Heng Xiao1,2,3, Sheng Deng1,4, Xiong Deng1, Shaojuan Gu1,2, Zhijian Yang1, Hang Yin1, Hao Deng5,6. 1. Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China. 2. Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China. 3. Department of Pathology, The Third Xiangya Hospital, Central South University, Changsha, China. 4. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China. 5. Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China, hdeng008@yahoo.com. 6. Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China, hdeng008@yahoo.com.
Abstract
BACKGROUND: Wilson's disease (WD) is an autosomal recessive disease, which is characterized by an excessive copper accumulation in the liver and brain, leading to subsequent hepatic and/or neurological disorders. The causative gene for WD has been identified as the ATPase Cu2+ transporting beta polypeptide gene (ATP7B), which encodes a protein called copper-transporting ATPase 2. ATP7B mutations may lead to reduced biliary excretion of excess copper and disrupted copper homeostasis, resulting in various clinical symptoms of WD. METHODS: Direct sequencing of the ATP7B gene was performed in 7 Han Chinese families with WD, and haplotype analysis was conducted in families having the same mutation. RESULTS: Nine ATP7B gene mutations were identified, including 7 missense mutations (p.Asp765Gly, p.Arg778Leu, p.Thr888Pro, p.Pro992Leu, p.Asp1047Val, p.Ile1148Thr and p.Ala1295Val), 1 duplication mutation (c.525dupA), and 1 nonsense mutation (p.Gly837*). Combined with our previous data, haplotype analysis revealed that the founder effect accounted for 48% of alleles in Han Chinese, constituted by high allele frequency mutations p.Arg778Leu, p.Pro992Leu and p.Ala1295Val. CONCLUSION: This study revealed genetic defects of 7 Han Chinese families with WD, and has implications for their genetic counseling and clinical management.
BACKGROUND:Wilson's disease (WD) is an autosomal recessive disease, which is characterized by an excessive copper accumulation in the liver and brain, leading to subsequent hepatic and/or neurological disorders. The causative gene for WD has been identified as the ATPase Cu2+ transporting beta polypeptide gene (ATP7B), which encodes a protein called copper-transporting ATPase 2. ATP7B mutations may lead to reduced biliary excretion of excess copper and disrupted copper homeostasis, resulting in various clinical symptoms of WD. METHODS: Direct sequencing of the ATP7B gene was performed in 7 Han Chinese families with WD, and haplotype analysis was conducted in families having the same mutation. RESULTS: Nine ATP7B gene mutations were identified, including 7 missense mutations (p.Asp765Gly, p.Arg778Leu, p.Thr888Pro, p.Pro992Leu, p.Asp1047Val, p.Ile1148Thr and p.Ala1295Val), 1 duplication mutation (c.525dupA), and 1 nonsense mutation (p.Gly837*). Combined with our previous data, haplotype analysis revealed that the founder effect accounted for 48% of alleles in Han Chinese, constituted by high allele frequency mutations p.Arg778Leu, p.Pro992Leu and p.Ala1295Val. CONCLUSION: This study revealed genetic defects of 7 Han Chinese families with WD, and has implications for their genetic counseling and clinical management.