X linked CMT Research

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1: J Neurosci Res 2002 Jun 1;68(5):522-34

Cellular mechanisms of connexin32 mutations associated with CNS

manifestations.

Kleopa KA, Yum SW, Scherer SS.

Department of Neurology, University of Pennsylvania

School of Medicine, Philadelphia, Pennsylvania.

ABSTRACT:

Both oligodendrocytes and myelinating Schwann cells express the gap

junction protein connexin32 (Cx32). Mutations in the gene encoding Cx32

(GJB1) cause the X-linked form of Charcot-Marie-Tooth disease (CMTX).

Although most CMTX patients do not have

clinical centralnervous system (CNS) manifestations, subclinical

evidence of CNS dysfunction is common. We investigated the cellular

effects of a subgroup of GJB1/Cx32 mutations that have been reported to

cause clinical CNS dysfunction. We hypothesized that these mutants have

dominant-negative effects on other connexins expressed by

oligodendrocytes, specifically Cx45. We expressed these and other Cx32

mutants in

communication-incompetent as well as Cx45-expressing HeLa cells, and

analyzed the transfected cells by immunocytochemistry and

immunoblotting.

In communication-incompetent cells, the mutants associated with CNS

phenotypes failed to reach the cell membrane and were instead retained

in the endoplasmic reticulum

(A39V, T55I) or Golgi apparatus (M93V, R164Q, R183H), although rare gap

junction

plaques were found in cells expressing M93V or R183H.

In HeLa cells stably expressing Cx45, these Cx32 mutants showed a

similar expression

pattern, and did not alter the pattern of Cx45 expression. These results

indicate that Cx32 mutants that are associated with a CNS phenotype do

not interact with Cx45, but may instead have other toxic effects in

oligodendrocytes.

Copyright 2002 Wiley-Liss, Inc.