Missence Mutation in the SH3TC2 protein causing CMT 4C Affect It's Localization

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Hum Mol Genet. 2009 Sep 10.

Missence Mutation in the SH3TC2 protein causing Charcot Marie Tooth Disease 4c

Affect its Localization in the plasma membrane and endocytic pathway.

Lupo V, Galindo MI, Martínez-Rubio D, Sevilla T, Vílchez JJ, Palau F, Espinós C.

Genetics and Molecular Medicine Unit, Instituto de Biomedicina de Valencia

(IBV), CSIC, 46010 Valencia, Spain.

Mutations in SH3TC2 (KIAA1985) cause Charcot-Marie-Tooth disease (CMT) type 4C,

a demyelinating inherited neuropathy characterized by early onset and scoliosis.

Here we demonstrate that the SH3TC2 protein is present in several components of

the endocytic pathway including early endosomes, late endosomes and

clathrin-coated vesicles close to the trans-Golgi network, and in the plasma

membrane. Myristoylation of SH3TC2 in glycine 2 is necessary but not sufficient

for the proper location of the protein in the cell membranes. In addition to

myristoylation, correct anchoring also needs the presence of SH3 and TPR

domains. Mutations that cause a stop codon and produce premature truncations

that remove most of the TPR domains are expressed as the wild type protein. In

contrast, missense mutations in or around the region of the first TPR domain are

absent from early endosomes, reduced in plasma membrane and late endosomes, and

are variably present in clathrin-coated vesicles. Our findings suggest that the

endocytic and membrane trafficking pathway is involved in the pathogenesis of

CMT4C disease. We postulate that missense mutations of SH3TC2 could impair

communication between the Schwann cell and the axon causing an abnormal myelin

formation.