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

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.

• Authors: Marina L Kennerson, Garth A Nicholson, Stephen G Kaler, Bartosz Kowalski, Julian F B Mercer, Jingrong Tang, Roxana M Llanos, Shannon Chu, Reinaldo I Takata, Carlos E Speck-Martins, Jonathan Baets, Leonardo Almeida-Souza, Dirk Fischer, Vincent Timmerman, Philip E Taylor, Steven S Scherer, Toby A Ferguson, Thomas D Bird, Peter De Jonghe, Shawna M E Feely, Michael E Shy, James Y Garbern
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 86 Issue 3 Pg. 343-52 (Mar 12 2010) ISSN: 1537-6605 [Electronic] United States
• PMID: 20170900 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cation Transport Proteins
• DNA Primers
• RNA, Messenger
• Copper
• Adenosine Triphosphatases
• ATP7A protein, human
• Copper-Transporting ATPases

Topics

• Adenosine Triphosphatases (chemistry, genetics, metabolism)
• Adolescent
• Adult
• Amino Acid Sequence
• Base Sequence
• Cation Transport Proteins (chemistry, genetics, metabolism)
• Cells, Cultured
• Child, Preschool
• Copper (metabolism)
• Copper-Transporting ATPases
• DNA Primers (genetics)
• Female
• Genetic Association Studies
• Genetic Complementation Test
• Genetic Diseases, X-Linked (genetics, metabolism)
• Humans
• Immunohistochemistry
• Male
• Menkes Kinky Hair Syndrome (genetics, metabolism)
• Middle Aged
• Models, Molecular
• Molecular Sequence Data
• Motor Neuron Disease (genetics, metabolism)
• Mutation, Missense
• Pedigree
• RNA, Messenger (genetics, metabolism)
• Sequence Homology, Amino Acid
• Syndrome
• Young Adult