CMT 4C: SH3TC2/KIAA1985 protein is required for proper myelination and the integ

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Proc Natl Acad Sci U S A. 2009 Sep 29.

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of

the node of Ranvier in the peripheral nervous system.

Arnaud E, Zenker J, de Preux AS, Stendel C, Roos A, Médard JJ, Tricaud

N, Weis J, Suter U, Senderek J, Chrast R.

Department of Medical Genetics and Graduate Program in Neurosciences, University

of Lausanne, CH-1005 Lausanne, Switzerland.

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.