Asai-Coakwell Mika, French Curtis R, Ye Ming, Garcha Kamal, Bigot Karin, Perera Anoja G, Staehling-Hampton Karen, Mema Silvina C, Chanda Bhaskar, Mushegian Arcady, Bamforth Steven, Doschak Michael R, Li Guang, Dobbs Matthew B, Giampietro Philip F, Brooks Brian P, Vijayalakshmi Perumalsamy, Sauvé Yves, Abitbol Marc, Sundaresan Periasamy, van Heyningen Veronica, Pourquié Olivier, Underhill T Michael, Waskiewicz Andrew J, Lehmann Ordan J
Department of Ophthalmology, University of Alberta, Edmonton, Canada.
Hum Mol Genet. 2009 Mar 15;18(6):1110-21. doi: 10.1093/hmg/ddp008. Epub 2009 Jan 6.
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.
骨形态发生蛋白（BMP）家族的蛋白质在眼部和骨骼发育中发挥作用；然而，由于它们广泛表达且功能冗余，在确定单个BMP在人类疾病中的作用方面进展较小。我们在患有眼部和脊椎异常的患者中，鉴定出骨形态发生蛋白家族成员生长分化因子6（GDF6）的七个杂合突变，通过SOX9报告基因检测和蛋白质印迹分析对其作用进行了表征，并在Gdf6功能降低的模式生物中证明了类似的表型。我们在吗啉代寡核苷酸注射的斑马鱼中观察到一系列眼部和骨骼异常，后者包括尾部形成缺陷以及体节标记物noggin1和noggin2的表达改变。Gdf6(+/-)小鼠表现出与患者和斑马鱼中观察到的表型相符的多种眼部表型。患者与动物模型之间明显的关键差异包括多效性效应、可变表达和不完全外显。这些数据确立了该决定因素在眼部和脊椎发育中的重要作用，证明了这些表型的复杂遗传模式，并进一步加深了对BMP功能及其对人类疾病影响的理解。
