CMT X: Connexin32 mutations cause loss of function in Schwann cells and oligoden

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J Neurosci. 2009 Apr 15;29(15):4736-49.

Connexin32 mutations cause loss of function in Schwann cells and

oligodendrocytes leading to PNS and CNS myelination defects.

Sargiannidou I, Vavlitou N, Aristodemou S, Hadjisavvas A, Kyriacou K, Scherer

SS, Kleopa KA.

Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, 1683

Nicosia, Cyprus.

The gap junction (GJ) protein connexin32 (Cx32) is expressed by myelinating

Schwann cells and oligodendrocytes and is mutated in X-linked

Charcot-Marie-Tooth disease. In addition to a demyelinating peripheral

neuropathy, some Cx32 mutants are associated with transient or chronic CNS

phenotypes.

To investigate the molecular basis of these phenotypes, we generated transgenic

mice expressing the T55I or the R75W mutation and an IRES-EGFP, driven by the

mouse Cnp promoter. The transgene was expressed in oligodendrocytes throughout

the CNS and in Schwann cells. Both the T55I and the R75W mutants were localized

in the perinuclear cytoplasm, did not form GJ plaques, and did not alter the

expression or localization of two other oligodendrocytic GJ proteins, Cx47 and

Cx29, or the expression of Cx29 in Schwann cells.

On wild type background, the expression of endogenous mCx32 was unaffected by

the T55I mutant, but was partly impaired by R75W. Transgenic mice with the R75W

mutation and all mutant animals with Gjb1-null background developed a

progressive demyelinating peripheral neuropathy along with CNS myelination

defects.

These findings suggest that Cx32 mutations result in loss of function in

myelinated cells without trans-dominant effects on other GJ proteins. Loss of

Cx32 function alone in the CNS causes myelination defects.