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PubMed1997

Confirmation of homozygosity for a single nucleotide substitution mutation in a Cockayne syndrome patient using monoallelic mutation analysis in somatic cell hybrids.

The identification of individuals homozygous for a specific mutation offers advantages for the elucidation of molecular mechanisms of hereditary disease states. Cockayne syndrome is a rare autosomal recessive disorder, the molecular basis of which is complicated by significant genetic and clinical heterogeneity. The genes associated with both genetic complementation groups, CSA and CS-B, have been identified. We have previously identified a number of CSA mutations, including a single base substitution that introduces a stop codon (322Tyr-->Stop) mutation in the C-terminal region for at least one allele of the CSA gene in a severely affected patient. We now present data confirming the existence of homozygosity in this patient using a strategy with general applicability. Somatic cell hybrids were established by fusing patient cells with mouse A9 cells. Screening with chromosome 5 specific polymorphic markers facilitated identification of hybrid clones bearing only one of the distinct CSA alleles. Sequencing of a portion of the human CSA gene in a subset of these hybrids permitted monoallelic mutation analysis and confirmed the presence of the 322Tyr-->Stop mutation in both alleles.

Alleles↗

PubMed1998

Two novel mutations of the arylsulfatase B gene in two Italian patients with severe form of mucopolysaccharidosis. Mutations in brief no. 127. Online.

Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome, is a autosomal recessive disorder, due to the deficiency of the lysosomal enzyme N-acetylgalactosamine-4-sulfatase (arylsufatase B, ASB: EC 3.1.6.12). Three classical forms of the disease have been differentiated: severe, intermediate, mild. Mutational analysis of the ASB gene resulted in the identification of 30 ASB mutant alleles, each of which was found to be unique among unrelated patients, demonstrating a broad molecular heterogeneity of the disease. In this communication we present two novel mutant alleles in two severely affected subjects. Both alterations, the missense mutation G302R and the nonsense Q456X, were found in homozygosity and were confirmed by amplification refractory mutation system (ARMS) or restriction analysis. The missense G302R mutation concerns an amino acid which may be of special importance to the polypeptide, since 302 position is completely conserved in all the eukaryotic sulfatases aligned so far; the nonsense mutation Q456X leads to the translation of a putative mutant ASB protein lacking the last 78 amino acids with a loss of the 8 kD mature polypeptide, one of the two peptides generated by intralysosomal proteolytic processing of the 64kD precursor.

Alleles↗

PubMed1998

Identification of 9 novel IDS gene mutations in 19 unrelated Hunter syndrome (mucopolysaccharidosis Type II) patients. Mutations in brief no. 202. Online.

Hunter syndrome is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). The IDS deficiency can be caused by several different types of mutations in the IDS gene. We have performed a molecular and mutation analysis of a total 19 unrelated MPS II patients of different ethnic origin and identified 19 different IDS mutations, 9 of which were novel and unique. SSCP analysis followed by DNA sequencing revealed four novel missense mutations: S143F, associated with the 562C-->T polymorphism, C184W, D269V and Y348H. Two novel nonsense mutations were found: Y103X (433C-->A) and Y234X (826C-->G). In two patients two novel minor insertions (42linsA and 499insA) were identified. In one patient a complete IDS deletion was found, extending from locus DXS1185 to locus DXS466).

Humans↗

PubMed1999

Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online.

Familial Alzheimer's disease (AD) is an autosomal dominant disorder characterized by memory impairment and multiple cognitive deficits which occurs in mid to late life. Early onset AD has been associated with mutations in three genes, of which presenilin 1 (PS1) mutations are the most frequent. We sequenced the open reading frame from genomic DNA of a series of 21 early onset AD (AD3) UK families in which there were at least two affected individuals in two or more generations with a diagnosis of probable or definite AD. We found PS1 mutations in six of these families with no sequence variation in the remaining 15. The six families contained between them five different mutations of which two, I143F and P436S, have not been found elsewhere. I143F shows incomplete penetration within the affected family. P436S is the most carboxy-terminal presenilin 1 mutation reported to date.

