Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies
Open Access
- 28 October 2009
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 19 (2), 287-298
- https://doi.org/10.1093/hmg/ddp496
Abstract
Ocular mal-development results in heterogeneous and frequently visually disabling phenotypes that include coloboma and microphthalmia. Due to the contribution of bone morphogenetic proteins to such processes, the function of the paralogue Growth Differentiation Factor 3 was investigated. Multiple mis-sense variants were identified in patients with ocular and/or skeletal (Klippel–Feil) anomalies including one individual with heterozygous alterations in GDF3 and GDF6. These variants were characterized, individually and in combination, through integrated biochemical and zebrafish model organism analyses, demonstrating appreciable effects with western blot analyses, luciferase based reporter assays and antisense morpholino inhibition. Notably, inhibition of the zebrafish co-orthologue of GDF3 accurately recapitulates patient phenotypes. By demonstrating the pleiotropic effects of GDF3 mutation, these results extend the contribution of perturbed BMP signaling to human disease and potentially implicate multi-allelic inheritance of BMP variants in developmental disorders.Keywords
This publication has 30 references indexed in Scilit:
- Mutations in BMP4 Are Associated with Subepithelial, Microform, and Overt Cleft LipAmerican Journal of Human Genetics, 2009
- An essential role for Radar (Gdf6a) in inducing dorsal fate in the zebrafish retinaProceedings of the National Academy of Sciences of the United States of America, 2009
- Mutations in BMP4 Cause Eye, Brain, and Digit Developmental Anomalies: Overlap between the BMP4 and Hedgehog Signaling PathwaysAmerican Journal of Human Genetics, 2008
- Loss-of-Function Mutations in Growth Differentiation Factor-1 (GDF1) Are Associated with Congenital Heart Defects in HumansAmerican Journal of Human Genetics, 2007
- GDF6, a Novel Locus for a Spectrum of Ocular Developmental AnomaliesAmerican Journal of Human Genetics, 2007
- BMP action in skeletogenesis involves attenuation of retinoid signalingThe Journal of cell biology, 2006
- Haploinsufficient Phenotypes inBmp4Heterozygous Null Mice and Modification by Mutations inGli3andAlx4Developmental Biology, 1997
- SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modelingElectrophoresis, 1997
- A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye.Genes & Development, 1995
- A transcript from a Drosophila pattern gene predicts a protein homologous to the transforming growth factor-β familyNature, 1987