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PubMed2002

Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease.

Canavan disease, an inherited leukodystrophy, is caused by mutations in the aspartoacylase (ASPA) gene. It is most common among children of Ashkenazi Jewish descent but has been diagnosed in many diverse ethnic groups. Two mutations comprise the majority of mutant alleles in Jewish patients, while mutations in the ASPA gene among non-Jewish patients are different and more diverse. In the present study, the ASPA gene was analysed in 22 unrelated non-Jewish patients with Canavan disease, and 24 different mutations were found. Of these, 14 are novel, including five missense mutations (E24G, D68A, D249V, C152W, H244R), two nonsense mutations (Q184X, E214X), three deletions (923delT, 33del13, 244delA), one insertion mutation (698insC), two sequence variations in one allele ([10T>G; 11insG]), an elimination of the stop codon (941A>G, TAG-->TGG, X314W), and one splice acceptor site mutation (IVS1 - 2A>T). The E24G mutation resulted in substitution of an invariable amino acid residue (Glu) in the first esterase catalytic domain consensus sequence. The IVS1 - 2A>T mutation caused the retention of 40 nucleotides of intron 1 upstream of exon 2. The results of transient expression of the mutant ASPA cDNA containing these mutations in COS-7 cells and assays for ASPA activity of patient fibroblasts indicated that these mutations were responsible for the enzyme deficiency. In addition, patients with the novel D249V mutation manifested clinically at birth and died early. Also, patients with certain other novel mutations, including C152W, E214X, X314W, and frame shift mutations in both alleles, developed clinical manifestations at an earlier age than in classical Canavan disease.

Amidohydrolases↗
PubMed2002

A novel nonsense mutation at E106 of the 2B rod domain of keratin 14 causes dominant epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is classified into three main types and is caused, in most cases, by missense mutations in the genes encoding keratin (K) 5 and K14. In this study, we clinically, ultrastructurally, immunohistochemically, and molecularly studied a patient with a dominant EBS, Köbner type. Using sequence analysis of genomic DNA, a novel K14 nonsense mutation was identified. A heterozygous mutation G1231T of KRT14 was found to be associated with the disease in the patient. The mutation created a premature stop codon (amino acid codon 411, residue 106 of the 2B helix) in the K14 molecule. This residue lies in a highly conserved region and was recently found to be absolutely required for molecular stability and intermediate filament assembly in K5 and K14. The E411X (E106X) heterozygous ablation, missing the last 16 amino acid residues of the 2B and the entire tail domain of K14, led to disease but did not result in clumping of keratin filaments. It is the first premature stop codon mutation of K14 found in dominant EBS.

Adult↗
PubMed2005

UPF3 suppresses aberrant spliced mRNA in Arabidopsis.

It has been reported that eukaryotic organisms have a nonsense-mediated mRNA decay (NMD) system to exclude aberrant mRNAs that produce truncated proteins. NMD is an RNA surveillance pathway that degrades mRNAs possessing premature translation termination codons (PTCs), thus avoiding production of possibly toxic truncated proteins. Three interacting proteins, UPF1, UPF2 and UPF3, are required for NMD in mammals and yeasts, and their amino acid sequences are well conserved among most eukaryotes, including plants. In this study, 'The Arabidopsis Information Resource' database was searched for mRNAs with premature termination codons. We selected five of these mRNAs and checked for the presence of PTCs in these mRNAs when translated in vivo. As a result we identified aberrant mRNAs produced by alternative splicing for each gene. These genes produced at least one alternative splicing variant including a PTC (PTC+) and another variant without a PTC (PTC-). We analyzed their PTC+/PTC- ratios in wild-type Arabidopsis and upf3 mutant plants and showed that the PTC+/PTC- ratios were higher in atupf3 mutant plants than wild-type plants and that the atupf3 mutant was less able to degrade mRNAs with premature termination codons than wild-type plants. This indicated that the AtUPF3 gene is required by the plant NMD system to obviate aberrantly spliced mRNA.

Alternative Splicing↗
PubMed2002

BRCA1 and BRCA2 mutations in Russian familial breast cancer.

We have screened index cases from 25 Russian breast/ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using multiplex heteroduplex analysis. In addition we tested 22 patients with breast cancer diagnosed before age 40 without family history and 6 patients with bilateral breast cancer. The frequency of families with germline mutations in BRCA was 16% (4/25). One BRCA1 mutation, 5382insC, was found in three families. The results of present study, and those of a separate study of 19 breast-ovarian cancer families, suggest that BRCA1 5382insC is a founder mutation in the Russian population. Three BRCA2 mutations were found in patients with breast cancer without family history: two in young patients and one in patients with bilateral breast cancer. Four novel BRCA2 mutations were identified: three frameshift (695insT, 1528del4, 9318del4) and one nonsense (S1099X).

