Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease

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.

A LRSAM1 mutation links Charcot–Marie–Tooth type 2 to Parkinson's disease

“…Recently, members of our group identified a frameshift mutation in LRSAM1 as the cause of dominantly inherited, axonal sensorimotor neuropathy in a Dutch family (Charcot–Marie–Tooth, CMT, type 2P) 1. This finding was confirmed by others,2, 3 and another homozygous mutation in this gene was previously found in a recessive CMT family (AR‐CMT2P) 4. In the original paper on the Dutch family, the clinical description incidentally mentioned that two of the affected members showed signs of Parkinson's disease (PD).…”

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease

“…The other two axonal CMT recently reported LRSAM1 mutations similarly cause disturbance or absence of the RING domain. The p.Glu638AlafsX7 mutation that has been reported in AR axonal CMT, 18 results in truncation of the protein at amino acid 645, totally abolishing the RING finger domain. The p.Leu708ArgfsX28 mutation that has been reported in AD axonal CMT, 19 results in the exchange of leucine at the C-terminal end of the RING motif to arginine and the production of an altered and elongated protein, thus also altering the RING finger domain of LRSAM1.…”

“…17 Recently, two novel LRSAM1 mutations were associated with axonal CMT neuropathies. 18,19 The p.Glu638AlafsX7 mutation has been reported in a family with AR axonal CMT and the p.Leu708ArgfsX28 mutation has been identified in a family with AD axonal CMT (CMT2). The leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1) protein is a RING finger protein with multiple functions that has a role in receptor endocytosis.…”

Wnt Signaling Network in Homo Sapiens

“…TSG101 itself is a tumor suppressor gene, which has a role in maturation of human immunodeficiency virus, and LRSAM1 is implicated in its metabolism directly by polyubiquitination (Guernsey et al, 2010). The functional disruption of TSG101 led both to cellular transformation and to tumors that metastasized spontaneously in nude mice (Li and Cohen, 1996).…”