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PubMed1997

[Detection of mit DNA point mutations by mutation-specific PCR].

Growing understanding in recent years about the prevalence and diversity of mitochondrial DNA mutations in human diseases has prompted a need for a simple screening method. We designed multiplex mutation-specific PCR, in which mutant DNAs were selectively amplified, for the 3243 (A to G) and 8344 (A to G) mutations. This method was simple and sensitive. We detected bands corresponding to the mutations in 1 and 2% mixtures of the 3243 and 8344 mutations respectively. Mutation-specific PCR is useful for detecting mutant mitochondrial DNA in peripheral blood, where its ratio to wild type DNA is sometimes too small to be detected by conventional assay, and for large scale screening to uncover a hitherto unknown relationship between mitochondrial DNA mutations and certain diseases.

DNA Mutational Analysis↗
PubMed1999

Identification of eleven novel tumor-associated E-cadherin mutations. Mutations in brief no. 215. Online.

The cell adhesion molecule E-cadherin (CDH1; MIM# 192090) has been implicated in numerous cellular functions, ranging from controlling morphogenesis to suppressing tumor invasion. We describe 11 previously unreported somatic E-cadherin mutations in two subgroups of gastric and breast cancer showing markedly reduced homophilic cell-to-cell interactions. Using reverse transcription-polymerase chain reaction (RT-PCR) and direct sequencing of the entire coding region 5 mutations were detected in diffuse-type gastric cancer specimens. The sequence alterations include 3 missense mutations affecting exons 3, 10, and 12. Furthermore, two in-frame deletions were identified removing 63 and 9 base pairs from exon 4 and 5, respectively. In invasive Lobular breast cancer 6 E-cadherin mutations were detected after RT-PCR amplification and direct sequencing or using single strand conformation polymorphism (SSCP) analysis followed by sequencing. In addition to two nonsense mutations affecting exon 2, four out-of-frame deletions removing 115 base pairs (entire exon 2), 224 base pairs (entire exon 3), 8 base pairs from exon 12 or 1 base pair from exon 13 were seen. Our report confirms the general principle that in diffuse-type gastric cancer E-cadherin mutations result in structurally altered proteins with possible reduced adhesive functions whereas in invasive lobular breast carcinomas complete loss-of-function mutations are characteristic.

Breast Neoplasms↗
PubMed1999

Three novel mutations in the gap junction beta 1 (GJB1) gene coding region identified in Charcot-Marie-Tooth patients of Greek origin: T55I, R164Q, V120E. Mutation in brief no 236. Online.

Charcot-Marie-Tooth (CMT) disease type CMTX has been linked with mutations in GJB1, a gene on chromosome X coding for a gap junction protein, Connexin 32. We screened the GJB1 gene for mutations by SSCP analysis and sequencing of candidate regions, in five unrelated CMT affected individuals, members of families presenting a mode of transmission and clinical findings compatible with CMTX. Mutations were detected in all five patients. Three not previously reported mutations were identified: C164T, G491A and T359A. Two patients shared the same mutation (C164T) while one had a reported mutation (C43T). Restriction enzyme digestion confirmed the sequencing results, as well as the co-segregation of the mutation with the disease. The same method was used to screen 150 control X chromosomes and the variations were not detected.

Charcot-Marie-Tooth Disease↗
PubMed1999

Rapid screening of the LDL receptor point mutation FH-Genoa/Palermo. Mutation in brief no. 238. Online.

The LDL-receptor gene point mutation FH-Genoa/Palermo is the most frequent mutation responsible for Familial Hypercholesterolemia in Sicily. The mutation does not introduce or abolish any useful restriction site. We establish a GeneComb-based strategy to identify this mutation in a population of Sicilian unrelated clinically diagnosed FH probands. The method was very sensitive and specific; 12 out of 90 (13.3%) unrelated FH probands were found to carry the FH-Genoa/Palermo mutation. According to these results, the FH-Genoa/Palermo is the more frequent LDL-receptor gene mutation among the Sicilian FH patients. Moreover FH-Genoa/Palermo is the mutation cluster to date more represented in Southern Italy.

