Genome sequencing is revolutionizing our understanding of skeletal biology. By determining the molecular basis of the skeletal dysplasias, a heterogeneous group of inherited disorders that have a profound effect on the skeleton, unanticipated molecules and mechanisms essential for normal skeletal development are being revealed. While the genes associated with most of the common skeletal dysplasias have been determined, short-rib polydactyly (SRP) is the most frequent perinatal lethal skeletal disorder for which the biological basis and mechanism are incompletely understood. SRP is also the most common skeletal ciliopathy, so determining the molecular basis and mechanism(s) of disease in SRP will define the components of the cilia that are most important in skeletal development. Through our main ascertainment vehicle, the International Skeletal Dysplasia Registry (ISDR), we have assembled a large cohort of SRP cases that will support a genomic strategy for genetically dissecting this disorder. The gene discovery studies will be followed by detailed mechanistic studies in tissues, cultured cells and mice to determine how each mutation exerts its phenotypic effect, to determine why mutations in the SRP genes have a differential effect on the skeleton, and to integrate the different molecules involved into a pathway for ciliary function in the skeleton. The findings will provide new insights into the complex biology of the skeleton, and will do so in the context of the SRP human phenotype. The proposed experiments are significant in that they represent the potential to have an extensive impact on our understanding of ciliary skeletal biology from both the mechanistic and clinical genetics perspectives. Once the associated genes are identified, immediate translational benefit will result by providing specific and appropriate genetic counseling to families with these conditions as well as opportunities for genetic testing. The results will reveal new molecules and mechanisms of normal skeletal development, and the proposed functional studies will both validate the molecular findings and identify the pathways through which cilia enable skeletogenesis.
The results of these studies will provide immediate translational benefit by providing accurate genetic counseling to families with short-rib polydactyly as well as opportunities for genetic testing. The results will reveal new molecules and pathways essential for normal cilia functions that are in turn necessary for proper skeletal development. The mechanistic studies in tissues, cultured cells and model organisms, will provide a deeper understanding of how the genes and mutations found lead to short-rib polydactyly and will be relevant to the ciliopathies in general.
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