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Ann Neurol. 2016 Dec;80(6):834-845. doi: 10.1002/ana.24776. Epub 2016 Sep 27.

A novel missense mutation of CMT2P alters transcription machinery.

Author information

1
Department of Neurology, Center for Human Genetic Research, and Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN.
2
Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL.

Abstract

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.

Comment in

PMID:
27615052
PMCID:
PMC5177458
DOI:
10.1002/ana.24776
[Indexed for MEDLINE]
Free PMC Article

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