Adult↗
PubMed2002

Molecular analysis of beta-thalassemia in South Vietnam.

In Vietnam, the carrier rate for beta-thalassemia varies from 1.5% to 25% depending on the ethnic groups of the population. The molecular basis of beta-thalassemia in South Vietnam was studied in 50 unrelated beta-thalassemia patients. Of these, 31 had beta-thalassemia/Hb E, 18 were homozygous for beta-thalassemia, and 1 carried the beta-thalassemia trait. The majority of the patients were Kinh, four were Chinese, and two were Kinh-Chinese. All had severe anemia and received blood transfusions regularly, every 1-3 months. Hepatosplenomegaly was found in all patients, and splenectomy had been done in six patients. Normal alpha-globin genotype (alpha alpha/alpha alpha) was found in all subjects. Reverse dot-blot hybridization using oligonucleotide probes specific for Southeast Asian mutations can detect beta-thalassemia in 60 chromosomes in addition to 31 chromosomes with beta(E) mutation. Excluding the beta(E) gene, six previously reported Thai and Chinese beta-thalassemia mutations were found, including codons 41/42 (-TCTT) 35.3%, codon 17 (A-->T) 25.0%, -28 (A-->G) 7.3%, codons 71/72 (+A) 7.3%, IVS-II nt 654 (C-->T) 7.3%, and IVS-I nt 1 (G-->T) 6.0%. The Vietnamese frameshift mutation at codon 95 (+A) was detected by ARMS in seven chromosomes (10.3%). DNA polymorphism of the beta-globin gene cluster carrying the codon 95 mutation was - + - - - - - + for (G)gamma/XmnI, epsilon/HincII, (G)gamma/HindIII, (A)gamma/HindIII, psi beta/HincII, 3' psi beta/HincII, beta/AvaII, and 3'beta/BamHI, respectively. The remaining mutation detected by the gap PCR was a large deletion known as the Chinese (G)gamma((A)gamma delta beta)(0)-thalassemia. The two most common mutations were the frameshift at codons 41/42 (-TCTT) and the nonsense mutation in codon 17 (A-->T). Thus beta-thalassemia mutations in South Vietnam is similar to the previous report from the North, although at different frequencies. This result will help to establish a center for prenatal diagnosis and for prevention and control of thalassemia in Vietnam.

Adolescent↗
PubMed1993

Mutations of the fumarylacetoacetate hydrolase gene in four patients with tyrosinemia, type I.

Tyrosinemia type I is an autosomal recessive inborn error of metabolism caused by deficiency of the enzyme fumaryl acetoacetate hydrolase (FAH, EC 3.7.1.2). We have used reverse transcription and the polymerize chain reaction to amplify the peptide coding region of the FAH cDNA from four patients with tyrosinemia type I. Chemical mismatch cleavage analysis and DNA sequencing were utilized to determine mutant alleles in all cases. A French Canadian patient was homozygous for a splice error mutation in the 3' portion of the gene. A second patient, from a consanguineous pedigree in Iran, had the identical splice alteration. The third patient has a missense mutation, changing valine to glycine in codon 166. And finally two nonsense mutations in codons 357 and 364 were found in the fourth patient.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

Novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1.