Genetic Testing↗
PubMed1999

IARC p53 mutation database: a relational database to compile and analyze p53 mutations in human tumors and cell lines. International Agency for Research on Cancer.

The tumor suppressor p53 gene is the most frequently mutated gene in human cancer. To date, more than 10,000 mutations have been described in the literature, and these data are available in various electronic formats on the World Wide Web. Here we describe the structure and format of the different p53 datasets maintained and curated at the International Agency for Research on Cancer (IARC) in Lyon, France. These include p53 somatic mutations (more than 10,000 entries), p53 germline mutations (144 entries), and p53 polymorphisms (13 entries), with the somatic mutations organized into a relational database using AccessTM. The main features of these datasets are (1) controlled entry with standardized format and restricted vocabulary, (2) inclusion of annotations on individual characteristics and exposures, and (3) a classification of pathologies based on the International Classification of Diseases for Oncology (ICD-O). In addition, several interfaces have been developed to analyze the data in order to produce mutation spectra, codon analyses, or visualization of the mutation with the tertiary structure of the protein. All datasets and tools for analysis are available at http://www.iarc.fr/p53/homepage.

Databases, Factual↗
PubMed1999

Acute intermittent porphyria: characterization of two novel mutations in the porphobilinogen deaminase gene, one amino acid deletion (453-455delAGC) and one splicing aceptor site mutation (IVS8-1G>T).

A partial deficiency of Porphobilinogen deaminase (PBG-D) is responsible for acute intermittent porphyria (AIP). AIP is inherited in an autosomal dominant fashion, and the prevalence in the Argentinean population is about 1:125,000. Here, two new mutations and three previously reported were found in the PBG-D gene in 12 Argentinean AIP patients corresponding to 5 different families. To screen for AIP mutations in symptomatic patients, genomic DNA isolated was amplified in 2 Multiplex PCR reactions, then all coding exons and flanking intronic regions were sequenced. The new mutations are 453-455delAGC in exon 9 which results in the loss of an alanine residue at position 152, and one new point mutation in the splicing aceptor site in the last position of intron 8 (IVS8-1G>T) which leds to a 15 bp deletion because a cryptic site (first AG upstream) is used. Both mutations produce amino acid deletion without frameshift effect. To further characterize the 453-455delAGC mutation, the pKK-PBGD construct for the mutant allele was expressed in E. coli, the enzymatic activity of the recombinant protein was 1.3% of the mean level expressed by the normal allele. Finally, three missense mutations, previously reported, were identified in three unrelated families.

Adolescent↗
PubMed2000

Molecular basis of very long chain acyl-CoA dehydrogenase deficiency in three Israeli patients: identification of a complex mutant allele with P65L and K247Q mutations, the former being an exonic mutation causing exon 3 skipping.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a life-threatening disorder of mitochondrial fatty acid beta-oxidation. We identified four novel mutations in three unrelated patients. All patients had the severe childhood form of VLCAD deficiency with early onset and high mortality. Immunoblot analysis revealed that VLCAD protein was undetectable in patients 2 and 3, whereas normal-size VLCAD protein and an aberrant form of VLCAD (4kDa smaller) were detected in patient 1. As expected, null mutations were found in patients 2 and 3: patient 2 is homozygous for a frameshift mutation, del 4 bp at 798-801, and patient 3 is homozygous for a nonsense mutation 65C>A(S22X). Patient 1 was homozygous for a complex mutant allele containing two alterations, including a 194C>T transition (P65L) and 739A>C transversion (K247Q); in the case of P65L, the amino acid change does not reduce enzyme activity. However, the nucleotide change resulted in exon 3 skipping, whereas the latter K247Q mutation had a drastic effect on enzyme activity. We verified these events by in vivo splicing experiments and transient expression analysis of mutant cDNAs. The P65L mutation locates 11 bases upstream of a splice donor site of intron 3. This is an example of an exonic mutation which affects exon-splicing.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1996

Mutational spectra of tamoxifen-induced mutations in the livers of lacI transgenic rats.

