Delineating molecular mechanism of developmental defects of TAR syndrome

Project Summary Birth defects involving skeletal and craniofacial development are among the most common human congenital diseases with unmet medical needs. Recent genetics studies have identified multiple robust and replicable risk loci to be associated with these devastating anomalies, offering new hope for those afflicted. Among them is the discovery that mutations in RBM8A cause a rare disease called thrombocytopenia-absent- radius (TAR) syndrome. RBM8A gene encodes a RNA-binding protein, yet the precise mechanism by which RBM8A deficiency causes tissue-specific abnormalities remains covered in mystery. In particular, the role of RBM8A deficiency in skeletal dysmorphogenesis and its direct targets in bone development are still unknown. Thus, there is a critical need to elucidate the underlying mechanism of RBM8A causing TAR syndrome, thereby enabling development of effective treatments. Our ultimate mission is to develop innovative strategies for prevention and treatment of structural abnormality disorders such as TAR syndrome. As an important step towards our goal, we have developed Rbm8a conditional knockout (cKO) mice and have revealed fascinating developmental defects. The objectives of our research are twofold: first, to examine the role of RBM8A in forelimb development, and second, to harness the power of viral gene therapy to reverse radial development defects in a TAR mouse model. Our rationale for this project is that its successful completion would provide a strong, conceptual, evidence-based framework to develop therapeutic strategies for congenital skeletal diseases. To achieve our objectives, we will rigorously test two Specific Aims: 1) Determine the role of Rbm8a in radial development; and 2) Determine the effects of RBM8A reinstatement therapy on anatomical and functional outcomes in cKO mice. At the completion of this project, we expect to discover important insights on the molecular basis of the radial development of a causal gene of TAR syndrome. The successful completion of the proposed studies would have an important positive impact on future drug screening and further development of novel therapeutic interventions for other developmental disorders.