Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies

TLDR

Ocular mal-development results in heterogeneous and frequently visually disabling phenotypes that include coloboma and microphthalmia. The study investigated the function of the bone morphogenetic protein paralogue Growth Differentiation Factor 3 due to its role in ocular development. Variants were characterized individually and in combination using integrated biochemical assays, zebrafish models, western blotting, luciferase reporter assays, and antisense morpholino inhibition. Multiple missense variants in GDF3 and GDF6 were found in patients with ocular and skeletal anomalies, and zebrafish inhibition of GDF3 recapitulated these phenotypes, demonstrating pleiotropic effects that extend BMP signaling’s role in human disease and suggest multi‑allelic inheritance.

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.