Grant: Operating Grant

Recessive Omodysplasia is a genetic disease characterized by severe short stature, shortened limbs and facial dysmorphism. It has recently been reported that this syndrome is caused by loss-of-function mutations of a gene called Glypican-6 (GPC6), The overall goal of this project is to uncover the molecular mechanism by which GPC6 regulates bone development.Our main hypothesis is that GPC6 stimulates the activity of a growth factor called Hedgehog which is very important for proper bone development, and that autosomal-recessive omodysplasia is caused, at least in part, by reduced Hedgehog activity in the developing bone. In our preliminary work we have generated mutant mice that lack GPC6, and we have shown that these mice display the typical features of patients with Recessive Omodysplasia. Our goals are to provide definitive molecular and genetic proof that GPC6-null mice display reduced Hegehog activity in the developing bone, and to uncover the molecular mechanism by which GPC6 stimulates Hedgehog activity. In addition, we will try to develop a treatment for patients with Recessive Omodysplasia. Significance: This study will generate critical knowledge not only on the molecular basis of Recessive Omodysplasia, but also on our basic understanding of the mechanism by which glypicans regulate Hedgehog activity. In addition, this study may contribute to the development of a treatment for omodysplastic patients.