The His1069Gln mutation in the ATP7B gene in Romanian patients with Wilson's disease referred to a tertiary gastroenterology center.
Răzvan IacobSperanţa IacobAnca NăstaseCodruţa VaguAna Maria EneAlexandru R. ConstantinescuDaniela AnghelConstanta BanicaLiliana PâslaruDaniel CoriuSimona DimaCristian GheorgheElena IonicaLiana Gheorghe
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Abstract:
Wilson's disease (WD) is a rare autosomal recessive disease. More than 500 mutations have been described so far, out of which 29 in exon 14. H1069Q mutation in the exon 14 of ATP7B gene is the most frequently encountered in Europe. The aim of the present study was to evaluate the incidence of mutations occurring in exon 14 of ATP7B gene in Romanian patients referred to a tertiary gastroenterology center, with known or suspected WD and in asymptomatic first degree relatives of index cases.93 patients were included in the study. Exon 14 of ATP7B gene has been amplified by PCR from genomic DNA and mutations identified by sequencing.Only H1069Q missense mutation was detected in our study group. In patients with an established diagnosis of WD (38 cases), 34.2% were heterozygous for H1069Q and 21.1% were homozygous, with an allelic frequency of 38.1%. In paediatric WD patients (12 cases) 25% were heterozygous and 16.7% were homozygous (not significant versus adult population). Among asymptomatic first degree relatives of patients with WD (12 siblings, 25 parents) there were 40.5% cases heterozygous for H1069Q. In patients with suspected WD (17 cases), only 5.9% were heterozygous and no homozygous patient was identified. In our study group, H1069Q screening alone could not raise the Leipzig score to confirm diagnosis in patients with suspected WD or in asymptomatic first degree relatives.H1069Q mutation is highly prevalent in Romanian WD patients and first degree relatives, similar to other central and continental western European populations.Keywords:
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Exon 7 of the phenylalanine hydroxylase (PAH) gene was analyzed in 45 children affected with classic phenylketonuria (PKU) from northern China by using PCR-single strand conformation polymorphism (PCR-SSCP) technique and DNA direct sequencing. Six missense mutations(i.e. R243Q, R241H, G247V, L249H, F2541 and G257V) and one silent mutation (V245v) were identified. The latter three missense mutations were demonstrated as novel mutations in comparison with the PAH mutation database. One missense mutation (R241H) was first documented in Chinese. Our results showed population and region differences in the PAH mutation distribution, and suggest that there is more than one founding population for PKU in China. The finding of novel mutations will enhence the molecular diagnosis of PKU.
Phenylalanine hydroxylase
Single-strand conformation polymorphism
Silent mutation
Chinese population
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Objective To identify SCN9A gene mutation in a family with severe primary erythermalgia.Methods Clinical data of family were collected and the encoding exons and their flanking sequences of SCN9A gene were amplified and sequenced from genomic DNA samples.Results A heterozygous c.1185C→G was found in exon 9 of the proband,which resulted in N395K amino acid substitution.The mutation was not detected in the proband's healthy mother or 50 unrelated healthy controls.Conclusion The missense mutation of SCN9A gene is the underlying cause of the patient's clinical phenotype.
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To study the effect of CCM1 gene mutations in Chinese patients with intracranial cavernous angiomas(ICCA).Twenty-one ICCA patients confirmed by pathology after operations in hospital from June 2002 to Feb.2003 and 15 healthy individuals as contrast were recruited. The peripheral venous blood samples of all the individuals were collected, and then DNA was extracted from the blood samples followed by amplification of exon 12 and some of its intron sequence using PCR. After purification, the PCR products were directly sequenced by ABI PRISM377 sequencing instrument.Three mutations of CCM1 gene were found in 5 patients and reported firstly. There existed a missense mutation of 1172C-->T in exon 12 in 5 patients, which led the No.391 amino acid of KRIT1 protein, serine, to phenyalanine. There existed a missense mutation of 1160A-->C in one patient, which led the No.387 amino acid, glutamine, to proline. Another mutation was an intronic mutation of IVS12-4C-->T in 4 patients. In contrast no mutations were found.The authors firstly report that mutations of CCM1 gene in exon 12 also exist in Chinese ICCA patients and those mutations are related with the occurring of ICCA.
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Exon 7 of the phenylalanine hydroxylase (PAH) gene was analyzed in 45 children affected with classic phenylketonuria (PKU) from northern China by using PCR-single strand conformation polymorphism (PCR-SSCP)technique and DNA direct sequencing. Six missense mutatiorm(i.e. R243Q,R241H,G247V,L249H,F2541 and G257V)and one silent mutation (V245v) were identified. The latter three mlssense mutations were demonstrated as novel mutations in comparison with the PAH mutation database. One missense mutation (R241H) was first documented in Chinese. Our results showed population and region differences in the PAH mutation distribution,and suggest that there is more than one founding population for PKU in China. The finding of novel mutations will enhence the molecular diagnosis of PKU.
