Identification of novel mutations and the three most common mutations in the human ATP7B gene of Korean patients with Wilson disease

Purpose: Wilson disease, an autosomal recessive disorder of copper transport, is probably the most common inherited metabolic disorder in Korea. 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 P-type ATPase (ATP7B). In this study, efforts were 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 polymerase chain reaction-amplified exon by exon and subsequently analyzed using heteroduplex or single-strand conformation polymorphism analysis. Specimens showing mobility shift on those studies were directly sequenced. Results: Twelve different mutations in 33 Korean families with Wilson disease were identified: Arg778Leu (R778L), Asn1270Ser (N1270S), Ala874Val (A874V), 2303-2305delC, 2630-2656del, 2460-2462insC, Cys656Stop (C656X), Pro768His (P768H), Leu1083Phe (L1083F), Ala1168Ser (A1168S), Leu1255lle (L12551), and Asp1267Ala (D1267A). Among these, six mutations (2630-2656del, 2460-2462insC, C656X, P768H, A1168S, and L12551) are novel. The R778L mutation is known to be highly prevalent in Asian patients. The allele frequency of R778L in Korean patients with Wilson disease was 37.9%, which was significantly higher than those of Japanese and Taiwanese patients. The N1270S mutation, originally described in an Italian patient, was the next most common mutation in Korean patients, with an allele frequency of 12.1%, which was presumed to disrupt the ATP hinge domain of the ATP7B protein. The A874V mutation was the third most common mutation with an allele frequency of 9.4%, which was presumed to disrupt the Td domain of the ATP7B protein. Conclusion: The R778L, N1270S, and A874V mutations are three major mutations representing approximately 60% of mutated alleles, although Korean patients with Wilson disease are genetically heterogeneous.