Alzheimer Disease↗

PubMed1999

Beta-thalassemia in the German population: mediterranean, Asian and novel mutations. Mutations in brief no.228. Online.

The beta-thalassemia mutations of 13 unrelated heterozygous Germans who remained unidentified in a previous study of 40 subjects were investigated at the DNA level. Two Mediterranean, one Asian and three novel mutations (CD6 -G, CDs 108 /112-12nt, CDs 130/131 + GCCT) were identified. Altogether, in 30 of the 35 subjects (86%) in which a mutation in the beta-globin gene was identified, the mutation was of Mediterranean origin. The geographical distribution suggests recent migration from the Mediterranean region as cause of the high proportion of frequent Mediterranean beta-thalassemia mutations in the German population. Our results support the notion that the majority of beta-thalassemia genes in the western and central European population are of Mediterranean origin.

DNA Mutational Analysis↗

PubMed1999

A novel frameshift mutation (141delT) in exon 1 of the 21-hydroxylase gene (CYP21) in a patient with the salt wasting form of congenital adrenal hyperplasia. Mutation in brief no. 255. Online.

Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disease with a wide range of clinical manifestation. In 90-95% of the cases it is caused by 21-hydroxylase deficiency (OMIM #201910) due to mutations of the CYP21 gene (GDB Accession #M12792). In most cases the CYP21-inactivating point mutations are transferred by apparent gene conversions from CYP21P to CYP21. In only a few cases point mutations have been described, which are not present in the pseudogene. Using Southern blot analysis and DNA sequencing we have identified a novel mutation (141delT) of the CYP21 gene in a patient suffering from the salt wasting form of CAH. This results in a premature termination of a truncated protein at amino acid position 51 (L51X), which is likely to result in an enzyme with no activity. This novel mutation has not been reported to occur in the CYP21P alleles and it was not found in the CYP21P alleles in this CAH family.

Adrenal Hyperplasia, Congenital↗

PubMed1999

Direct detection of common mutations in the familial Mediterranean fever gene (MEFV) using naturally occurring and primer mediated restriction fragment analysis. Mutation in brief no. 257. Online.

The MEFV gene involved in familial Mediterranean fever was recently cloned and four distinct sequence alterations (M680I, M694V, M6941 and V726A) were identified at the 3'-most exon. We genotyped 170 unrelated FMF patients from various ethnic groups in Israel and found that mutation M694V predominates in North African Jews, that mutation V726A is common in Jewish patients other than North African Jews and that all four mutations occur in patients of Arabian origin, namely, Moslems, Christians and Druze. Since these four distinct sequence alterations seem to account for the majority of mutations identified in FMF patients from the middle east, we have devised a simple protocol using PCR mediated site directed mutagenesis or naturally occurring recognition sites to scan for these mutations.

Cytoskeletal Proteins↗

PubMed1999

Several mutations including two novel mutations of the glucose-6-phosphate dehydrogenase gene in Polish G6PD deficient subjects with chronic nonspherocytic hemolytic anemia, acute hemolytic anemia, and favism.

DNA sequencing revealed seven different glucose-6-phosphate dehydrogenase (G6PD) mutations in G6PD deficient subjects from 10 Polish families. Among them we found two novel mutations: 679C-->T (G6PD Radlowo, class 2) and a 1006A-->G (G6PD Torun, class 1). Variant G6PD Radlowo was characterized biochemically. Both novel mutations were analyzed using a model of the tertiary structure of the human enzyme. The main chain of G6PD Torun is different from the wild-type G6PD. The remaining mutations identified by us in deficient Polish patients were: 542A-->T (G6PD Malaga), 1160G-->A (G6PD Beverly Hills), 1178G-->A (G6PD Nashville), 1192G-->A (G6PD Puerto Limon), and 1246G-->A (G6PD Tokyo). Variant Tokyo was found in four families. In one of them favism was the first clinical sign of G6PD deficiency and chronic nonspherocytic hemolytic anemia (CNSHA) was diagnosed later. Variants G6PD Nashville and G6PD Puerto Limon were accompanied by the silent mutation 1311C-->T of the G6PD gene.

