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Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation
  1. L I Elizondo1,2,
  2. K S Cho3,
  3. W Zhang4,
  4. J Yan5,
  5. C Huang5,
  6. Y Huang1,
  7. K Choi1,
  8. E A Sloan5,
  9. K Deguchi5,
  10. S Lou5,
  11. A Baradaran-Heravi1,
  12. H Takashima6,
  13. T Lücke7,
  14. F A Quiocho4,
  15. C F Boerkoel1
  1. 1
    Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
  2. 2
    Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA
  3. 3
    Department of Biological Sciences, Konkuk University, Hwayang-dong, Kwangjin-gu, Seoul, Republic of Korea (South)
  4. 4
    Department of Biochemistry, Baylor College of Medicine, Houston, Texas, USA
  5. 5
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  6. 6
    Department of Neurology and Geriatrics, Kagoshima University Graduate, School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, Japan
  7. 7
    Departments of Pediatric Nephrology, Hepatology and Metabolic Diseases, Hanover Medical School, Hannover, Germany
  1. Dr C F Boerkoel, Provincial Medical Genetics Program, Department of Medical Genetics, Children’s and Women’s Health Centre of BC, 4500 Oak Street, Room C234, Vancouver, BC V6H 3N1 Canada; boerkoel{at}


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 remodelling proteins.

Methods: To assess the affect of SMARCAL1 mutations associated with SIOD on SMARCAL1 expression and function, we characterised the effects of various mutations on mRNA and protein expression in patient tissues and cell lines, and the ATPase activity, subcellular localisation, and chromatin binding of SMARCAL1 missense mutants.

Results: The SIOD associated SMARCAL1 mutations affected SMARCAL1 protein expression, stability, subcellular localisation, chromatin binding, and enzymatic activity. Further, expressing SMARCAL1 missense mutants in Drosophila melanogaster 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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  • Funding: This work was supported in part by a Ruth L Kirschstein National Research Service Award (LIE) and grants from the March of Dimes (CFB), the Gillson Longenbaugh Foundation (CFB), the Dana Foundation (CFB) and the New Development Award, Microscopy, and Administrative Cores of the Mental Retardation and Developmental Disabilities Research Center at Baylor College of Medicine (CFB), the Burroughs Wellcome Foundation (CFB), the National Institute of Diabetes, Digestive, and Kidney Diseases, NIH (CFB), and the Association Autour D’Emeric et D’Anthony (CFB).

  • Competing interests: None.

  • Patient consent: Obtained.