タイトル厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

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厚生労働科学研究費補助金（難治性疾患克服研究事業）「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」平成23-24年度 総合研究報告書

240 Current Drug Metabolism, 2012, Vol. 13, No. 3 Kodama et al.Fig. (3). Copper metabolism in normal and abnormal (affected by Wilson’s disease) hepatocytes. CTR1, copper transporter 1; ATP7B, copper-transporting P-type ATPase ; Cp?, ceruloplasmin; ?: copper.Left, copper metabolism in normal hepatocytes. Right, copper metabolism in hepatocyte of patient with Wilson’s disease. In hepatocytes affected by Wilson’sdisease, copper cannot be transported from the cytosol to the Golgi apparatus due to a defect in ATP7B, so copper accumulates in the cytosol. Copper deficiencyin the Golgi apparatus results in reduced secretion of copper into the blood as ceruloplasmin, during which biliary excretion of copper is disturbed.Accumulated copper in the hepatocyte is released into the blood as non-ceruloplasmin-bound copper, although the mechanism is unclear.Fig. (4). Domain organization and catalytic cycle of human copper-ATPases (ATP7A and ATP7B).A: membrane topology and domain organization of Cu-ATPase; MBDs, metal-binding domains; A-domain, the actuator domain; P-domain, phosphorylationdomain; N-domain, nucleotide-binding domain. Modified from Lutsenko et al. Physiol Rev. 2007, 87: 1011. Used with permission.netic analysis indicates that about 75% of patient’s mothers arecarriers, while the remaining 25% are not. This observation suggeststhat new mutations in ATP7A gene have been acquired in MDpatients [41]. Cases of MD in females have been reported, but arerare. In a recent study, Sirleto et al. described 8 females who reportedlyhad MD, and showed that 5 of them carried X-linkedchromosomal abnormalities [42].OHS is the mildest and a rare form of MD, although the prevalencehas not been reported. Mild MD has also been reported, andexhibits intermediate phenotypes between classical MD and OHS[40]. Most ATP7A gene mutations occurring in OHS and mild MDare splice-site or missense mutations [10,40]. Thus, residualATP7A activity can exist [38-40].29