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

Department of Ophthalmology, University of Alberta, Edmonton, Canada.
Human Molecular Genetics (Impact Factor: 6.39). 02/2009; 18(6):1110-21. DOI: 10.1093/hmg/ddp008
Source: PubMed


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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    • "Growth differentiation factor 5 (GDF5/BMP-14/CDMP-1) and growth differentiation factor 6 (GDF6/BMP-13/CDMP-2) are members of the TGF superfamily and are associated with skeletal development [13-15]. We previously demonstrated that they are expressed by human NP cells and that GDF5 increases type II collagen and aggrecan gene expression by degenerate human NP cells in vitro[16]. "
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    • "A further alternative explanation for deficits in swimming performance could be morphological changes resulting from long-term loss of gdf6a. Skeletal changes might be anticipated from BMP namesake functions in bone morphogenesis, from skeletal defects observed in patients with GDF6 mutations [39]–[42] or past analysis of zebrafish gdf6a morphants [43]. In adult zebrafish, skeletal deficits in the axial skeleton were not observed (Figure 1, Supplemental Movie S1). "
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