期刊
HUMAN MOLECULAR GENETICS
卷 19, 期 2, 页码 287-298出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddp496
关键词
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资金
- Canadian Institutes of Health Research
- Alberta Heritage Foundation for Medical Research
- Canadian Foundation for Innovation
- National Scientific Engineering Council and Alberta Ingenuity Fund
- Retina_France and Ministere de la Recherche et de l'Enseignemement Superieur of France
- QEII scholarship
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.
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