(mentions CMT X) : Gap junction disorders of myelinating cells.

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Rev Neurosci. 2010;21(5):397-419

Gap junction disorders of myelinating cells.

Kleopa KA, Orthmann- J, Sargiannidou I.

Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics,

Nicosia, Cyprus.

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Abstract

Gap junctions (GJs) are channels that allow the diffusion of ions and small

molecules across apposed cell membranes. In peripheral nerves, Schwann cells

express the GJ proteins connexin32 (Cx32) and Cx29, which have distinct

localizations. Cx32 forms GJs through non-compact myelin areas, whereas Cx29

forms hemichannels in the innermost layers of myelin apposing axonal Shaker-type

K+ channels.

In the CNS, rodent oligodendrocytes express Cx47, Cx32 and Cx29. Cx47 is

expressed by all types of oligodendrocytes both in the white and grey matter and

forms GJs on cell bodies and proximal processes, as well as most of the

intercellular channels with astrocytes. Cx32 is expressed mostly by white matter

oligodendrocytes and is localized in the myelin sheath of large diameter fibers.

Cx29, and its human ortholog Cx31.3, appear to be restricted to oligodendrocytes

that myelinate small caliber fibers, likely forming hemichannels.

The importance of intercellular and intracellular GJs in myelinating cells are

demonstrated by human disorders resulting from mutations affecting GJ proteins.

The X-linked Charcot Marie Tooth disease (CMT1X) is caused by hundreds of

mutations affecting Cx32. Patients with CMT1X present mainly with a progressive

peripheral neuropathy, which may be accompanied by CNS myelin dysfunction.

Mutations in Cx47 may cause a devastating leukodystrophy called

Pelizaeus-Merzbacher-like disease or a milder spastic paraplegia. In addition,

CNS demyelination may be caused by defects in genes expressing astrocytic GJ

proteins, which are essential for oligodendrocytes.

Findings from in vitro and in vivo models of these disorders developed over the

last decade indicate that most mutations cause loss of function and an inability

of the mutant connexins to form functional GJs. Here we review the clinical,

genetic, and neurobiological aspects of GJ disorders affecting the PNS and CNS

myelinating cells.