CONNEXIN32-NULL MICE DEVELOP DEMYELINATING PERIPHERAL NEUROPATHY

Mutations in the gene encoding the gap junction protein connexin32 (Cx 32) cause X-linked Charcot-Marie-Tooth disease (CMTX), a common form o f inherited demyelinating peripheral neuropathy. To learn more about t he pathogenesis of CMTX, we examined the PNS and CNS of cx32-null mice (cx32 -/Y males and cx32 -/- females) by light and electron microscop y. These mice develop a progressive demyelinating peripheral neuropath y beginning by 3 months of age, and at all ages, motor fibers are more affected than sensory fibers. Like other genes of the X chromosome, t he cx32 gene appears to be randomly inactivated, since only some myeli nating Schwann cells express Cx32 in heterozygous cx32+/- females. Het erozygous cx32+/- females have fewer demyelinated and remyelinated axo ns than age-matched homozygous cx32-/- females and cx-32-/Y males. Alt hough oligodendrocytes also express Cx32, no abnormalities in CNS myel in were found. These findings indicate that a null cx32 allele in myel inating Schwann cells is sufficient to cause an inherited demyelinatin g neuropathy, so that Cx32 has an essential role in myelinating Schwan n cells both in mice and in humans. GLIA 24:8-20, 2998. (C) 1998 Wiley -Liss, Inc.