Mutations in the SMARCAL1 gene cause Schimke immuno-osseous dysplasia (SIOD), an autosomal recessive multisystem disorder. Our preliminary data suggest that SMARCAL1 may be involved in tissue maintenance and cellular proliferation. The goal of this research project is to clarify the molecular pathophysiology underlying the skeletal defect in SIOD through the development of a murine model. I will accomplish this by 1) characterizing the expression pattern of mSmarcal1 in the developing bone to obtain insights into potential roles for SMARCAL1 during development, 2) generating mice over-expressing mSmarcal1 in chondrocytes to determine whether mSmarcal1 regulates chondrocyte proliferation and induces abnormal bone growth, and 3) generating mice with mSmarcal1 knockout (KO) mutations and conditional knockout (cKO) mutations. By comparing the phenotype of the KO and cKO mice, I will be able to determine whether a lack of mSmarcal1 in chondrocytes alone can lead to the skeletal defects observed in SIOD patients. The mouse is a well-developed vertebrate model system and is crucial to understanding SIOD because many of the affected tissues are only found in vertebrates. ? ?
