SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve

Abstract

Charcot-Marie-Tooth neuropathy type 1C (CMT1C) is an autosomal dominant demyelinating peripheral neuropathy caused by missense mutations in the small integral membrane protein of lysosome/late endosome (SIMPLE) gene. To investigate the prevalence of SIMPLE mutations, we screened a cohort of 152 probands with various types of demyelinating or axonal and pure motor or sensory inherited neuropathies. SIMPLE mutations were found only in CMT1 patients, including one G112S and one W116G missense mutations. A novel I74I polymorphism was identified, yet no splicing defect of SIMPLE is likely. Haplotype analysis of STR markers and intragenic SNPs linked to the gene demonstrated that families with the same mutation are unlikely to be related. The clustering of the G112S, T115N, and W116G mutations within five amino acids suggests this domain may be critical to peripheral nerve myelination. Electrophysiological studies showed that CMT1C patients from six pedigrees (n = 38) had reduced nerve conduction velocities ranging from 7.5 to 27.0m/sec (peroneal). Two patients had temporal dispersion of nerve conduction and irregularity of conduction slowing, which is unusual for CMT1 patients. We report the expression of SIMPLE in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in CMT1C.

Original article Charcot-Marie-Tooth type 1C disease coexisting with progressive multiple sclerosis: a study of an overlapping syndrome

“…The Gly112Ser mutation in the LITAF gene detected in the CMT family may act in our patient at least in two independent ways. In the peripheral nerve, the mutated LITAF gene causes a typical course of mild peripheral demyelinating neuropathy seen in our proband's affected family members, and was previously described in other CMT1C patients harbouring Gly112Ser mutation [1,8,16,18].…”

“…CMT1C disease is caused by mutations in the lipopolysaccharide-induced tumor necrosis factor-α (LITAF) gene on chromosome 16p12-16p13.3 [1,18,19]. To date only nine pathogenic mutations in the LITAF gene have been reported [6].…”

Mutations associated with Charcot–Marie–Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome–autophagy pathways

“…Genetic studies have identified eight missense mutations in small integral membrane protein of lysosome/late endosome (SIMPLE) that cause autosomal dominant, demyelinating CMT type 1C (CMT1C) (Street et al, 2003;Bennett et al, 2004;Saifi et al, 2005;Latour et al, 2006;Gerding et al, 2009). SIMPLE, also known as lipopolysaccharide-induced TNF-a factor (LITAF), is a 161 amino acid protein that has been implicated in cytokine signaling (Moriwaki et al, 2001;Bolcato-Bellemin et al, 2004) and tumor suppression (Mestre-Escorihuela et al, Wang et al, 2009), but its precise cellular function remains elusive.…”

Dysregulated Inflammatory Signaling upon Charcot-Marie-Tooth Type 1C Mutation of SIMPLE Protein

“…SIMPLE is also clinically important in that specific point mutations in one of the alleles causes autosomal-dominant Charcot-Marie-Tooth type 1C (CMT1C) demyelination (25)(26)(27)(28)(29). To better character CMT1C pathogenesis, we generated a physiological knock-in mouse model with one mutated SIMPLE allele (Simple T115N/ϩ ) (24 (24).…”