Acute Disease↗

PubMed2000

Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.

Consistent gene mutation nomenclature is essential for efficient and accurate reporting, testing, and curation of the growing number of disease mutations and useful polymorphisms being discovered in the human genome. While a codified mutation nomenclature system for simple DNA lesions has now been adopted broadly by the medical genetics community, it is inherently difficult to represent complex mutations in a unified manner. In this article, suggestions are presented for reporting just such complex mutations.

Base Sequence↗

PubMed2001

Two novel mutant alleles of the gene encoding neurotrophic tyrosine kinase receptor type 1 (NTRK1) in a patient with congenital insensitivity to pain with anhidrosis: a splice junction mutation in intron 5 and cluster of four mutations in exon 15.

Congenital insensitivity to pain with anhidrosis (CIPA), also called hereditary sensory and autonomic neuropathy type IV (HSAN IV), is caused by mutations of the NTRK1 gene coding for the neurotrophic tyrosine kinase receptor type 1. We report the results of the NTRK1 sequence analysis in a CIPA family from Poland. We found that the patient was in a state of compound heterozygosity. He had one mutant allele with a novel G>A substitution in the conserved splice junction donor site affecting the first base pair of intron 5 (IVS5+1G>A). In the other allele he had a cluster of four single nucleotide substitutions in exon 15: an 1876C>T change (relative to the transcription start site) and three G>T changes (1904G>T, 1909G>T and 1915G>T). All of these mutations change the sense of the codons: H598Y, G607V, E609X and V611L, respectively. Mutations E609X and V611L are novel and unique to the patient family and at least one of them, which creates a premature stop codon in position 609, should have a deleterious effect on the gene function. The other two substitutions H598Y and G607V are most likely rare polymorphisms, which are in linkage disequilibrium. They occur together with an estimated allele frequency of about 6%. Our report increases the spectrum of NTRK1 mutations in CIPA patients and describes an unusual case of a cluster of four mutations located close to each other in one exon.

Alleles↗

PubMed2000

Distribution of spontaneous CpG-associated G:C --> A:T mutations in the lacZ gene of Muta mice: effects of CpG methylation, the sequence context of CpG sites, and severity of mutations on the activity of the lacZ gene product.

In our previous study using transgenic Muta mice, G:C --> A:T transitions at 5'-CG-3' (CpG) sites, which are the most common mammalian spontaneous mutation, were detected in 197 of 330 spontaneous lacZ mutants. These transitions were recovered at only 27 of the 357 mutable G:C pairs within CpG sites where the transition could produce a missense or termination codon in the lacZ gene. To address the underlying mechanism for the uneven distribution of mutated CpG sites, the CpG methylation status of the Muta lacZ gene was analyzed by a bisulfite method. All the CpG sites examined in the coding region were evenly methylated at a high level, and no site-specific methylation was evident. Analysis of the sequence context around the mutated CpG sites, however, revealed that 21 of these 27 sites contained a CpG flanked by a pyrimidine on the 5' side, and that 187 of the 197 mutants resulted from substitutions at these sites. Moreover, we found five hotspots among those sites, the location of which was intimately related to the enzymatic activity of the gene product: one site produced a nonsense codon; three sites, one of which corresponded to the nucleophile at the active site, resided in the substrate-binding pocket; and the other site was located in a region conserved in the beta-galactosidase family. These results strongly suggest that recovery of lacZ mutations at each site largely depend on the adjacent sequence context and the extent to which the mutation damages the enzymatic activity of the gene product.

Animals↗

PubMed2005

Mutations in the MCFD2 gene and a novel mutation in the LMAN1 gene in Indian families with combined deficiency of factor V and VIII.

