A novel missense mutation of CMT2P alters transcription machinery

Objective Charcot–Marie–Tooth type 2P (CMT2P) has been associated with frameshift mutations in the RING domain of LRSAM1 (an E3 ligase). This study describes families with a novel missense mutation of LRSAM1 gene and explores pathogenic mechanisms of CMT2P. Methods Patients with CMT2P were characterized clinically, electrophysiologically, and genetically. A neuronal model with the LRSAM1 mutation was created using CRISPR/Cas9 technology. The neuronal cell line along with fibroblasts isolated from the patients was used to study RNA‐binding proteins. Results This American family with dominantly inherited axonal polyneuropathy reveals a phenotype similar to those in previously reported non‐US families. The affected members in our family cosegregated with a novel missense mutation Cys694Arg that alters a highly conserved cysteine in the RING domain. This mutation leads to axonal degeneration in the in vitro neuronal cell line. Moreover, using protein mass spectrometry, we identified a group of RNA‐binding proteins (including FUS, a protein critically involved in motor neuron degeneration) that interacted with LRSAM1. The interactions were disrupted by the Cys694Arg mutation, which resulted in reduction of intranuclear RNA‐binding proteins. Interpretation Our findings suggest that the mutant LRSAM1 may aberrantly affect the formation of transcription machinery. Given that a similar mechanism has been reported in motor neuron degeneration of amyotrophic lateral sclerosis, abnormalities of RNA/RNA‐binding protein complex may play a role in the neuronal degeneration of CMT2P. Ann Neurol 2016;80:834–845