Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy

Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Concord, Australia.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2010; 86(3):343-52. DOI: 10.1016/j.ajhg.2010.01.027
Source: PubMed


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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    • "ATP7A mutations also underlie occipital horn syndrome (OHS), a milder disease with moderate neurologic symptoms and prominent connective tissue disturbances (Kaler, 2011). Recently, a novel ATP7A-related disease phenotype was discovered, spinal muscular atrophy, distal , X-linked 3 (SMAX3), which is characterized by atrophy of the lower limb muscles (Kennerson et al., 2010). ATP7A is targeted to the trans-Golgi network from where it supplies copper to the copper-dependent enzymes as they migrate through the secretory pathway. "
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    • "ATP7A gene on X-chromosome was shown to be responsible for Menkes disease.[1112] Other phenotypes associated with ATP7A mutations are Occipital Horn Syndrome and adult-onset distal motor neuropathy.[13] ATP7A plays a critical role in axonal outgrowth, synapse integrity and neuronal activation.[14] "
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