Combined deficiency of factors V (FV) and factor VIII (FVIII) (F5F8D) is an autosomal recessive bleeding disorder caused by simultaneous moderate-to-mild decrease of both clotting proteins. Mutations in two components of the ER-Golgi intermediate compartment (ERGIC-53), i.e., lectin mannose binding protein (LMAN1) and multiple coagulation factor deficiency 2 (MCFD2), have been found to be responsible for this dual deficiency in most of the cases reported in literature. Three Indian families with F5F8D were analyzed for the presence of mutations in their LMAN1 and MCFD2 genes. One of the three families showed the presence of a G to A substitution in exon 2 of the MCFD2 gene, whereas another family showed a nonsense mutation, i.e., G to T substitution, in exon 2 of the LMAN1 gene, the latter being a novel mutation not previously reported. The third family did not show mutations in either of the two genes, suggesting that a significant subset of F5F8D cases may be due to additional genes resulting in a similar phenotype.

Adolescent↗

PubMed2004

The Ser(+r83k) mutation is a second site mutation of SerD affecting the N-terminus of serrate.

The Serrate gene encodes an essential ligand for Notch signaling used during development of the adult wing and other systems in Drosophila melanogaster. Animals heterozygous or homozygous for the Ser(D) allele of this gene display characteristic defects in wing margin formation. We have characterized a spontaneously arising intragenic suppressor of Ser(D) named Ser(+r83k). Homozygous double mutant Ser(+r83k), Ser(D) animals are viable, with normal wing margin formation, but display an aberrant outspread wing posture. The two mutations can be separated by meiotic recombination which restores the Ser(D) mutant phenotype and demonstrates that in the absence of Ser(D) the Ser(+r83k) mutation is homozygous lethal. These two mutations therefore display allelic compensation. Molecular analysis reveals a single C-T transition mutation within the 5' (protein encoding region) of the Ser(+r83k) transcript. This mutation is predicted to change Arginine(176) to Cysteine, possibly leading to altered interactions with the Notch receptor.

Amino Acid Sequence↗

PubMed1995

Heterozygosity for an exon 12 splicing mutation and a W234G missense mutation in an American child with chronic tyrosinemia type 1.

Hereditary tyrosinemia type 1, an autosomal recessive disorder caused by deficiency of fumarylace-toacetate hydrolase (FAH), manifests in either an acute or a chronic form. We used reverse transcription and the polymerase chain reaction to amplify the FAH cDNA of a 12-year-old American boy with chronic tyrosinemia type 1. The patient is a compound heterozygote for mutations in the FAH gene. One allele contains a missense mutation in codon 234 changing a tryptophan to a glycine; this allele was of maternal origin. Mutagenesis and transfection into COS cells demonstrated that the W234G mutation abolishes FAH activity. The patient's paternally derived allele is a splicing mutation in the +5 position of intron 12, causing either insertion of a 105 bp fragment due to a cryptic splice site, or skipping of exon 12, or skipping of both exons 12 and 13. The chronic phenotype of tyrosinemia type 1 in this patient may be due to some residual, correct splicing by the allele with the splicing mutation.

Amino Acid Metabolism, Inborn Errors↗

PubMed1994

A K-ras 13Gly-->Asp mutation is recognized by HLA-DQ7 restricted T cells in a patient with colorectal cancer. Modifying effect of DQ7 on established cancers harbouring this mutation?

We have characterized and described in detail 2 CD4+ T-lymphocyte clones (TLC) from a colonic cancer patient. These TLC specifically recognize a K-ras-derived peptide carrying the 13Asp mutation commonly found in adenocarcinomas of the colon. The TLC were independently derived, as they carried 2 different T-cell receptors. The TLC recognized partly overlapping epitopes within the 13Asp peptide, presented by HLA-DQ7 molecules, suggesting that this molecule might confer some protective immunity against the mutation. On the basis of analysis of 251 colonic carcinomas, the presence of HLA-DQ7 did not seem to protect against the establishment of carcinomas carrying the 13Asp mutation, since the frequency of the DQ7 haplotype was not decreased among patients having this mutation. A modifying effect of DQ7 on the development of carcinomas with a 13Asp mutation was, however, observed, resulting in fewer tumours reaching advanced Dukes stages when DQ7 was present.

Amino Acid Sequence↗

PubMed1997

The rat corpulent (cp) mutation maps to the same interval on (Pgm1-Glut1) rat chromosome 5 as the fatty (fa) mutation.

