A Novel CMT2P Missense Mutation in the RING Domain of LRSAM1 Impairs the Nuclear Transport of FUS (P5.027)

Objective: To describe a novel molecular mechanism for Charcot-Marie-Tooth disease type-2P (CMT2P). Background: has been associated with loss of function of LRSAM1 (an E3 ligase) or frame-shift mutations in the RING domain of LRSAM1. This disease has not been reported from USA and its pathogenic mechanism is unknown. Methods: Two families with CMT2P were clinically and electrophysiologically characterized. Proteins isolated from patient fibroblasts were examined by a variety of protein chemistry assays, including Mass Spectometry, co-immunoprecipiation and Western blot. Results: We have identified two families with dominantly inherited axonal polyneuropathy that is identical to those in previously reported non-US CMT2P 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 of LRSAM1. Using Mass Spectrometry, we have identified several transcriptome proteins that interact with LRSAM1, including FUS, a nuclear protein critically involved in motor neuron degeneration of amyotrophic lateral sclerosis (ALS). The C694R mutation weakens the interaction between LRSAM1 and FUS, and decreases the nuclear transport of FUS. Conclusions: Our findings suggest that the mutant LRSAM1 may contribute to axonal degeneration by a novel molecular mechanism - interfering nuclear transcriptome formation. Disclosure: Dr. Arpag has nothing to disclose. Dr. Hu has nothing to disclose. Dr. Parker has nothing to disclose. Dr. Hamilton has nothing to disclose. Dr. Yawn has nothing to disclose. Dr. Howard has nothing to disclose. Dr. Burnette has nothing to disclose. Dr. Zuchner has received license fee payments from Athena Diagnostics. Dr. Li has nothing to disclose.