Journal Article

Mutation of the bone morphogenetic protein <i>GDF3</i> causes ocular and skeletal anomalies

Ming Ye, Karyn M. Berry-Wynne, Mika Asai-Coakwell, Periasamy Sundaresan, Tim Footz, Curtis R. French, Marc Abitbol, Valerie C. Fleisch, Nathan Corbett, W. Ted Allison, Garry Drummond, Michael A. Walter, T. Michael Underhill, Andrew J. Waskiewicz and Ordan J. Lehmann

in Human Molecular Genetics

Volume 19, issue 2, pages 287-298
Published in print January 2010 | ISSN: 0964-6906
Published online November 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp496
Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies

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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.

Journal Article.  6053 words.  Illustrated.

Subjects: Genetics and Genomics

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