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Identification of Novel Mutations and Three Most Common Mutations in the Human ATP7B Gene of Korean Patients with Wilson Disease

Journal of the Korean Pediatric Society 2001;44(5):569-576.
Published online May 15, 2001.
Identification of Novel Mutations and Three Most Common Mutations in the Human ATP7B Gene of Korean Patients with Wilson Disease
Han-Wook Yoo1, Gu-Hwan Kim2, Ji-Won Chung2, Chang-Yeon Lee3, Kyung-Mo Kim4
1Department of Pediatrics, Medical Genetics Clinic & Laboratory, Asan Medical Center, College of Medicine, Ulsan University, Seoul,Korea
2Department of Pediatrics, Medical Genetics Clinic & Laboratory, Asan Medical Center, College of Medicine, Ulsan University, Seoul,Korea
3Department of Pediatrics, College of Medicine, Kosin University, Busan, Korea
4Department of Pediatrics, Medical Genetics Clinic & Laboratory, Asan Medical Center, College of Medicine, Ulsan University, Seoul,Korea
한국인 윌슨병 환자의 ATP7B 유전자의 새로운 돌연변이 유전자형 발견과 한국인에 흔한 세 종류 유전자형의 빈도
유한욱1, 김구환2, 정지원2, 이창연3, 김경모4
1울산의대 서울중앙병원 의학유전학클리닉 및 검사실
2울산대학교 의과대학 소아과학교실
3고신대학교 의과대학 소아과학교실
4울산대학교 의과대학 소아과학교실, 의학유전학클리닉 및 검사실
Correspondence: 
Han-Wook Yoo, Email: hwyoo@www.amc.seoul.kr
Abstract
Purpose
: Wilson disease is an autosomal recessive disorder of copper transport, which is probably the most common inherited metabolic disorder in Korea. It is characterized by defective biliary excretion of copper and impairment in the corporation of copper into ceruloplasmin. In Wilson disease, synthesis of a defective copper transporting enzyme leads to the accumulation of copper in the liver, brain and kidney. The product of the Wilson disease gene is a copper transporting Ptype ATPase(ATP7B). In this study, efforts have been made to identify novel mutations and investigate the frequency of the common mutations in Korean patients with Wilson disease.
Methods
: This study includes 37 patients from 33 unrelated Korean families with Wilson disease. Genomic DNA from peripheral leukocytes or skin fibroblasts and cDNA from liver tissue were PCR amplified exon by exon, and subsequently analyzed using heteroduplex or SSCP analysis. Specimens showing mobility shift on those studies were directly sequenced.
Results
: We identified 12 different mutations in 33 Korean families with Wilson disease; Arg778Leu (R778L), Asn1270Ser(N1270S), Ala874Val(A874V), 2304 del C, 27bp deletion in exon 11, 2461 ins C, Cys656Sop(C656X), Pro768His(P768H), Leu1083Phe(L1083F), Ala1168Ser(A168S), Leu1255Ile(L1255I), and Asp1267Ala(A1267A). Among these, 6 mutations(27bp deletion in exon 11, 2461 ins C, C656X, P768H, A1168S, and L1255I) are novel. The R778L mutation has been known to be highly prevalent in Asian patients. The allele frequency of the R778L in Korean patients with Wilson disease was 37.9%, which was slightly higher than those of Japanese and Taiwanese. Interestingly, the N1270S, originally described in an Italian patient, was the next common mutation in Korean patients with Wilson disease with the allele frequency of 12.1%, which was presumed to disrupt ATP hinge domain of the ATP7B protein. The A874V mutation was the third most common mutation with the allele frequency of 9.4%, which was presumed to disrupt Td domain of the ATP7B protein.
Conclusion
: R778L, N1270S, and A874V mutations are three major mutations covering upto nearly 60% of mutated alleles, though Korean patients with Wilson disease are genetically heterogeneous.
Key Words: Wilson disease, ATP7B protein, Three major mutations


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