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.

• Authors: Craig L Bennett, Andrew J Shirk, Huy M Huynh, Valerie A Street, Eva Nelis, Lionel Van Maldergem, Peter De Jonghe, Albena Jordanova, Velina Guergueltcheva, Ivailo Tournev, Peter Van Den Bergh, Pavel Seeman, Radim Mazanec, Tomas Prochazka, Ivo Kremensky, Jana Haberlova, Michael D Weiss, Vincent Timmerman, Thomas D Bird, Phillip F Chance
• Journal: Annals of neurology (Ann Neurol) Vol. 55 Issue 5 Pg. 713-20 (May 2004) ISSN: 0364-5134 [Print] United States
• PMID: 15122712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• LITAF protein, human
• Nuclear Proteins
• Transcription Factors

Topics

• Aged
• Charcot-Marie-Tooth Disease (genetics, pathology, physiopathology)
• Female
• Humans
• Male
• Middle Aged
• Mutation
• Nuclear Proteins (analysis, genetics)
• Pedigree
• Sciatic Nerve (chemistry, pathology, physiology)
• Transcription Factors (analysis, genetics)