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 three unrelated families associated with novel missense mutations in ATP7A. The three alterations impact highly conserved amino acids in the carboxyl half of ATP7A, and do not directly involve the copper transporters 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 temperature-sensitive 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 a knock-in mouse model, 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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