Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. Affected individuals manifest progressive weakness and wasting beginning in the distal muscles of the limbs, without notable sensory symptoms. Distal HMNs have been classified into seven subgroups based on mode of inheritance, age of onset, distribution of muscle weakness, and clinical progression. Fifteen genetic loci for distal HMN have been mapped with eight genes identified to date. These encode a functionally diverse array of gene products including a transfer RNA synthetase, two heat shock proteins and a microtubule motor protein involved in axonal transport. We recently identified an X-linked form of this disorder in two unrelated families associated with novel missense mutations in ATP7A. The two alterations impact highly conserved amino acids in the carboxyl half of ATP7A, and do not directly involve the copper transporter's critical functional domains. Functional characterization of mutant alleles included western blotting, immunocytochemical analysis of cultured fibroblasts, and yeast complementation assays. Results indicated normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. While ATP7A defects are typically associated with severe Menkes disease, or its milder allelic variant, occipital horn syndrome, we have demonstrated 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 novel genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor neuron maintenance and function. Our immediate plans include creation and evaluation of knock-in mouse models, additional analyses of ATP7A function and trafficking in cultured cells from affected patients, expression of the mutant alleles in a mouse motor neuron-like cell line (NSC-34), and clinical evaluation of additional affected patients (under protocol #09-CH-0059).

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Yi, Ling; Kaler, Stephen G (2018) Interaction between the AAA ATPase p97/VCP and a concealed UBX domain in the copper transporter ATP7A is associated with motor neuron degeneration. J Biol Chem 293:7606-7617
Yi, Ling; Kaler, Stephen G (2015) Direct interactions of adaptor protein complexes 1 and 2 with the copper transporter ATP7A mediate its anterograde and retrograde trafficking. Hum Mol Genet 24:2411-25
Yi, Ling; Kaler, Stephen (2014) ATP7A trafficking and mechanisms underlying the distal motor neuropathy induced by mutations in ATP7A. Ann N Y Acad Sci 1314:49-54
Kaler, Stephen G (2014) Translational research investigations on ATP7A: an important human copper ATPase. Ann N Y Acad Sci 1314:64-8
Yi, Ling; Donsante, Anthony; Kennerson, Marina L et al. (2012) Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy. Hum Mol Genet 21:1794-807
Donsante, Anthony; Yi, Ling; Zerfas, Patricia M et al. (2011) ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model. Mol Ther 19:2114-23
Kaler, Stephen G (2011) ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol 7:15-29
Møller, Lisbeth B; Hicks, Julia D; Holmes, Courtney S et al. (2011) Diagnosis of copper transport disorders. Curr Protoc Hum Genet Chapter 17:Unit17.9
Kennerson, Marina L; Nicholson, Garth A; Kaler, Stephen G et al. (2010) Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet 86:343-52
Desai, Vishal; Kaler, Stephen G (2008) Role of copper in human neurological disorders. Am J Clin Nutr 88:855S-8S

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