Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy
Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy
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DOI：
10.1016/j.ajhg.2010.01.027
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发表时间：
2010-03-12
影响因子：
9.8
通讯作者：
Garbern, James Y.
中科院分区：
文献类型：
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作者：
Kennerson, Marina L.;Nicholson, Garth A.;Garbern, James Y.
远端遗传性运动神经病包括一组临床和遗传上异质性的疾病。我们最近将这种情况的 X 连锁形式映射到两个不相关的大家族的染色体 Xq13.1-q21 上。遗传连锁区域包括 ATP7A，它编码一种铜转运 P 型 ATP 酶，该酶在门克斯病（一种严重的婴儿期发病的神经退行性疾病）患者中发生突变。我们在两个家族中患有远端运动神经病的男性中发现了两种独特的 ATP7A 错义突变（p.P1386S 和 p.T9941）。这些分子改变影响 ATP7A 羧基半部中高度保守的氨基酸，但不直接涉及铜转运蛋白的已知关键功能域。对 p.P1386S 的研究揭示了正常的 ATP7A mRNA 和蛋白质水平、ATP7A 运输缺陷以及酿酒酵母铜运输敲除的部分挽救。尽管 ATP7A 突变通常与严重的门克斯病或其较温和的等位基因变异、枕角综合征相关，但我们在此证明，该位点的某些错义突变可导致仅限于进行性远端运动神经病的综合征，而没有明显的全身铜缺乏迹象。这种先前未被认识的基因型-表型相关性表明 ATP7A 铜转运蛋白在运动神经元的维持和功能中发挥着重要作用。
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.T9941) 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.