OBJECTIVE: To identify MEN1 gene mutations and characterize clinical manifestations in Chinese kindred with multiple endocrine neoplasia type 1 (MEN1) in Taiwan. PATIENTS AND METHODS: Eight unrelated subjects (one male and seven females, age range 26-70 years) with clinical manifestations of MEN1 were analysed. In addition, 45 relatives that included 10 affected (three males and seven females, age range 32-53 years) and 35 unaffected (17 males and 18 females, age range 15-80 years) subjects were evaluated. Genomic DNA extraction, polymerase chain reaction (PCR) and DNA sequence analysis were performed according to standard procedures. RESULTS: We identified heterozygous MEN1 gene mutations in all eight probands and 10 affected subjects as well as in 13 clinically asymptomatic relatives. Novel mutations included a missense mutation in a heterozygous mutation in exon 9 (GAC --> CAC) resulting in a substitution of aspartic acid by histidine at codon 418 (family 1); a nonsense mutation at codon 556 of exon 10 (GAG --> TAG) resulting in a stop codon and termination (family 2); a missense mutation in exon 2 (GGG --> GAG) causing the substitution of glycine by glutamic acid at codon 110 (family 3); and a deletion/insertion mutation in nucleotide 1200 of exon 8 resulting in frameshift and early termination (family 4). Affected subjects in families 5-7 shared the same C insertion at nucleotide 1650 of exon 10, similar to that previously described as a hotspot for mutation, and proband 8 had a previously described mutation in intron 4 of the MEN1 gene (IVS4-9 G --> A). We also found that 18 (58%) of our 31 MEN1 mutant carriers had clinical symptoms, whereas four (13%) had biochemical abnormalities without clinical symptoms, and nine (29%) were unaffected both clinically and biochemically. CONCLUSIONS: We have identified four novel mutations in the MEN1 gene in patients with MEN1 in Taiwan.

Adolescent↗
PubMed1990

[Studies of beta-thalassemia mutations and prenatal diagnosis in Guangxi, Guangdong and Sichuan Provinces of south China].

beta-Thalassemia is one of the most common single gene disorders in South China, and ten different point mutations and frameshifts have been observed among Chinese. We studied 150 chromosomes of 95 beta-thalassemia patients from Guangxi, Guangdong and Sichuan Provinces using the polymerase chain reaction followed by dot hybridization with specific oligonucleotide probes. The most common mutations were the frameshift at codon 41-42 and the nonsense mutation at codon 17 in Guangxi and Sichuan, and the codon 41-42 frameshift and IVS-II-654 mutation in Guangdong. The A-G mutation at -28 of the promoter was common in Sichuan but not in the other two provinces. Three mutations, -30, IVS-I-1 and IVS-I-5, were not observed. A prenatal diagnosis program using these techniques has been initiated based on these data. Fourteen pregnancies at risk for beta-thalassemia have been diagnosed successfully.

China↗
PubMed1996

p27/Kip1 mutation found in breast cancer.

The p27/Kip1 protein belongs to the recently identified family of proteins called cyclin-dependent kinase inhibitors. These proteins play an important role as negative regulators of cell cycle-dependent kinase activity during progression of the cell cycle. Since cyclin-dependent kinase inhibitors can inhibit cell proliferation, they may have a role as tumor suppressor genes. To determine whether p27 alterations may be involved in tumorigenesis, we examined its mutational status in 36 primary breast carcinomas and 9 breast cancer cell lines using PCR-single-strand conformational polymorphism, direct DNA sequencing, and Southern blot analysis. Southern blot analysis showed no homozygous deletions of the p27 gene in either the clinical samples or cell lines. Two point mutations were found in primary tumors. One represents a previously undescribed polymorphism at codon 142; another is a nonsense mutation at codon 104. The latter mutation was absent in the normal matched control sample, and, in addition, it was accompanied with the loss of heterozygosity (LOH) of a microsatellite marker in the vicinity of the p27 gene on chromosome 12p13. These data indicate that p27 mutations are a rare event in breast cancer, but may play an important role in the development of a minority of these cancers. Furthermore, LOH analysis of the 12p13 locus revealed that an additional four of six matched DNA samples had LOH at 12p13 but did not have an alteration of the p27 gene, suggesting that another tumor suppressor gene is located on the short arm of human chromosome 12 which may be frequently involved in the pathogenesis of breast cancers.

Base Sequence↗
PubMed1996

Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product.

The Wiskott-Aldrich syndrome protein (WASP) gene was found to be mutated in patients presenting with WAS and in patients showing X-linked thrombocytopenia. Mutation analysis in 19 families of German, Swiss and Turkish descent by single-strand conformation polymorphism and sequencing resulted in the detection of seven novel and 10 known mutations. A striking clustering of missense mutations in the first four exons contrasted with a random distribution of nonsense mutations. More than 85% of all known missense mutations were localized in the amino-terminal stretch of the WASP gene product; this region contained a mutational hot spot at codon 86. No genotype-phenotype correlation emerged after a comparison of the identified mutations with the resulting clinical picture for a classical WAS phenotype. A substitution at codon 86 resulted in an extremely variable expression of the disease in a large Swiss family. An extended homology search revealed a distant relationship of this stretch to the vasodilator-stimulated phosphoprotein (VASP), which is involved in the maintenance of cyto-architecture by interacting with actin-like filaments.

Adult↗