title: Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease.
abstract: Recessive mutations in GJA12/Cx47, the gene encoding the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), which is characterized by severe CNS dysmyelination. Three missense PMLD mutations, P87S, Y269D and M283T, were expressed in communication-incompetent HeLa cells, and in each case the mutant proteins appeared to at least partially accumulate in the ER. Cells expressing each mutant did not pass Lucifer Yellow or neurobiotin in scrape loading assays, in contrast to robust transfer in cells expressing wild type Cx47. Dual whole-cell patch clamping of transfected Neuro2A cells demonstrated that none of the mutants formed functional channels, in contrast to wild type Cx47. Immunostaining sections of primate brains demonstrated that oligodendrocytes express Cx47, which is primarily localized to their cell bodies. Thus, the Cx47 mutants associated with PMLD likely disrupt the gap junction coupling between astrocytes and oligodendrocytes.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Room 464 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104-6077, USA. lorthman@mail.med.upenn.edu
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Orthmann-Murphy
authors.forename: Alan D
authors.initials: AD
authors.lastname: Enriquez
authors.forename: Charles K
authors.initials: CK
authors.lastname: Abrams
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002450:Cell Communication / Q000235:genetics*; D017630:Connexins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017629:Gap Junctions / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009154:Mutation; D009836:Oligodendroglia / Q000378:metabolism; D018408:Patch-Clamp Techniques; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014162:Transfection
chemical_list: D017630:Connexins; C427305:connexin 47