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UBC Theses and Dissertations

Schimke immuno-osseous dysplasia : association of SMARCAL1 mutations with genetic and environmental disturbances of gene expression Baradaran-Heravi, Alireza


Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an incompletely penetrant autosomal recessive multisystem disorder characterized by dysmorphic facies, short stature, renal failure, and T-cell immunodeficiency. Biallelic loss-of-function mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response enzyme with annealing helicase activity, are associated with SIOD. My studies focused on further delineation of the molecular basis of SIOD by assessing the contribution of defective DNA repair to the pathophysiology of SIOD and a mechanism by which SMARCAL1 can modulate trait penetrance. Through collaborative analyses of the clinical data and molecular studies of SIOD patients, my coworkers and I observed that SIOD patients have a high frequency of non-Hodgkin lymphoma and showed that despite similarities among SIOD and other DNA repair diseases, SMARCAL1-deficient cells do not have increased baseline DNA breaks detectable by comet assay. Additionally, SIOD patients do not have a detectable defect of nucleotide excision repair (NER), homologous recombination (HR) or nonhomologous end joining (NHEJ) to explain their ectodermal or immunological features, although Smarcal1-deficient mice are hypersensitive to several DNA damaging agents. Furthermore, my colleagues and I found that SMARCAL1 orthologues localize to transcriptionally active chromatin and modulate gene expression, that deficiency of the SMARCAL1 orthologues alone is insufficient to cause disease in fruit flies and mice, that SMARCAL1 deficiency causes modest diffuse alterations in gene expression, and that SMARCAL1 deficiency causes disease via interaction with genetic and environmental factors that further alter gene expression. In summary, our findings provide guidance for clinical management of SIOD and suggest that alterations in the variance of gene expression levels contribute to the penetrance of SIOD.

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