ATP7A型
门克斯病
错义突变
遗传学
生物
铜缺乏
等位基因
基因座(遗传学)
表型
基因
运输机
化学
铜
有机化学
铜代谢
作者
Marina Kennerson,Garth A. Nicholson,Stephen G. Kaler,Bartosz Kowalski,Julian F. B. Mercer,Jingrong Tang,Roxana M. Llanos,Sheng Chu,Reinaldo Issao Takata,Carlos E. Speck‐Martins,Jonathan Baets,Leonardo Almeida-Souza,Dirk Fischer,Vincent Timmerman,Philip Taylor,Steven S. Scherer,Toby A. Ferguson,Thomas D. Bird,Peter De Jonghe,Shawna Feely,Michael E. Shy,James Garbern
标识
DOI:10.1016/j.ajhg.2010.01.027
摘要
Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function.
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