Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.


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.

DOI: 10.1016/j.ajhg.2010.01.027

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@article{Kennerson2010MissenseMI, title={Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.}, author={Marina L. Kennerson and Garth A. Nicholson and Stephen G Kaler and Bartosz Kowalski and Julian F. B. Mercer and Jingrong Tang and Roxana M. Llanos and Shannon Chu and Reinaldo Issao Takata and Carlos Eduardo Speck-Martins and Jonathan Baets and Leonardo Almeida-Souza and Dirk Fischer and Vincent Timmerman and P. E. Taylor and Steven S . Scherer and Toby A. Ferguson and Thomas D. Bird and Peter de Jonghe and Shawna M. E. Feely and Michael E. Shy and James Y. Garbern}, journal={American journal of human genetics}, year={2010}, volume={86 3}, pages={343-52} }