Connexin32 mutations cause loss of function in Schwann cells and oligodendrocytes leading to PNS and CNS myelination defects.
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.
Sargiannidou
Irene
I
Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus.
Vavlitou
Natalie
N
Aristodemou
Sophia
S
Hadjisavvas
Andreas
A
Kyriacou
Kyriacos
K
Scherer
Steven S
SS
Kleopa
Kleopas A
KA
D000818:Animals; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D017630:Connexins / Q000235:genetics* / Q000502:physiology; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D017933:Peripheral Nervous System / Q000378:metabolism / Q000473:pathology*; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology*; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D000097002:Gap Junction beta-1 Protein