title: Specific functional pathologies of Cx43 mutations associated with oculodentodigital dysplasia.
abstract: Oculodentodigital dysplasia (ODDD) is a rare genetic disease that affects the development of multiple organs in the human body. More than 70 mutations in the gap junction connexin43 (Cx43) gene, GJA1, are associated with ODDD, most of which are inherited in an autosomal dominant manner. Many patients exhibit similar clinical presentations. However, there is high intrafamilial and interfamilial phenotypic variability. To better understand this variability, we established primary human dermal fibroblast cultures from several ODDD patients and unaffected controls. In the present study, we characterized three fibroblast lines expressing heterozygous p.L7V, p.G138R, and p.G143S Cx43 variants. All ODDD fibroblasts exhibited slower growth, reduced migration, and defective cell polarization, traits common to all ODDD fibroblasts studied so far. However, we found striking differences in overall expression levels, with p.L7V down-regulated at the mRNA and protein level. Although all of the Cx43 variants could traffic to the cell surface, there were stark differences in gap junction plaque formation, gap junctional intercellular communication, Cx43 phosphorylation, and hemichannel activity among Cx43 variants, as well as subtle differences in myofibroblast differentiation. Together these findings enabled us to discover mutation-specific pathologies that may help to predict future clinical outcomes.
authors.affiliation: Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kelly
authors.affiliation: Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Esseltine
authors.affiliation: Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
authors.affiliation: Department of Neurology, Stanford University Medical Center, Palo Alto, CA 94304.
authors.forename: Jacinda
authors.initials: J
authors.lastname: Sampson
authors.affiliation: Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Auranen
authors.affiliation: Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Donglin
authors.initials: D
authors.lastname: Bai
authors.affiliation: Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 5C1, Canada Physiology and Pharmacology, University of Western Ontario, London, ON N6A 5C1, Canada Dale.Laird@schulich.uwo.ca.
authors.forename: Dale W
authors.initials: DW
authors.lastname: Laird
mesh_terms: D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005532:Foot Deformities, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017629:Gap Junctions / Q000378:metabolism; D006801:Humans; D009154:Mutation; D015398:Signal Transduction; D013576:Syndactyly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014071:Tooth Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human