Background: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive pleiotropic disorder caused by mutations in SMARCAL1. SMARCAL1 encodes an enzyme with homology to the SNF2 chromatin remodeling proteins.
Methods: To assess the affect of SMARCAL1 mutations associated with SIOD on SMARCAL1 expression and function, we characterized the effects of various mutations on mRNA and protein expression in patient tissues and cell lines, and the ATPase activity, subcellular localization, and chromatin binding of SMARCAL1 missense mutants.
Results: The SIOD-associated SMARCAL1 mutations affected SMARCAL1 protein expression, stability, subcellular localization, chromatin binding, and enzymatic activity. Further, expressing SMARCAL1 missense mutants in Drosophila showed that disease severity was inversely proportionate to overall SMARCAL1 activity.
Conclusion: Our results show for the first time that SMARCAL1 binds chromatin in vivo and that SIOD arises from impairment of diverse SMARCAL1 functions.
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