title: A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia.
abstract: Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder characterized by pleiotropic developmental anomalies of the limbs, teeth, face and eyes that was shown recently to be caused by mutations in the gap junction protein alpha 1 gene (GJA1), encoding connexin 43 (Cx43). In the course of performing an N-ethyl-N-nitrosourea mutagenesis screen, we identified a dominant mouse mutation that exhibits many classic symptoms of ODDD, including syndactyly, enamel hypoplasia, craniofacial anomalies and cardiac dysfunction. Positional cloning revealed that these mice carry a point mutation in Gja1 leading to the substitution of a highly conserved amino acid (G60S) in Cx43. In vivo and in vitro studies revealed that the mutant Cx43 protein acts in a dominant-negative fashion to disrupt gap junction assembly and function. In addition to the classic features of ODDD, these mutant mice also showed decreased bone mass and mechanical strength, as well as altered hematopoietic stem cell and progenitor populations. Thus, these mice represent an experimental model with which to explore the clinical manifestations of ODDD and to evaluate potential intervention strategies.
authors.affiliation: Centre For Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Flenniken
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Osborne
authors.forename: Nicole
authors.initials: N
authors.lastname: Anderson
authors.forename: Nadia
authors.initials: N
authors.lastname: Ciliberti
authors.forename: Craig
authors.initials: C
authors.lastname: Fleming
authors.forename: Joanne E I
authors.initials: JE
authors.lastname: Gittens
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Gong
authors.forename: Lois B
authors.initials: LB
authors.lastname: Kelsey
authors.forename: Crystal
authors.initials: C
authors.lastname: Lounsbury
authors.forename: Luisa
authors.initials: L
authors.lastname: Moreno
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nieman
authors.forename: Katie
authors.initials: K
authors.lastname: Peterson
authors.forename: Dawei
authors.initials: D
authors.lastname: Qu
authors.forename: Wendi
authors.initials: W
authors.lastname: Roscoe
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.forename: Dan
authors.initials: D
authors.lastname: Tong
authors.forename: Gregory I L
authors.initials: GI
authors.lastname: Veitch
authors.forename: Irina
authors.initials: I
authors.lastname: Voronina
authors.forename: Igor
authors.initials: I
authors.lastname: Vukobradovic
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Wood
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Zirngibl
authors.forename: Jane E
authors.initials: JE
authors.lastname: Aubin
authors.forename: Donglin
authors.initials: D
authors.lastname: Bai
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.forename: Marc
authors.initials: M
authors.lastname: Grynpas
authors.forename: Janet E
authors.initials: JE
authors.lastname: Henderson
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Colin
authors.initials: C
authors.lastname: McKerlie
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: Dale W
authors.initials: DW
authors.lastname: Laird
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Kidder
authors.forename: S Lee
authors.initials: SL
authors.lastname: Adamson
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001842:Bone and Bones / Q000002:abnormalities / Q000503:physiopathology; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics; D003744:Dental Enamel Hypoplasia / Q000235:genetics; D004195:Disease Models, Animal; D005038:Ethylnitrosourea; D005124:Eye Abnormalities / Q000235:genetics; D017629:Gap Junctions / Q000502:physiology / Q000648:ultrastructure; D006330:Heart Defects, Congenital / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D051379:Mice; D019683:Penetrance; D017354:Point Mutation; D013234:Stem Cells / Q000473:pathology; D013576:Syndactyly / Q000235:genetics
chemical_list: D018031:Connexin 43; D005038:Ethylnitrosourea