The autosomal recessive obesity mutations fatty (fa) and corpulent (cp) arose in separate rat strains, 13M and Koletsky, respectively. By complementation analysis, the two mutations appear to be in the same gene. The somewhat different phenotypes of fa/fa and cp/cp animals probably reflect the fact that the mutations are segregating on different rat strains. The fa mutation has been mapped to the interval between Pgm1 and Glut1 on rat Chr 5, but cp has not been mapped genetically. We mapped cp in 30 obese progeny of a LA/N-BN cp/+ intercross using microsatellite markers for these flanking genes. Cp maps to the same genetic interval as rat fa and mouse db. Cp is flanked by Glut1 and Pgm1: Pgm1-------- cp -------- Glut1 map distance (cM) 1.67 6.67 Thus, cp and fa map to the same approximately 8 cm interval of the rat genome. In conjunction with the complementation studies alluded to above, these findings indicate that cp and fa are mutations in the same gene (Lepr).

Adipose Tissue↗

PubMed1994

Absence of p53 mutations and various frequencies of Ki-ras exon 1 mutations in rat hepatic tumors induced by different carcinogens.

Mutations of p53 and Ki-ras exon 1 were investigated in rat hepatic lesions induced by four kinds of hepatocarcinogenic protocols: continuous feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB), daily intraperitoneal injection of aflatoxin B1 (AFB1), and the Solt and Farber regimen (Nature 236:701-703, 1976), in which diethylnitrosamine (DEN) or nitrosomethylurea (NMU) was used as initiating agents. DNA from microdissected tissue sections was amplified by the polymerase chain reaction (PCR) directly using primers for p53 exons 5-8 and Ki-ras exon 1 and analyzed for mutations by denaturing gradient gel electrophoresis (DGGE) or constant denaturant gel electrophoresis (CDGE). One or both of the p53 PCR primers were located within introns to prevent amplifying the p53 processed pseudogenes. In a total of 59 hepatocellular carcinomas (HCCs), no p53 aberrations were detected, indicating that p53 mutations are not very important in rat hepatic carcinogenesis. On the other hand, Ki-ras codon 12 mutations were found at low frequency in HCCs, hyperplastic foci, and cholangiofibroses induced by 3'-Me-DAB and by AFB1 but not in the lesions induced by the Solt and Farber regimen. Although Ki-ras codon 12 mutations are generally infrequent in rat hepatic tumors, their incidence thus appears to vary depending on the carcinogen used for their induction.

Animals↗

PubMed1995

Ki-ras mutations with frequent normal allele loss versus absence of p53 mutations in rat prostate and seminal vesicle carcinomas induced with 3,2'-dimethyl-4-aminobiphenyl.

We have developed a prostate carcinogenesis model in Fischer 344 rats using 3,2'-dimethyl-4-aminobiphenyl (DMAB) as a carcinogen to examine various potential modifying factors. In this study, mutational changes in the ras and p53 genes were assessed in DMAB-induced rat prostate and seminal vesicle carcinomas by single-strand conformation polymorphism analysis and subsequent direct DNA sequencing. Eight of 22 prostate adenocarcinomas (three of nine (33.3%) from the ventral lobe and five of 13 (38.5%) from the dorsolateral lobe, including three transplantable tumors) and one of 11 seminal vesicle adenocarcinomas (9.1%) demonstrated point mutations in the Ki-ras gene. One prostate malignant fibrohistiocytoma examined was negative. Among the positive cases, five (three ventral prostate carcinomas and two transplantable tumors) also showed loss of the normal allele. In contrast, other than one mutation in the p53 gene in the malignant fibrohistiocytoma, there were no mutations in the Ha-ras or p53 genes. These results indicate that mutational activation of the Ki-ras gene, but not of the Ha-ras or p53 genes may play a mechanistic role in prostate and seminal vesicle carcinogenesis by DMAB and that a loss of the normal allele of the Ki-ras gene may also be involved in the process.

Adenocarcinoma↗