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Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the  GJC2  gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher–like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse  Gjc2  gene and inserted the  mCx47M282T  coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous  Cx47M282T  mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous  Cx47M282T  and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of  mCx47M282T  resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous  Cx47M282T  mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult  mCx47M282T  expressing mice did not show substantial myelin alterations, but homozygous  Cx47M282T  mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue.

Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans