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

• DOI: 10.1371/journal.pgen.1002146
• Publication Date: 2011-07-07T20:58:09Z
• Authors: Oliver Tress; Marta Maglione; Armin Zlomuzica; Dennis May; Nikolai Dicke; Joachim Degen; Ekrem Dere; Helmut Kettenmann; Dieter Hartmann; Klaus Willecke
• Keywords: Astrogliosis; Null allele; Proteolipid protein 1; Nonsense mutation

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