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

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in 430 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance. All available family members were clinically evaluated and samples were collected from consenting individuals. Initially, we excluded known CMT2 genes/loci in this family. We then conducted a genome-wide linkage analysis and mapped the gene to chromosome 9q33-q34. Refined linkage and haplotype analyses defined an 11.6-Mb candidate region with a maximum LOD score of 8.06. Following exclusion of several candidate genes from the region, we targeted the LRSAM1 (leucine-rich repeat and sterile alpha motif-containing 1) gene, very recently found to be associated with autosomal recessive CMT2 in one family. For a more efficient investigation of this large gene, already available proband RNA (cDNA) was initially analyzed. Targeted DNA analysis then confirmed a novel LRSAM1 splice-site (c.2047-1G4A) mutation, causing a frameshift that introduces a stop codon three amino acids further down the new reading frame (p.Ala683ProfsX3). This mutation is located in the C-terminal RING finger motif of the encoded protein and leads to premature truncation of the protein. In the course of our work, a second LRSAM1 mutation dominantly transmitted was identified by another group. Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance.

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 mutation in LRSAM1 causes axonal Charcot-Marie-Tooth disease with dominant inheritance

“…Homozygosity mapping yielded a splice site mutation c.1913-1G >A in the LRSAM1 gene giving rise to a premature stop codon 20 bp inside the penultimate exon. Subsequently, two further mutations in LRSAM1 were identified in a Dutch and a Sardinian family with dominant axonal CMT [8,9]. In both studies, the clinical and electrophysiological findings were very similar to that reported by Guernsey et al [7].…”

“…Consistent with this idea, the mutant protein could be detected in blood cells of heterozygous mutation carriers in one family [9]. It is tempting to speculate that such a dominant negative effect results immediately from the disruption of the RING domain, where all three mutations occur (Table 2).…”

PHF23 (plant homeodomain finger protein 23) negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1

“…Therefore, it was deduced that PHF23 may exert antagonistic effects on LRSAM1 in normal physiological conditions. In view of the functional multiplicity of LRSAM1 on anti-infection, 13 Charcot-Marie-Tooth disease, [15][16][17] and colorectal cancer, 19 whether PHF23 is involved in these diseases deserves further study.…”

“…Clinical reports indicate that mutations of LRSAM1 cause Charcot-Marie-Tooth disease. [15][16][17] Loss of LRSAM1 increases the sensitivity of peripheral axon degeneration in a mouse model of Charcot-Marie-Tooth disease, 18 indicating that dysregulation of LRSAM1 is implicated in neuronal development and homeostasis. A recent finding indicates that the level of LRSAM1 is significantly upregulated in patients with colorectal cancer, 19 implying that the aberrant expression of LRSAM1 may be involved in the cancer process.…”