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

Abstract

BackgroundCharcot-Marie-Tooth disease (CMT) refers to a heterogeneous group of genetic motor and sensory neuropathies. According to the primary site of damage, a distinction is made between demyelinating and axonal forms (CMT1 and 2, respectively, when inherited as an autosomal dominant trait). Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) is a ubiquitin-protein ligase with a role in sorting internalised cell-surface receptor proteins. So far, mutations in the LRSAM1 gene have been shown to cause axonal CMT in three different families and can confer either dominant or recessive transmission of the disease.Case presentationWe have identified a novel mutation in LRSAM1 in a small family with dominant axonal CMT. Electrophysiological studies show evidence of a sensory axonal neuropathy and are interesting in so far as giant motor unit action potentials (MUAPs) are present on needle electromyography (EMG), while motor nerve conduction studies including compound motor action potential (CMAP) amplitudes are completely normal. The underlying mutation c.2046+1G >T results in the loss of a splice donor site and the inclusion of 63 additional base pairs of intronic DNA into the aberrantly spliced transcript. This disrupts the catalytically active RING (Really Interesting New Gene) domain of LRSAM1.ConclusionsOur findings suggest that, beyond the typical length-dependent degeneration of motor axons, damage of cell bodies in the anterior horn might play a role in LRSAM1-associated neuropathies. Moreover, in conjunction with other data in the literature, our results support a model, by which disruption of the C-terminal RING domain confers dominant negative properties to LRSAM1.

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).…”

9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping

“…We believe that the deletion of LRSAM1 should not lead to features of CMT disease in the future, as patients reported to date either followed autosomal-recessive inheritance in the presence of 2 null alleles or autosomal-dominant inheritance in the presence of heterozygous null variants in the C-terminal domain, thus suggesting a dominant-negative effect. 20 Likewise, the DNM1 gene, encoding dynamin-1, a GTPase involved in synaptic vesicle endocytosis in the brain during early neuronal development and postnatal synaptic maturation, 21 is deleted in three out of our four patients. So far, five patients with missense heterozygous de novo variants of DNM1 have been reported.…”

Charcot–Marie–Tooth disease type 2G redefined by a novel mutation in LRSAM1

“…32 The only known ubiquitylation target of LRSAM1 is the tumor susceptibility 101 protein (TSG101), which is involved in lysosomal sorting of ubiquitylated cargo. [17][18][19][20] Here, we report the first causal missense mutation in LRSAM1, which also targets the RING zinc finger. 33 The 4 reported LRSAM1 mutations truncate, disrupt, or abolish its catalytic RING zinc finger domain.…”

“…Mutations in LRSAM1 were recently found to cause autosomal dominant [18][19][20] and recessive 17 CMT2P. The dominant mutations described so far are associated with a relatively mild, very slowly progressive sensorimotor axonal neuropathy initially affecting lower limbs.…”

“…Reported LRSAM1 mutations affect the length [18][19][20] or abundance 17 of the protein. Therefore, we compared LRSAM1 protein levels in lymphoblasts from 5 mutation carriers and 4 noncarriers, yet observed no difference in expression between both groups ( Fig 4A).…”