J Med Genet. Published Online First: 19 September 2008. doi:10.1136/jmg.2008.060095
Letters to JMG |
Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation
1 Baylor College of Medicine, United States
2 Konkuk University, Korea, Republic of
3 University of British Columbia, Canada
4 Kagoshima University School of Medicine, Japan
5 Hanover Medical School, Germany
* To whom correspondence should be addressed. E-mail: boerkoel{at}interchange.ubc.ca.
Accepted 22 August 2008
Abstract
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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