SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve.
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.
Bennett
Craig L
CL
Department of Pediatrics, Division of Genetics and Developmental Medicine, University of Washington, Seattle, WA, USA. cbenet@u.washington.edu
Shirk
Andrew J
AJ
Huynh
Huy M
HM
Street
Valerie A
VA
Nelis
Eva
E
Van Maldergem
Lionel
L
De Jonghe
Peter
P
Jordanova
Albena
A
Guergueltcheva
Velina
V
Tournev
Ivailo
I
Van Den Bergh
Peter
P
Seeman
Pavel
P
Mazanec
Radim
R
Prochazka
Tomas
T
Kremensky
Ivo
I
Haberlova
Jana
J
Weiss
Michael D
MD
Timmerman
Vincent
V
Bird
Thomas D
TD
Chance
Phillip F
PF
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*
C118738:LITAF protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors