Charcot-Marie-Tooth Disease Type-2P is Associated with a Missense Mutation in the RING Domain of LRSAM1 (P2.033)

OBJECTIVE: To describe a novel mutation of RING domain in an E3 ligase LRSAM1, which is associated with Charcot-Marie-Tooth type 2P (CMT2P). BACKGROUND: has been associated with LRSAM1 null or mutations that alter a large segment of amino acid sequence in the RING domain of LRSAM1. CMT2P has not been reported in the USA. Here, we describe two American families with a missense mutation that alters a highly conserved cysteine in the RING DESIGN/METHODS: All participants were studied by neurological examination, CMT neuropathy score, nerve conduction studies and DNA sequencing. LRSAM1 constructs were made to express both wide-type and mutant proteins in culture cells for ubiquitination assay. RESULTS: first American family exhibits a dominantly inherited axonal polyneuropathy. The phenotype was identical to those in previously reported non-US families. The affected members in our family were co-segregated with a novel missense mutation Cys694Arg that alters a highly conserved cysteine in the RING domain. The same mutation was also found in another patient from an unrelated American family who exhibited a similar phenotype. We are testing whether this mutation disrupt ubiquitination function of LRSAM1 in our in vitro assay. CONCLUSIONS: Our findings suggest that the mutant RING domain of LRSAM1 plays a key role in the pathogenesis of CMT2P. Study Supported by: NINDS and Muscular Dystrophy Association Disclosure: Dr. Zhu has nothing to disclose. Dr. Arpag has nothing to disclose. Dr. Hamilton has nothing to disclose. Dr. Yawn has nothing to disclose. Dr. Zuchner has received license fee payments from Athena Diagnostics. Dr. Li has nothing to disclose.