AR CMT: Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with C

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PLoS Genet. 2010 Aug 26;6(8). pii: e1001081.

Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with

Charcot-Marie-Tooth Disease.

Guernsey DL, Jiang H, Bedard K, SC, Ferguson M, Matsuoka M, Macgillivray

C, Nightingale M, S, Rideout AL, Orr A, Ludman M, Skidmore DL, Benstead T,

s ME.

Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.

Abstract

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor

neuropathies. We studied a large family from a rural eastern Canadian community,

with multiple individuals suffering from a condition clinically most similar to

autosomal recessive axonal CMT, or AR-CMT2.

Homozygosity mapping with high-density SNP genotyping of six affected

individuals from the family excluded 23 known genes for various subtypes of CMT

and instead identified a single homozygous region on chromosome 9, at

122,423,730-129,841,977 Mbp, shared identical by state in all six affected

individuals.

A homozygous pathogenic variant was identified in the gene encoding leucine rich

repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes

within the region in affected DNA samples. The single nucleotide change mutates

an intronic consensus acceptor splicing site from AG to AA.

Direct analysis of RNA from patient blood demonstrated aberrant splicing of the

affected exon, causing an obligatory frameshift and premature truncation of the

protein. Western blotting of immortalized cells from a homozygous patient showed

complete absence of detectable protein, consistent with the splice site defect.

LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for

proper adhesion of neuronal cells in culture.

Other ubiquitin ligases play documented roles in neurodegenerative diseases.

LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our

kindred.