Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive fatal multisystem disease. The features of SIOD include the invariant findings of skeletal dysplasia, renal failure, and T cell deficiency as well as other symptoms such as adontia, arteriosclerosis, and hypothyroidism. SIOD is caused by loss-of-function mutations in SMARCAL1 (swi/snf related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1), which encodes a protein with homology to SF2 helicases and SNF2 chromatin remodeling proteins. SMARCAL1 resides in both the nucleus and the cytoplasm. Within the nucleus of Hela cells, SMARCAL1 forms aggregates that frequently co-localize with coilin, a marker of Cajal bodies, and when expressed in Drosophila, it specifically binds euchromatic DNA. Our Drosophila genetic studies have shown that SMARCAL1 is an antagonist of Polycomb group proteins and functions upstream of the trithorax protein BRM. Our observations suggest that SMARCAL1 potentially regulates RNA transcription or processing as a SNF2-related chromatin remodeling protein or as a DNA helicase. To extend the results from our biochemical, cell line, and Drosophila studies to understanding the pathophysiology of SIOD requires a mammalian model. Therefore the objective of this application is to characterize the role of SMARCAL in skeletal development and maintenance through characterization of Smarcal1 expression for wild-type bone development, over-expression of Smarcal1 in bone development, and loss of Smarcal1 expression in bone development. Ultimately our goal is to understand the role of Smarcal1 in mammalian biology, to clarify the human biology underlying SIOD and to use this understanding to ameliorate or treat SIOD and related diseases. The funding provided by this R21 is critical for me, as a new investigator, to develop these murine models. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Genetics of Health and Disease Study Section (GHD)
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Malozowski, Saul N
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Baylor College of Medicine
Schools of Medicine
United States
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Morimoto, Marie; Boerkoel, Cornelius F (2013) The role of nuclear bodies in gene expression and disease. Biology (Basel) 2:976-1033
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