CMT 4C: Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-M

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Hum Mol Genet. 2009 Dec 22.

Mistargeting of SH3TC2 away from the recycling endosome causes

Charcot-Marie-Tooth Disease Type 4C.

RC, Peden AA, Buss F, Bright NA, Latouche M, Reilly MM, Kendrick-

J, Luzio JP.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge,

CB2 0XY, UK.

Mutations in the functionally uncharacterized protein SH3TC2 are associated with

the severe hereditary peripheral neuropathy, Charcot-Marie-Tooth disease type 4C

(CMT4C). Similarly to other proteins mutated in CMT, a role for SH3TC2 in

endocytic membrane traffic has been previously proposed. However, recent

descriptions of the intracellular localization of SH3TC2 are conflicting.

Furthermore, no clear functional pathogenic mechanisms have so far been proposed

to explain why both nonsense and missense mutations in SH3TC2 lead to similar

clinical phenotypes.

Here, we describe our intracellular localization studies, supported by

biochemical and functional data, using wild type and mutant SH3TC2. We show that

wild type SH3TC2 targets to the intracellular recycling endosome by associating

with the small GTPase, Rab11, which is known to regulate the recycling of

internalized membrane and receptors back to the plasma membrane. Furthermore, we

demonstrate that SH3TC2 interacts preferentially with the GTP-bound form of

Rab11, identifying SH3TC2 as a novel Rab11 effector.

Of clinical pathological relevance, all SH3TC2 constructs harbouring

disease-causing mutations are shown to be unable to associate with Rab11 with

consequent loss of recycling endosome localization. Moreover, we show that wild

type SH3TC2, but not mutant SH3TC2, influences transferrin receptor dynamics,

consistent with a functional role on the endocytic recycling pathway. Our data

therefore implicate mistargeting of SH3TC2 away from the recycling endosome as

the fundamental molecular defect that leads to CMT4C.