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

ABSTRACT

PURPOSE: Wilson disease is an autosomal recessive disorder of copper transport, which is proba bly 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 dis ease, 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 P- type ATPase(ATP7B). In this study, efforts have been made to identify novel mutations and in vestigate 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. Speci mens 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 withWilson 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. (J Korean Pediatr Soc 2001;44569-576)