CMT 2B: Characterization of the Rab7K157N mutant protein associated with

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Biochem Biophys Res Commun. 2008 May 20.

Characterization of the Rab7K157N mutant protein associated with

Charcot-Marie-Tooth type 2B.

De Luca A, Progida C, Spinosa MR, Alifano P, Bucci C.

Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali

(DiSTeBA), Università del Salento, Via Provinciale Monteroni, 73100

Lecce, Italy.

Four missense mutations, that target highly conserved amino acid

residues in the small GTPase Rab7, have been associated with the

Charcot-Marie-Tooth (CMT) type 2B phenotype. CMT2B peripheral axonal

neuropathies are characterized by severe sensory loss, often

complicated by infections, arthropathy, and amputations.

Here, we have investigated the biochemical and functional properties

of the Rab7 K157N mutated protein. Interestingly, Rab7 K157N showed

altered nucleotide exchange rate and GTP hydrolysis compared to the

wild type protein. Consistently, the majority of the expressed

protein in HeLa cells was bound to GTP. In addition, Rab7 K157N was

able to restore EGF degradation, previously inhibited by Rab7

silencing.

Altogether these data indicate that Rab7 K157N, similarly to the

other three mutated proteins causative of CMT2B, is predominantly in

the GTP-bound form and behaves as an active mutant. Therefore,

activated forms of Rab7 protein cause the CMT2B disease.