Human Molecular Genetics Advance Access originally published online on January 6, 2009
Human Molecular Genetics 2009 18(6):1110-1121; doi:10.1093/hmg/ddp008
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Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes
1 Department of Ophthalmology, University of Alberta, Edmonton T6G 2H7, Canada 2 Department of Biological Sciences, University of Alberta, Edmonton T6G 2E9, Canada 3 Department of Cell and Developmental Biology, University of British Columbia, Vancouver V6T 1Z3, Canada 4 CERTO–EA No 2502 du ministère de la recherche, Faculty of Medicine 75015, Paris, France 5 Stowers Institute for Medical Research, Kansas, MO 64110, USA 6 Department of Medical Genetics, University of Alberta, Edmonton T6G 2H7, Canada 7 Department of Pharmacy and Pharmaceutical Science, University of Alberta, Edmonton, Canada 8 Department of Orthopedic Surgery, Washington University, St Louis, MO 63130, USA 9 Department of Medical Genetic Services, Marshfield Clinic, Marshfield, WI 54449, USA 10 Ophthalmic Genetics and Visual Function Branch, NEI, NIH, Bethesda, MD 20892, USA 11 Department of Paediatric Ophthalmology and Strabismus, Aravind Eye Hospital, Madurai, Tamilnadu, India 12 Department of Genetics, Aravind Medical Research Foundation, Madurai, Tamilnadu, India 13 MRC Human Genetics Unit, Edinburgh EH4 2XU, UK
* To whom correspondence should be addressed. Tel: +1 780 492 8550; Fax: +1 780 492 6934; Email: olehmann{at}ualberta.ca
Received October 8, 2008; Accepted December 19, 2008
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.
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