title: SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.
abstract: Charcot-Marie-Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2/KIAA1985, was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2(DeltaEx1/DeltaEx1) knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2(DeltaEx1/DeltaEx1) animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2(DeltaEx1/DeltaEx1) animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.
authors.affiliation: Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Estelle
authors.initials: E
authors.lastname: Arnaud
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zenker
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: de Preux Charles
authors.forename: Claudia
authors.initials: C
authors.lastname: Stendel
authors.forename: Andreas
authors.initials: A
authors.lastname: Roos
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Médard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tricaud
authors.forename: Henning
authors.initials: H
authors.lastname: Kleine
authors.forename: Bernhard
authors.initials: B
authors.lastname: Luscher
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Roman
authors.initials: R
authors.lastname: Chrast
mesh_terms: D000818:Animals; D001706:Biopsy; D002462:Cell Membrane / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005091:Exons; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009154:Mutation; D009186:Myelin Sheath / Q000473:pathology; D015995:Prevalence; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012583:Schwann Cells / Q000473:pathology; D013497:Sural Nerve / Q000473:pathology; D018909:src Homology Domains / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C488620:SH3TC2 protein, human