Tamoxifen, an important drug in breast cancer treatment, causes liver cancer in rats. The standard range of in vitro tests have failed to show that it causes DNA damage, but 32P-postlabelling and DNA-binding studies have shown that tamoxifen forms DNA adducts in rat liver. In 1995 a transgenic rat (Big Blue; Stratagene, La Jolla, CA) became available which harbours the bacterial lacI gene, thereby allowing the in vivo study of tamoxifen mutagenesis. Recently, we [Styles JA et al. (1996): Toxicologist 30; 161] showed that tamoxifen caused on increase in the mutation frequency at the lacI gene in these transgenic rats. In this study, we report on our preliminary analysis of the mutational spectra of 33 control and 38 tamoxifen-induced mutant lacI genes. Plasmid DNA containing the lacI gene was isolated from the mutant phages and its DNA sequence determined. In the control animal group, 81% of the mutant lacI genes were point mutations, whilst in the tamoxifen-treated group, 62% of the mutant lacI genes were point mutations. Of the tamoxifen-induced mutants, 43% were GC-->TA transversions and 70% of point mutations. In the control group, GC-->TA transversions were 19% of all mutations and 24% of point mutations. Thus, compared with control animals, tamoxifen treatment had significantly increased the proportion of GC-->TA transversions.

Animals↗
PubMed1993

Rare mutations of the Gs alpha subunit gene in human endocrine tumors. Mutation detection by polymerase chain reaction-primer-introduced restriction analysis.

BACKGROUND: The Gs alpha (Gs alpha) gene can be activated to the putative oncogene gsp by specific point mutations at codons 201 or 227. Such mutations have been reported in growth hormone (GH)-secreting pituitary adenomas and thyroid tumors. To clarify the role of Gs alpha gene in human endocrine tumors, 197 tumors were screened for point mutations at codons 201 or 227 of the Gs alpha gene. METHODS: Mutations were detected by primer-introduced restriction analysis (PIRA) of the polymerase chain reaction (PCR) product of genomic DNA. RESULTS: These Gs alpha mutations were present in 4 of 53 pituitary adenomas (4 of 43 GH-secreting adenomas; 1 of these 4 was a GH- and prolactin-secreting adenoma from a patient with familial multiple endocrine neoplasia Type 1), 4 of 66 thyroid tumors (4 of 30 papillary carcinomas), and 1 of 19 adrenocortical adenomas (1 of 6 aldosterone-secreting adenomas). In contrast, none of these Gs alpha mutations were detected in parathyroid tumors, endocrine pancreatic tumors, or pheochromocytomas. CONCLUSIONS: Gs alpha mutations at these two loci may play a role in the pathogenesis of a small population of GH-secreting pituitary adenomas, papillary thyroid carcinomas, and adrenocortical adenomas, but that they are not involved in the pathogenesis of other types of endocrine tumors.

Acromegaly↗
PubMed2001

Nitric oxide donors induce large-scale deletion mutations in human lymphoblastoid cells: implications for mutations in T-lymphocytes from arthritis patients.

Rheumatoid arthritis (RA) is an inflammatory disease in which high levels of reactive nitrogen oxygen species (RNOS) may be present in the affected joints. RNOS are known to produce small-scale mutational events (transitions, transversions, small insertions, and small deletions) but the ability of these compounds to cause deletion of large segments of genomic DNA has not been previously determined. To address this question, a human lymphoblastoid cell line (WIL2-NS) was exposed to nitric oxide (NO)-donating drugs and hypoxanthine phosphoribosyltransferase (hprt)-negative clones were selected and analyzed by multiplex-PCR. Large-scale deletions accounted for 60-80% of hprt mutations arising in drug-treated cultures compared to 12% in untreated cultures (P-values of 0.006 and 0.0001, respectively, in two experiments). Deletion mutations in untreated cultures affected exon 9, whereas 75% of drug-induced deletion mutations affected exons 2, 3, and 9, and the remainder were very large, ranging from 26 to 1200 kbp. To compare this spectrum of NO-induced mutations in a lymphoblastoid line to that arising in vivo in arthritis patients, T-cells from RA patients, osteoarthritis (OA) patients, and controls were cloned and similarly analyzed. We previously showed that the overall frequency of Hprt mutant clones from patients is appreciably elevated compared to that of control subjects. Large-scale hprt deletions (0.5 to >26 kb) were detected in mutant T-cell clones from both RA and OA patients and also from control subjects. A total of 54 mutant clones from 16 RA patients and 19 mutant clones from 6 OA patients were studied. Of these, 6 clones (from 3 RA and 1 OA patient) had suffered large-scale deletions. A total of 9 control subjects were studied and 62 mutant clones were obtained. Of these, 19 had suffered large-scale deletions, arising in 7 of 9 control subjects. In conclusion, (1) RNOS are capable of inducing large-scale deletion mutations in a human lymphoblastoid cell line and (2) large-scale deletion mutations were found in 10-30% of T-cell clones from RA and OA patients and controls, which we hypothesize may be induced by RNOS.

Arthritis↗
PubMed2004

Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database.

In this report, we analyze data assembled in the Blood Group Antigen Gene Mutation Database (www.bioc.aecom.yu.edu/bgmut/index.htm), which describes sequence information on human genes associated with expression of the various serologically-determined blood group phenotypes. The database documents 38 genetic loci and a total of 624 alleles that together encode a large repertoire of proteins and constitute 27 serologically-defined blood group systems. Analysis of sequence variation patterns across alleles of a number of genes is focused on their molecular profiles, including mutational sites and recurrence, patterns of gene rearrangements in duplicated gene families, correlation of predicted location of epitopes in extracellular loops with sites of alterations, and effects of mutations on protein expression. That information, and the relative ease of identifying individuals bearing variant alleles, has led to the proposal that genes encoding blood group antigens are an important and unique resource for studies of human DNA variation. Another focus is on mutations in regions that encode the antigenic epitopes and on their occurrence in world populations. These mutations may be viewed as coding single nucleotide polymorphisms (cSNPs). We propose that one group of these cSNPs, which are known to occur with significant frequency in all world populations, could serve as well-validated genetic markers. In addition, specific mutations in a number of "low incidence" and rare alleles could serve as cSNPs specific for a given population. The allelic frequencies of these mutations and knowledge of their world-wide occurrence add a valuable dataset to the existing cSNP pools documented in SNP databases.

Alleles↗
PubMed2001

Variable expressivity and mutation databases: The androgen receptor gene mutations database.

For over 50 years genetics has presumed that variations in phenotypic expression have, for the most part, been the result of alterations in genotype. The importance and value of mutation databases has been based on the premise that the same gene or allelic variation in a specific gene that has been proven to determine a specific phenotype, will always produce the same phenotype. However, recent evidence has shown that so called "simple" Mendelian disorders or monogenic traits are often far from simple, exhibiting phenotypic variation (variable expressivity) that cannot be explained solely by a gene or allelic alteration. The AR gene mutations database now lists 25 cases where different degrees of androgen insensitivity are caused by identical mutations in the androgen receptor gene. In five of these cases the phenotypic variability is due to somatic mosaicism, that is, somatic mutations that occur in only certain cells of androgen-sensitive tissue. Recently, a number of other cases of variable expressivity have also been linked to somatic mosaicism. The impact of variable expressivity due to somatic mutations and mosaicism on mutation databases is discussed. In particular, the effect of an organism exhibiting genetic heterogeneity within its tissues, and the possibility of an organism's genotype changing over its lifetime, are considered to have important implications for mutation databases in the future.

Androgen-Insensitivity Syndrome↗
PubMed2005

Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare disorder caused by mutations in the autoimmune regulator gene (AIRE) and characterized by a variable combination of organ-specific autoimmune diseases. Studies on AIRE-deficient mice suggest that AIRE is an important factor in the establishment and maintenance of self-tolerance. The AIRE protein contains several structural domains often found in transcriptional regulators and functions as a transcriptional transactivator in vitro. To date, more than 50 patient mutations have been identified in the coding region of the AIRE gene. So far, APECED has been reported to be inherited in an autosomal recessive manner. However, in contrast to all other AIRE mutations, a novel mutation c.682T>G (p.G228W) in the DNA-binding and/or multimerization domain SAND was recently described to be inherited in a dominant fashion. We analyzed the effects of mutant AIRE proteins containing the patient mutations c.682T>G (p.G228W) and c.755C>T (p.P252L) located in the SAND domain on the properties of the wild-type AIRE in a heterozygous situation in vitro. In addition to the patient mutations, we analyzed the effects of a double mutation [c.727A>G;c.728A>C;c.739C>G;c740G>C] (p.K243A;R247A) of positively charged amino acids in the SAND domain. Of the mutants studied, only c.682T>G (p.G228W) mutant changed the subcellular localization and in addition severely disrupted the transactivating capacity of the wild-type AIRE. Our results indicate that the c.682T>G (p.G228W) mutant AIRE protein acts with a dominant negative effect by binding to the wild-type AIRE, thus preventing the protein from forming the complexes needed for transactivation.

Animals↗
PubMed2006

An interactive web database of factor H-associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations.

Factor H (FH) is a central complement regulator comprised of 20 short complement repeat (SCR) domains. Nucleotide changes within this gene (CFH) have been observed in patients with hemolytic uremic syndrome (HUS), and also membranoproliferative glomerulonephritis and age-related macular degeneration. All parts of FH are affected, but many mutations are clustered in the C-terminal part of FH. Up to now, structural analyses of HUS have been based on SCR-20, a domain that is involved in FH interactions with C3b, heparin, and endothelial cells. In order to identify the structural and functional consequence of HUS mutations, further disease-associated mutations were analyzed in terms of homology and nuclear magnetic resonance (NMR) models for factor H SCR domains. An interactive web database of 54 human HUS-associated mutations and others was created from the literature (www.FH-HUS.org). This has comprehensive search and analysis tools, integrating phenotypic and genetic data with structural analysis. Each mutation can be highlighted on the SCR structure together with the patient FH and C3 levels where available. Two new insights were obtained from our collection of data. First, phenotypic data on FH clarify our previously-proposed classification of Type I and Type II disorders that both lead to HUS, where Type I affects FH secretion and folding, and Type II leads to expressed protein in plasma that is functionally defective. Second, the new mutations show more clearly that SCR domains from SCR-16 to SCR-19 are important for the ligand binding activities of FH as well as SCR-20. This FH web database will facilitate the interpretation of new mutations and polymorphisms when these are identified in patients, and it will clarify the functional role of FH.

Amino Acid Sequence↗
PubMed2007

The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models.

Atypical hemolytic uremic syndrome (aHUS) is a disease of hemolytic anemia, thrombocytopenia, and renal failure associated with defective alternative pathway (AP) complement control. Previously, we presented a database (www.FH-HUS.org) focusing on aHUS mutations in the Factor H gene (CFH). Here, new aHUS mutations are reported for the complement regulatory proteins Factor H (FH), Factor I (FI), and membrane cofactor protein (MCP). Additional mutations or polymorphisms within CFH have been associated with membranoproliferative glomerulonephritis (MPGN) and age-related macular degeneration (AMD). Accordingly, the database now includes substitutions that predispose to aHUS, MPGN, and AMD. For this, structural models for the domains in MCP and FI were developed using homology modeling. With this new database, patients with mutations in more than one gene can be displayed and interpreted in a coherent manner. The database also includes SNP polymorphisms in CFH, MCP, and IF. There are now a total of 167 genetic alterations, including 100 in CFH, 43 in MCP, and 24 in IF. The mutations characterize clinical outcomes that vary from several AMD-associated polymorphisms to those associated with aHUS, MPGN, or FI deficiency. A consensus short complement regulator (SCR) domain structure facilitated the interpretations of aHUS mutations. Specific locations within this consensus domain often correlate with the occurrence of clinical phenotypes. The AMD Tyr402His polymorphism is structurally located at a hotspot for several aHUS mutations. The database emphasizes the causative role of the alternative pathway of complement in disease and provides a repository of knowledge to assist future diagnosis and novel therapeutic approaches.

