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

Kennerson, Marina L. and Nicholson, Garth A. and Kaler, Stephen G. and Kowalski, Bartosz and Mercer, Julian F. B. and Tang, Jingrong and Llanos, Roxana M. and Chu, Shannon and Takata, Reinaldo I. and Speck-Martins, Carlos E. and Baets, Jonathan and Almeida-Souza, Leonardo and Fischer, Dirk and Timmerman, Vincent and Taylor, Philip E. and Scherer, Steven S. and Ferguson, Toby A. and Bird, Thomas D. and De Jonghe, Peter and Feely, Shawna M. E. and Shy, Michael E. and Garbern, James Y.. (2010) Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. American journal of human genetics, Vol. 86, H. 3. pp. 343-352.

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Official URL: http://edoc.unibas.ch/dok/A6004488

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Abstract

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.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Neuro- und Entwicklungspädiatrie (Weber)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Neuro- und Entwicklungspädiatrie (Weber)
UniBasel Contributors:Fischer, Dirk
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Univ. of Chicago Press
ISSN:0002-9297
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:07 Dec 2012 13:04
Deposited On:07 Dec 2012 13:03

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