Phenylalanine hydroxylase
Single-strand conformation polymorphism
Silent mutation
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Purpose To detect and analyze the mutation frequency of the exon 8 of ATP7B gene in Chinese patients with Wilson disease. Methods We preliminarily studied the mutation frequency of the exon 8 of ATP7B gene using a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and silver staining technique in sample of 30 patients with Wilson disease and 15 normal controls. Then we made correlative analysis between mutations and phenotypes. Results Abnormal migration bands in PCR-SSCP were observed in 6 het-erozygoteof 30 patients (20% ,6/30),among them,4 patients presented missense mutations with 2 273G→T (Arg778Leu), which disrupted Tm4 domain of ATPase7B, and simultaneously with synonymous mutations in 2 250C→G and 2 280G→T. One patient existed four mutation motifs, ie, 2 099A→G( Lys720Arg) with missense mutation and Tm3 domain disrupted;2 273G→*T(Arg778Leu) with missense mutation and Tm4 domain disrupted;250C→G and 2 280G→T, with the same amino-acid Leu, were considered conservative changes; Another insertion mutation with 2 245G(769inser His) was also detected,which changed amino acid sequences and disrupted Tm4 domain. Conclusions Exon 8 might be a hot spot of mutation in ATP7B gene in Chinese. 2 273G→T (Arg778Leu) is one common mutation type. Tm4 is one of the most frequent disrupted domains.
Single-strand conformation polymorphism
Mutation Testing
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Objective To analyze the mutation characterization in exon 8 of ATP7B gene in Chinese Patients with Wilson disease(WD).Methods The genomic DNA of 146 patients with WD from 141 unrelated families and 50 healthy control children were extracted and the exon 8 of ATP7B gene were amplified with polymerase chain reaction.Screening for the mutation was done by direct sequencing.Results Ninety-three of the 146 patients were found with mutations.The mutation frequency was 40.78% in missense mutation of c.2333GT(Arg778Leu),including 26 cases homozygosis mutations and 63 cases heterozygosis mutations,always accompanied with c.2250CG(Leu770Leu),the mutation frequency was 0.35 % in missense mutation of c.2294AG(Asp765Gly).The mutation frequency was 1.77% in the insertion mutation of c.2298_2299insC.No mutation in exon 8 of ATP7B was found in 50 healthy control children.Conclusions Except for the hot point mutation of Arg778Leu in exon 8 of ATP7B gene and the mutation of c.2294AG,the noval insertion mutation of c.2298_2299insC is identified in Chinese patients.
Mutation frequency
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genomic DNA
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To study the feature of disease-causing mutation of exon 12 of Wilson disease (WD) gene in Chinese and evaluate its value in direct gene diagnosis.Genomic DNA of 44 unrelated WD patients and 60 normal controls was prepared from peripheral blood leukocytes by a salt-out method. The mutation of exon 12 in these subjects was identified by PCR-single strand conformation polymorphism (SSCP) and further confirmed by direct sequencing.Two missense mutations were identified in 8 cases (18%), including 6 cases of heterozygous for Thr935Met mutation and 2 of heterozygous for Gly943Asp mutation. Different features of mutation of exon 12 were noted between Chinese and Caucasian. Both Thr935Met and Gly943Asp were novel missense mutations and exon 12 was another hot point mutation of WD in Chinese besides exon 8.The finding helps establish a fast and effective direct gene diagnosis.
Single-strand conformation polymorphism
genomic DNA
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Objective To study mutation in exon 6 and 7 of the gene for the phenylalanine hydroxylase (PAH).Methods The mutations in exon 6 and 7 and flanking sequence of PAH gene were detected by DNA sequencing,involved in 56 patients with phenylketonuria and112 healthy kids.Results Two synonymous mutations-Q232Q (CAA→CAG) and V245V (GTG→GTA) were also detected,which the frequency of cDNA 696 mutation G type and cDNA735-A point mutation was respectively up to 96.2% and 76.1%,we concluded that the 696 735 wild-type site may be G,A in Shanxi Province. Besides,thirty-seven different mutations account for 33.04% of mutant alleles,Y204C was found in exon6; In exon 7,R243Q was the highest incidence,accounting for 10.7%,followed by Ivs7 + 2 TA,5.4%,G247V,R252Q,L255S,R261Q,T278I and E280K accounting for 0.9%,0.9%,0.9%,0.9%,2.7%,0.9% respectively. 7 missense mutations and 2 splice site mutation were included in 9 kinds of different mutations.Conclusions The mutation characteristics and distribution in exon 6 and 7 of PAH gene has been identified,which showed that the Y204C and R243Q were the hot region of PAH gene mutation in Shanxi PKU population.
Phenylalanine hydroxylase
Splice site mutation
Silent mutation
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Objective: To Study the frequency of mutation in exon 12 of Wilson's disease(WD) gene in Chinese people. Methods: Screening for exon12 mutation was conducted in 70 unrelated WD patients and 30 normal controls. Mobility shift of exon12 was analyzed by SSCP and further confirmed by direct sequencing. Results: No abnormality was found in 30 controls. In 70 patients, two missense mutation were identified in 11 cases(15.7%),Including 9 cases of Thr935Met mutation(12.9%) and 2 of Lys952Arg mutation(2.8%). Conclusion: Exon12 was one of hot point mutation of WD in Chinese people, A novel missense mutation was identified.
Chinese family
Single-strand conformation polymorphism
Mutation Testing
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Objective: To Study the frequency of mutation in exon 12 of Wilson's disease(WD) gene in Chinese people. Methods: Screening for exon12 mutation was conducted in 70 unrelated WD patients and 30 normal controls. Mobility shift of exon12 was analyzed by SSCP and further confirmed by direct sequencing. Results: No abnormality was found in 30 controls. In 70 patients, two missense mutation were identified in 11 cases(15. 7%), Including 9 cases of Thr 935 Met mutation(12. 9%) and 2 of Lys 952 Arg mutation (2. 8%). Conclusions: Exon 12 was one of hot point mutation of WD in Chinese people, A novel missense mutation was identified
Single-strand conformation polymorphism
Mutation Testing
Chinese family
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