mutation in some of the genes with polytract coding sequences. There was no difference in p53 mutation between the cell lines and the original tumors. The frequency of LOH was similar between the cell lines and each original tumor, in the range 30.8% to 85.7%. The difference in the LOH results between the cell lines and the original tumors was not greater than the difference between the different areas of the original tumors. The above results suggested that most of the genetic alterations, such as MSI, LOH, and p53 gene mutation, were sustained during the establishment of gastric cancer cell lines. Minor genetic differences between original tumor tissues and cancer cell lines could be explained as a tumor heterogeneity because separate areas of the original tumor tissues manifest similar variations.

Frameshift Mutation↗
PubMed2003

Molecular, ultrastructural and functional characterization of a Spanish family with Hermansky-Pudlak syndrome: role of insC974 in platelet function and clinical relevance.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder, which is genetically heterogeneous. In humans, mutations associated with this syndrome have been identified that affect four genes, most of them located in the HPS-1 gene. We evaluated the clinical, molecular, platelet ultrastructure and platelet function data obtained from one Spanish HPS patient and his relatives. The proband was compound heterozygous for a de novo nonsense mutation (Arg-131Stop), which has not been described previously, and for a common frameshift mutation (insC974). These two mutations were also identified by reverse transcription polymerase chain reaction (RT-PCR) in half the RNA, supporting the premise that they have minor effects on either transcription or RNA stability. The patient had an almost complete absence of platelet-dense granules. Accordingly, his platelets showed a small aggregatory response, reduced CD63 surface expression after platelet activation and minor serotonin uptake. Interestingly, despite the absence of clinical symptoms, two relatives carrying only one HPS-1 mutation (insC974) presented a decreased content of platelet-dense granules and showed significant reductions in platelet aggregation, expression of CD63 after platelet activation and serotonin uptake. Data show that the presence of a single mutation affecting one allele of the HPS-1 gene might have relevance in the organogenesis of platelet-dense granules, affecting platelet function. However, these functional defects were not of a great enough magnitude to have clinical significance and, thus, these subjects were clinically asymptomatic.

Blood Platelets↗
PubMed2005

Case reports of oculofaciocardiodental syndrome with unusual dental findings.

We report on two new cases of oculofaciocardiodental (OFCD) syndrome characterized by cataracts, microphthalmia, facial anomalies, cleft palate, cardiac septal defects, and canine radiculomegaly. We also review previous patients. The syndrome is caused by mutations in the BCOR gene, which maps to Xp11.4. Mutational analysis in one of our patients showed a deletion of a single nucleotide, c.2613delC, predicting a novel frameshift mutation with a premature stop codon, p.F871Lfs8X.

Abnormalities, Multiple↗
PubMed1994

Mutagenicity of butadiene and its epoxide metabolites: II. Mutational spectra of butadiene, 1,2-epoxybutene and diepoxybutane at the hprt locus in splenic T cells from exposed B6C3F1 mice.

The mutagenic potential and mutational spectra of butadiene (BD), 1,2-epoxybutene (EB), and diepoxybutane (DEB) were determined in splenic T cells from exposed B6C3F1 mice. Mice exposed by inhalation to 625 p.p.m. BD for 2 weeks displayed an average hprt- mutation frequency of 6.2 x 10(-6) compared to 1.2 x 10(-6) in controls. Mice were also given three daily i.p. doses of 60, 80 and 100 mg EB/kg or 7, 14 and 21 mg DEB/kg. Average hprt- frequencies of 5.4 x 10(-6), 4.1 x 10(-6) and 8.6 x 10(-6) were seen in the EB groups, respectively, while average frequencies of 4.6 x 10(-6), 9.4 x 10(-6) and 13 x 10(-6) were seen in the DEB groups. DNA sequencing revealed that approximately half of the mutations induced in vivo by BD, EB and DEB were frameshift mutations. A +1 frameshift 'hotspot' in six consecutive guanine bases in exon 3 was observed with all three compounds. The remaining mutations produced by BD, EB and DEB were transition and transversion mutations at both AT and GC base pairs. Base pair substitutions induced by BD were biased in favor of mutation at AT base pairs. The mutational spectra produced by BD, EB and DEB were very similar to that observed previously with ethylene oxide, suggesting that these epoxide agents may be working through a similar mutagenic mechanism.

Animals↗
PubMed2005

Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation.

