A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia.
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.
Flenniken
Ann M
AM
Centre For Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Osborne
Lucy R
LR
Anderson
Nicole
N
Ciliberti
Nadia
N
Fleming
Craig
C
Gittens
Joanne E I
JE
Gong
Xiang-Qun
XQ
Kelsey
Lois B
LB
Lounsbury
Crystal
C
Moreno
Luisa
L
Nieman
Brian J
BJ
Peterson
Katie
K
Qu
Dawei
D
Roscoe
Wendi
W
Shao
Qing
Q
Tong
Dan
D
Veitch
Gregory I L
GI
Voronina
Irina
I
Vukobradovic
Igor
I
Wood
Geoffrey A
GA
Zhu
Yonghong
Y
Zirngibl
Ralph A
RA
Aubin
Jane E
JE
Bai
Donglin
D
Bruneau
Benoit G
BG
Grynpas
Marc
M
Henderson
Janet E
JE
Henkelman
R Mark
RM
McKerlie
Colin
C
Sled
John G
JG
Stanford
William L
WL
Laird
Dale W
DW
Kidder
Gerald M
GM
Adamson
S Lee
SL
Rossant
Janet
J
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
D018031:Connexin 43; D005038:Ethylnitrosourea