Amino Acid Sequence↗
PubMed2005

SALL1 mutation analysis in Townes-Brocks syndrome: twelve novel mutations and expansion of the phenotype.

Townes-Brocks syndrome is an autosomal dominantly inherited disorder, which comprises multiple birth defects including renal, ear, anal, and limb malformations. TBS has been shown to result from mutations in SALL1, a human gene related to the developmental regulator SAL of Drosophila melanogaster. The SALL1 gene product is a zinc finger protein thought to act as a transcription factor. It contains four highly conserved, evenly distributed C2H2 double zinc finger domains. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL1 contains a C2HC motif. Most mutations causing TBS are clustered in the N-terminal third of the SALL1 coding region and result in the production of truncated proteins containing only one or none of the C2H2 domains and the N-terminal transcriptional repressor domain of SALL1. Twenty-three SALL1 mutations were reported prior to this work, 22 of which are located in exon 2, 5' of the second double zinc finger-encoding region. Here we present 12 novel mutations in SALL1 associated with Townes-Brocks syndrome in 13 unrelated families. These include three nonsense mutations, three short insertions and six short deletions. Thus the number of SALL1 mutations increases to 35. Rare phenotypical features among mutation positive patients include hypothyroidism, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, dorsal hypoplasia of the corpus callosum, and umbilical hernia.

Abnormalities, Multiple↗
PubMed1993

Mutations in type 1 procollagen that cause osteogenesis imperfecta: effects of the mutations on the assembly of collagen into fibrils, the basis of phenotypic variations, and potential antisense therapies.

Work by a large number of investigators over the last decade has established that over 90% of patients with osteogenesis imperfecta have mutations in one of the two genes for type I procollagen, that most unrelated probands have different mutations in the genes, and that the mutations found in most of the serious variants of the disease cause synthesis of abnormal pro alpha chains of the protein. The results have demonstrated that synthesis of structurally abnormal but partially functional pro alpha chains can interfere with folding of the central region of the protein into a triple-helical conformation, prevent processing of the N-terminal propeptides of procollagen, or produce subtle alterations in conformation that interfere with the self-assembly of the protein into collagen fibrils. One of the unsolved mysteries about the disease is why some mutations produce severe phenotypes, whereas very similar mutations produce mild phenotypes. Recent studies in transgenic mice suggest that nongenetic factors, such as stochastic events during development, may determine the severity of the disease phenotype produced by a specific mutation. Also, recent results raised the possibility that strategies of antisense gene therapy may be effective in treating the disease some time in the future. Specific inhibition of expression of a mutated collagen gene has been obtained with antisense oligonucleotides in cell culture experiments. However, there is no means of selective delivery of antisense oligonucleotides to the appropriate tissues.

Cells, Cultured↗
PubMed2006

Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule.

The severe Duchenne and milder Becker muscular dystrophy are both caused by mutations in the DMD gene. This gene codes for dystrophin, a protein important for maintaining the stability of muscle-fiber membranes. In 1988, Monaco and colleagues postulated an explanation for the phenotypic difference between Duchenne and Becker patients in the reading-frame rule: In Duchenne patients, mutations induce a shift in the reading frame leading to prematurely truncated, dysfunctional dystrophins. In Becker patients, in-frame mutations allow the synthesis of internally deleted, but largely functional dystrophins. Currently, over 4700 mutations have been reported in the Leiden DMD mutation database, of which 91% are in agreement with this rule. In this study we provide an update of the mutational variability in the DMD gene, particularly focusing on genotype-phenotype correlations and mutations that appear to be exceptions to the reading-frame rule.

Databases, Genetic↗