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

Inherited Cu Disorders Current Drug Metabolism, 2012, Vol. 13, No. 3 239Genetic disorders involving copper metabolism are characterizedby either copper deficiency or accumulation, which manifest inthe form of MD, OHS, and WD (Table 1). Recently, missense mutationsin ATP7A, resulting in normal protein levels but defects incopper trafficking, have been identified and reported to cause X-linked distal hereditary motor neuropathy without overt signs ofsystemic copper deficiency [30].III. GENE, STRUCTURE, AND FUNCTION OF ATP7A ANDATP7BThe ATP7A gene maps to chromosome Xq13.3 and encodes aprotein that is 1,500 amino acids long with a molecular weight of165 kDa [7-9]. ATP7A protein is expressed in almost all tissuesexcept the liver. In an animal model of MD, ATP7A is expressed inastrocytes and cerebrovascular endothelial cells comprising theblood-brain barrier, as well as in neurons and choroid plexus cells,indicating that ATP7A plays a role in intracellular copper transportin these cell types [31,32]. In contrast, the ATP7B gene maps tochromosome 13q14.3 and encodes a protein that is 1,411 aminoacids long [12-15]. The overall sequence homology betweenATP7A and ATP7B is 56%, with greater homology observed in thephosphate domain (78%), transduction and phosphorylation domains(89%), and ATP-binding domain (79%). ATP7B is predominantlyexpressed in the liver, kidney, and placenta, and poorly expressedin the heart, brain, lung, muscle, pancreas, and intestine.The function of ATP7B in non-liver tissues remains unclear.ATP7A and ATP7B contain six amino-terminal metal bindingdomains, a phosphorylation and phosphatase domain, and eighttransmembrane domains (Fig. 4). Each protein contains six repeatingmotifs, GMXCXXC, that bind copper stoichiometrically ascopper(I) ion at 5-6 nmol of copper/nmol of protein. This suggeststhat each motif binds one copper atom. ATP7A and ATP7B arepredominately localized in the trans-Golgi network and transportcopper from the cytosol into the Golgi apparatus. When copperlevels rise inside cells, ATP7A and ATP7B traffic towards theplasma membrane to excrete excess copper [33]. Functional assaysinvolving yeast complementation [34,35] and insect cells [36] havebeen reported, however, these assays are too complicated to standardizeand use in a clinical test. Establishing a functional assaythat can be used clinically to test for ATP7A and ATP7B activitywill be beneficial not only for diagnosis of these disorders, but alsoto study genotype-phenotype correlations.IV. MENKES DISEASE (MD) AND OCCIPITAL HORNSYNDROME (OHS)4.1. GeneticsGenetic disorders associated with mutations in the ATP7A geneare clinically divided into three categories: classical MD (referredto as MD in this review), mild MD, and OHS. MD and OHS areboth X-linked recessive disorders which typically occur in malepatients. In Japan, the incidence of MD is estimated to be 1/140,000live male births [37]. Patients diagnosed with MD have a largevariety of mutations in the ATP7A gene [17,38-40]. About 357different mutations, including insertions and deletions (22%), nonsense(18%), missense (17%), partial deletions (17%), and splicesitemutations (16%) have been described [40]. Furthermore, ge-Table 1.Characteristics of Inherited Copper Transport Disorders in HumansCharacteristics Menkes Disease Occipital Horn Syndrome Wilson’s DiseaseInheritance X-linked recessive Autosomal recessivePrevalence 1/140,000 male births Rare 1/30,000-1/35,000Responsible gene ATP7A ATP7BGene location Xq13.3 13q14.3Gene product Copper-transporting P-type ATPase (ATP7A) Copper-transporting P-type ATPase (ATP7B)ExpressionAlmost all tissues except liverLiver, kidney, placenta, lung, brain, heart, muscle,pancreas, and intestine.MutationsNo common mutationsSplice-site mutations, missensemutationsR778L and H1069Q substitutions are common inAsian and European patients, respectively.PathogenesisDefect of intestinal Cu absorption;reduced activities of Cu-dependentenzymesPartial defect of intestinal Cu absorption;reduced activities of CudependentenzymesCopper toxicosis; defects of biliary Cu excretionand Cu incorporation into ceruloplasmin in theliver; copper accumulates in various tissuesClinical featuresSevere neurological degeneration,abnormal hair, hypothermia, and connectivetissue disordersConnective tissue disorders, gaitabnormalities, muscle hypotoniaLiver diseases, neurological diseases and psychiatricmanifestations, Kayser-Fleischer rings, hematuria,arthritis, cardiomyopathy, and pancreatitisLaboratory featuresDecreased serum Cu and ceruloplasmin,and increased Cu concentrationsin cultured fibroblastsSlightly decreased serum Cu andceruloplasmin, increased Cu concentrationsin cultured fibroblasts,and exostosis on occipital bonesDecreased serum Cu and ceruloplasmin, increasedurinary Cu excretion, and increased liver CuconcentrationTreatmentCu-histidine injectionsChelating agents (e.g., penicillamine, trientine),zinc and liver transplantationAnimal modelsMacular and brindled miceBlotchy mouseLong?Evans Cinnamon (LEC) ratToxic milk mouse28