DiGeorge syndrome (DGS) is the most common human chromosomal deletion syndrome and is frequently associated with deletions on chromosome 22q11. Approximately 17% of patients with the phenotypic features of this syndrome have no detectable genomic deletion. Animal studies using mouse models have implicated Tbx1 as a critical gene within the commonly deleted region, and several mutations in TBX1 have been identified recently in non-deleted patients, including missense and frameshift mutations. The mechanisms by which these mutations cause disease have remained unclear. We have identified a previously unrecognized and novel nuclear localization signal (NLS) at the C-terminus of Tbx1 that is deleted by the 1223delC mutation, thus explaining the mechanism of disease in these patients. This NLS is conserved across species, among a subfamily of T-box proteins including Brachyury and Tbx10, and among additional nuclear proteins. By providing functional data to indicate loss-of-function produced by the 1223delC TBX1 mutation, our results provide strong support for the conclusion that TBX1 mutations can cause DGS in humans.

Amino Acid Motifs↗
PubMed2000

Clinical, radiographic, and genetic evaluation of a novel form of autosomal-dominant oligodontia.

A frameshift mutation recently identified within the paired domain of the transcription factor, PAX9, has been linked to a unique form of oligodontia in a single, multigenerational family (Stockton et al., 2000). We now describe the phenotypic and segregation analyses of this remarkable kindred, the initial approach taken to identify a candidate gene involved in this form of oligodontia, and the power of this single-family pedigree to generate significant linkage in a genome search. Of the 43 family members enrolled in this study, 21 individuals were affected with several congenitally missing permanent teeth. The pattern of inheritance of the oligodontia trait suggested the involvement of a single gene bearing a dominant mutation. To various degrees, affected members lacked permanent first, second, and third molars in all four quadrants. Several individuals with missing molars also lacked second premolars- most commonly, maxillary second premolars and mandibular central incisors. To the best of our knowledge, this pattern of non-syndromic, familial tooth agenesis has not been previously described in the literature. Since a missense mutation in the homeobox gene, MSX1, was previously linked to tooth agenesis in a single family lacking second premolars and third molars, we performed a mutational analysis of MSX1 by PCR. The absence of a mutation in exons 1 and 2 of MSX1 suggested that allelic mutations in the coding region of MSX1 are not associated with this phenotypically distinct form of oligodontia. Computer simulation of linkage analysis further proved that this pedigree alone was sufficient to generate a significant result for a total genome scan.

Adolescent↗
PubMed2004

Novel androgen receptor gene mutations in Australian patients with complete androgen insensitivity syndrome.

We have identified androgen receptor (AR) gene mutations in eight Australian subjects with complete androgen insensitivity syndrome (AIS). Four individuals, from three families, have novel mutations that introduce premature termination codons. Two siblings have the nonsense mutation Glu681X, and another subject has the nonsense mutation p.Ser884X. The other subject has a CA insertion at codon 829 (c.2847_2848insCA), causing a frameshift mutation that introduces four nonsense amino acids prior to a Stop codon. All the termination codons occur in the ligand binding domain, and cause reduced androgen binding in patient genital skin fibroblasts. Four further patients have missense mutations. One subject has two different mutations, p.Ala645Asp in the hinge region of the receptor, and p.Arg752Gln in the ligand binding domain. Both these mutations have previously been reported in patients with AIS, but the combination of these two mutations in one subject is unique. Another subject has a novel c.2533G>C transversion at the first nucleotide in exon 5, introducing the amino acid change p.Gly724Ala at a highly conserved residue in the ligand binding domain. Androgen binding is normal in fibroblasts from this subject, although other point mutations at this amino acid totally abolish binding. Two other subjects have mutations previously described as causing AIS, namely p.Arg779Trp and p.Val889Met substitutions in the ligand binding domain of the receptor. The p.Arg779Trp mutation is associated with the detection of a truncated AR protein in this patient's fibroblasts, suggesting the mutation renders the receptor susceptible to proteolysis.

Adult↗
PubMed1997

PIG-A gene mutations in four Taiwanese patients with paroxysmal nocturnal haemoglobinuria following aplastic anaemia.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemolytic disorder caused by deficient biosynthesis of the glycosyl phosphatidylinositol (GPI) anchor in haemopoietic stem cells. PIG-A, an X-linked gene that participates in the first step of GPI-anchor synthesis, is responsible for PNH. Various abnormalities of the PIG-A gene have been demonstrated in all patients with PNH so far examined. In this study we characterized the somatic mutations in PIG-A gene in four Taiwanese patients with PNH. We identified five novel mutations in the PIG-A gene, three single nucleotide substitution mutations (-342, C-->G, codon 335, GGT-->AGT and codon 405, GCT-->GTT) and two frameshift mutations (codon 22, GGA-->G-A and codon 356, TGT-->TGTT) in the PIG-A gene. The -342 mutation was judged to be a polymorphism. Furthermore, three patients had previous clinicopathologic evidence which suggested aplastic anaemia (AA), before the development of PNH. One of these was found to have thrombocytopenia during follow-up. We suggest that the somatic PIG-A gene mutations highlight a subgroup of AA having a pathogenetic link with PNH.

