title: 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.affiliation: Department of Pediatrics, Division of Genetics and Developmental Medicine, University of Washington, Seattle, WA, USA. cbenet@u.washington.edu
authors.forename: Craig L
authors.initials: CL
authors.lastname: Bennett
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Shirk
authors.forename: Huy M
authors.initials: HM
authors.lastname: Huynh
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Street
authors.forename: Eva
authors.initials: E
authors.lastname: Nelis
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.forename: Peter
authors.initials: P
authors.lastname: Van Den Bergh
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Radim
authors.initials: R
authors.lastname: Mazanec
authors.forename: Tomas
authors.initials: T
authors.lastname: Prochazka
authors.forename: Ivo
authors.initials: I
authors.lastname: Kremensky
authors.forename: Jana
authors.initials: J
authors.lastname: Haberlova
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weiss
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Phillip F
authors.initials: PF
authors.lastname: Chance
mesh_terms: D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D010375:Pedigree; D012584:Sciatic Nerve / Q000737:chemistry* / Q000473:pathology / Q000502:physiology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*
chemical_list: C118738:LITAF protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors