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Cited by 231Connexins and lens biologydental development and anomaliesCongenital limb and hand anomalies

A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia

Flenniken, Ann M., Osborne, Lucy R., Anderson, Nicole, Ciliberti, Nadia, Fleming, Craig, Gittens, Joanne E. I., Gong, Xiang-Qun, Kelsey, Lois B. +27 more·2005·Development
DOI 10.1242/dev.02011
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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.

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Authors
Flenniken, A. M., Osborne, L. R., Anderson, N., Ciliberti, N., Fleming, C., Gittens, J. E. I., Gong, X.-Q., Kelsey, L. B., Lounsbury, C., Moreno, L., Nieman, B. J., Peterson, K., Qu, D., Roscoe, W., Shao, Q., Tong, D., Veitch, G. I. L., Voronina, I., Vukobradovic, I., Wood, G. A., Zhu, Y., Zirngibl, R. A., Aubin, J. E., Bai, D., Bruneau, B. G., Grynpas, M., Henderson, J. E., Henkelman, R. M., McKerlie, C., Sled, J. G., Stanford, W. L., Laird, D. W., Kidder, G. M., Adamson, S. L., & Rossant, J.
Affiliations
  • Mount Sinai Hospital (CA)
  • University of Toronto (CA)
  • Western University (CA)
  • Hospital for Sick Children (CA)
  • McGill University (CA)
Corresponding author
Rossant, Janet
ORCID
Venue
Development
Publisher
The Company of Biologists
Published
2005-10-01
Volume
132
Issue
19
Pages
4375-4386
ISSN
  • 0950-1991 (ISSN-L)
  • 1477-9129
DOI
10.1242/dev.02011
OpenAlex
W2041134529
Cited by
231
References
42
Citations by year
2026: 4 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 3 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 10 · 2016: 7 · 2015: 16 · 2014: 13 · 2013: 17 · 2012: 17
FWCI
6.78
Type
journal article
Language
en
Open access
closed
Locations
  • Development (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
Keywords
oculodentodigital dysplasia, connexin 43, missense mutations, mouse model, dominant negative mutation, gap junction assembly, syndactyly, enamel hypoplasia, craniofacial anomalies, cardiac dysfunction, bone mass, hematopoietic stem cells, N-ethyl-N-nitrosourea mutagenesis, positional cloning
MeSH terms
Abnormalities, Multiple, Animals, Biomechanical Phenomena, Bone and Bones, Dental Enamel Hypoplasia, Disease Models, Animal, Ethylnitrosourea, Eye Abnormalities, Heart Defects, Congenital, Humans, Stem Cells, Syndactyly, Bone Density, Point Mutation, Gap Junctions, Connexin 43, Craniofacial Abnormalities, Penetrance, Mice

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