Anemia, Aplastic↗
PubMed2003

Clinical and molecular characterization of 6 patients affected by severe deficiency of coagulation factor V: Broadening of the mutational spectrum of factor V gene and in vitro analysis of the newly identified missense mutations.

Severe factor V (FV) deficiency is a rare bleeding disorder, whose genetic bases have been characterized only in a limited number of cases. We investigated 6 unrelated patients with extremely reduced plasma FV levels, associated with a bleeding tendency ranging from moderately severe to severe. Clinical manifestations were substantially concordant with the previously established spectrum of hemorrhagic symptoms of the disease. Molecular analysis of FV gene identified 9 different mutations, 7 hitherto unknown, and 2 previously reported (Arg712ter and Tyr1702Cys). Four of 6 analyzed patients were compound heterozygotes, indicating the high allelic heterogeneity of this disease. Among novel mutations, 5 led to premature termination codons, because of nonsense (Arg1002ter, Arg1606ter, and Trp1854ter), or frameshift mutations (5127-5128insA and 6122-6123insAACAG). The remaining 2 were missense mutations (Cys472Gly and Val1813Met), located in FV A2 and A3 domains. Their effect on FV expression was studied by transient transfection experiments, demonstrating that the presence of each mutation impaired FV secretion. These data increase the number of severe FV deficiency-causing mutations by about 50%. The high number of "private" mutations identified in FV-deficient families indicates that full mutational screening of FV gene is still required for molecular diagnosis.

Adolescent↗
PubMed1994

Identification of comS, a gene of the srfA operon that regulates the establishment of genetic competence in Bacillus subtilis.

Genetic competence (the ability to internalize exogenous DNA) in Bacillus subtilis is dependent on a regulatory pathway that activates the expression of a battery of competence-specific genes. The srfA operon, encoding the subunits of surfactin synthetase, which catalyzes the nonribosomal synthesis of the peptide antibiotic surfactin, also functions in the competence regulatory pathway. The DNA encoding only one of the seven amino acid-activating domains of surfactin synthetase, the valine-activating domain (srfAB1), is necessary for competence. Deletion analysis revealed that a 569-bp fragment of srfAB1, fused to the srfA promoter, complements a srfA deletion mutation (delta srfA) with respect to competence. This fragment contains an open reading frame consisting of 46 amino acids (orf46), which is out of frame with srfAB1. A frameshift mutation in srfAB upstream of orf46 has no effect on competence but a frameshift and nonsense mutation in orf46 resulted in failure to complement the delt srfA mutation. These results indicate that orf46 encodes the srfA-associated competence regulatory factor. Computer-aided analysis of the putative orf46 product (ComS) shows similarity to the homeodomain of the POU domain class of eukaryotic transcriptional regulators.

Amino Acid Sequence↗
PubMed2006

Methylation and repeats in silent and nonsense mutations of p53.

All exonic CG sequences in p53 are methylated; this epigenetic modification is correlated with frequent G:C-->A:T transitions in p53. Recent reports reveal the presence in p53 of non-CG methylation in CC and CCC sequences, complementary to sites of selective guanosine adduct formation (GG and GGG), and the association of genetic instability with methylation at repetitive sequences. We presently investigated the distribution of methylation sites and repetitive elements in silent and nonsense p53 mutations (2051) among the IARC's TP53 somatic mutation database for exons 5-8. Silent mutations are nonrandom, but mostly involve G:C-->A:T transitions (62%); in particular C-->T mutations (39% of all silent mutations) are mostly correlated with CC and CCC sequences, while G-->A mutations with GG sequences. Sequence analysis of all non-G:C-->A:T silent mutations reveals the frequent formation of new methylation sites (CG), new CCC and GGG sequences in the resulting sequence, refinement of symmetry elements at interrupted microsatellite-like sequences and formation of small repeats (55.3%). The G:C-->A:T silent mutations characterize cancers associated with cigarette smoking (e.g. bladder or lung and bronchus cancer versus colorectal cancer); on the contrary, non-G:C-->A:T silent mutations have similar frequencies in most cancers. Nonsense mutations in exons 5-8, all resulting in mutants lacking amino acids 307-393, which are crucial for p53 activity, were also analyzed. The frequency of nonsense mutations is higher at methylated sites or repeats 1-2 nucleotides removed from methylation sites. Frameshift mutations are also more frequent at repeated sequences. The frequent G:C-->A:T silent mutations could indicate that CC and CCC sequences of exons 5-8 are occasionally targets of non-CpG methylation of cytosine. This process of de novo methylation in the presence of microsatellite-like sequences and small repeats might influence the genetic stability of a variety of genes.

