Human Molecular Genetics Advance Access first published online on October 28, 2009
This version [Corrected Proof] published online on November 9, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp496
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Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies
1 Departments of Ophthalmology, 2 Biological Sciences and 3 Medical Genetics, University of Alberta, Edmonton, Canada, 4 Department of Genetics, Aravind Medical Research Foundation, Madurai, India, 5 Faculté de Médecine Paris-descartes-Site Necker, Université Paris-Descartes, EA no. 2502 du Ministère de la Recherche, AP-HP, CHU Necker-Enfants Malades, 75015 Paris, France and 6 Department of Cell and Developmental Biology, University of British Columbia, Vancouver, Canada
* To whom correspondence should be addressed at: Departments of Ophthalmology and Medical Genetics, University of Alberta, 8-29 Medical Sciences Building, Edmonton, AB, Canada, T6G 2H7. Tel: +1 7804928550; Fax: +1 7804926934; E-mail: olehmann{at}ualberta.ca
Received July 10, 2009; Revised October 19, 2009; Accepted October 26, 2009
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.
These two authors contributed equally to this work.