Journal Article

Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes

Mika Asai-Coakwell, Curtis R. French, Ming Ye, Kamal Garcha, Karin Bigot, Anoja G. Perera, Karen Staehling-Hampton, Silvina C. Mema, Bhaskar Chanda, Arcady Mushegian, Steven Bamforth, Michael R. Doschak, Guang Li, Matthew B. Dobbs, Philip F. Giampietro, Brian P. Brooks, Perumalsamy Vijayalakshmi, Yves Sauvé, Marc Abitbol, Periasamy Sundaresan, Veronica van Heyningen, Olivier Pourquié, T. Michael Underhill, Andrew J. Waskiewicz and Ordan J. Lehmann

in Human Molecular Genetics

Volume 18, issue 6, pages 1110-1121
Published in print March 2009 | ISSN: 0964-6906
Published online January 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp008
Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes

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Proteins of the bone morphogenetic protein (BMP) family are known to have a role in ocular and skeletal development; however, because of their widespread expression and functional redundancy, less progress has been made identifying the roles of individual BMPs in human disease. We identified seven heterozygous mutations in growth differentiation factor 6 (GDF6), a member of the BMP family, in patients with both ocular and vertebral anomalies, characterized their effects with a SOX9-reporter assay and western analysis, and demonstrated comparable phenotypes in model organisms with reduced Gdf6 function. We observed a spectrum of ocular and skeletal anomalies in morphant zebrafish, the latter encompassing defective tail formation and altered expression of somite markers noggin1 and noggin2. Gdf6+/− mice exhibited variable ocular phenotypes compatible with phenotypes observed in patients and zebrafish. Key differences evident between patients and animal models included pleiotropic effects, variable expressivity and incomplete penetrance. These data establish the important role of this determinant in ocular and vertebral development, demonstrate the complex genetic inheritance of these phenotypes, and further understanding of BMP function and its contributions to human disease.

Journal Article.  7144 words.  Illustrated.

Subjects: Genetics and Genomics

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