Base Sequence↗
PubMed2000

Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis.

The polydactyly, imperforate anus, vertebral anomalies syndrome (PIV, OMIM 174100) was determined as a distinct syndrome by Say and Gerald in 1968 (Say B, Gerald PS. Lancet 1968: 2: 688). We noted that the features of PIV overlap with the VATER association and Pallister-Hall syndrome (PHS, OMIM 146510), which includes polydactyly, (central or postaxial), shortened fingers, hypoplastic nails, renal anomalies, imperforate anus, and hypothalamic hamartoma. Truncation mutations in GL13, a zinc finger transcription factor gene, have been shown to cause PHS. We performed a molecular evaluation on a patient diagnosed with PIV, whose mother, grandfather, and maternal aunt had similar malformations. We sequenced the GLI3 gene in the patient to determine if she had a mutation. The patient was found to have a deletion in nucleotides 2188-2207 causing a frameshift mutation that predicts a truncated protein product of the gene. Later clinical studies demonstrated that the patient also has a hypothalamic hamartoma, a finding in PHS. We concluded that this family had atypical PHS and not PIV. This result has prompted us to re-evaluate the PIV literature to see if PIV is a valid entity. Based on these data and our examination of the literature, we conclude that PIV is not a valid diagnostic entity. We conclude that patients diagnosed with PIV should be reclassified as having VACTERL, or PHS, or another syndrome with overlapping malformations.

Abnormalities, Multiple↗
PubMed2005

Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.

Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised pathologically by elastic fibre mineralisation and fragmentation (so called "elastorrhexia"), and clinically by high heterogeneity in age of onset and the extent and severity of organ system involvement. PXE was recently associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. At least one ABCC6 mutation is found in about 80% of patients. These mutations are identifiable in most of the 31 ABCC6 exons and consist of missense, nonsense, frameshift mutations, or large deletions. No correlation between the nature or location of the mutations and phenotype severity has yet been established. Recent findings support exclusive recessive inheritance. The proposed prevalence of PXE is 1/25,000, but this is probably an underestimate. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP dependent transmembrane transporter family that is expressed predominantly in the liver and kidneys, and only to a lesser extent in tissues affected by PXE. The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres.

Adenosine Triphosphate↗
PubMed1999

Mutation analysis of the BRCA1 and BRCA2 genes results in the identification of novel and recurrent mutations in 6/16 flemish families with breast and/or ovarian cancer but not in 12 sporadic patients with early-onset disease. Mutations in brief no. 224. Online.

Since the identification of the BRCA1 and BRCA2 genes (MIM#s 113705 and 600185), more than hundred different mutations throughout both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. We analyzed 12 sporadic female patients with breast cancer before age 35, as well as 16 unrelated families, presenting with either (i) at least 3 first degree relatives with breast and/or ovarian cancer diagnosed at any age, or (ii) at least 2 first and/or second degree relatives with breast and/or ovarian cancer before age 45 years. We performed a protein truncation test for BRCA1 exon 11 and BRCA2 exons 10 and 11 and heteroduplex analysis for all the remaining exons of BRCA1 and 2. Presence of genomic deletions encompassing exons 13 or 22 of BRCA1, known to be Dutch founder mutations, was investigated by PCR. In 6/16 (37.5%) unrelated families the causal mutation in either the BRCA1 or BRCA2 gene was identified. Four different mutations were found in the BRCA1 gene: IVS5+3A>G (intron 5), 1191delC (exon 11), R1443X (exon 13), IVS22+5G>A (intron 22) and two in the BRCA2 gene: 6503delTT (exon 11), 6831delTG (exon 11). 1191delC (BRCA1) and 6831delTG (BRCA2) are novel mutations. IVS5+3A>G in exon 5 of BRCA1 published by Peelen et al. (1997) as a novel Belgian mutation, was identified in one additional family, not fulfilling our inclusion criteria. In the group of 12 sporadic female patients no mutations were found.

Adult↗