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Acta Myol. 2009 July; 28(1): 41.
PMCID: PMC2859651

O-4. The effects of CMT1X mutations in myelinating cells

X-linked Charcot-Marie-Tooth disease (CMT1X) is an inherited peripheral neuropathy caused by mutations affecting the gap junction protein connexin32 (Cx32), which is expressed in myelinating Schwann cells and oligodendrocytes. A number of Cx32 mutations also cause transient or chronic CNS phenotypes in addition to peripheral neuropathy. In order to clarify the cellular mechanisms of these mutants, we generated transgenic mice expressing the human T55I and R75W Cx32 mutations in myelinating cells both on cx32-wild type (WT) and on cx32-knockout (KO) background. Both mutants were retained in the perinuclear compartment of myelinating cells and did not form gap junction-like plaques. On WT background the expression of endogenous mCx32 was unaffected by the T55I mutant, but was impaired in the presence of R75W. Both the R75W mutant on WT background, as well as both mutants on KO background developed progressive demyelinating neuropathy as well as mild CNS myelination defects. The expression and localization of two other gap junction proteins in myelinating cells, Cx47 and Cx29, was not altered in the presence of Cx32 mutants. These findings suggest that CMT1X mutations result in loss of function in myelinating cells and do not cause trans-dominant negative effects on other gap junction proteins. The loss of Cx32 function is less detrimental to CNS myelinating cells, likely due to higher functional reserve of gap junctional connectivity in oligodendrocytes. CNS phenotypes in patients with CMT1X may occur with age and under conditions of additional metabolic stress such as inflammation or hypoxia.

Articles from Acta Myologica are provided here courtesy of Pacini Editore