CMT 1X: Molecular mechanisms of gap junction mutations in myelinating cells

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Histol Histopathol. 2010 Sep;25(9):1191-206.

Molecular mechanisms of gap junction mutations in myelinating cells.

Sargiannidou I, Markoullis I, Kleopa A.

Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics,

Nicosia, Cyprus.

Abstract

There is an emerging group of neurological disorders that result from genetic

mutations affecting gap junction proteins in myelinating cells. The X-linked

form of Charcot Marie Tooth disease (CMT1X) is caused by numerous mutations in

the GJB1 gene encoding the gap junction protein connexin32 (Cx32), which is

expressed in both Schwann cells in the PNS and oligodendrocytes in the CNS.

with CMT1X present mainly with a progressive peripheral neuropathy, showing

mixed axonal and demyelinating features. In many cases there is also clinical or

subclinical involvement of the CNS with acute or chronic phenotypes of

encephalopathy.

Furthermore, mutations in the GJA12/GJC2 gene encoding the gap junction protein

Cx47, which is expressed in oligodendrocytes, have been identified in families

with progressive leukodystrophy, known as Pelizaeus-Merzbacher-like disease, as

well as in patients with hereditary spastic paraplegia.

Recent studies have provided insights into the pattern of gap junction protein

expression and function in CNS and PNS myelinating cells. Furthermore, in vitro

and in vivo disease models have clarified some of the molecular and cellular

mechanisms underlying these disorders.

Here we provide an overview of the clinical, genetic, and neurobiological

aspects of gap junction disorders affecting the nervous system.