Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7Rα) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7Rα expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients.
Bibliographical noteFunding Information:
We would like to thank all of the patients and family members who have contributed to this study. This work was supported in part by grants from the Dana Foundation (C.F.B. and D.B.L.); the Burroughs Wellcome Foundation (1003400) (C.F.B.); the Association Autour D'Emeric et D'Anthony (C.F.B.); the Michael Smith Foundation for Health Research ((CI-SCH-O1899(07-1)) (C.F.B.); the Little Giants Foundation (C.F.B.); the Child & Family Research Institute of British Columbia Children's Hospital (C.F.B.); and the Asociacion Española de Displasias Oseas Minoritarias (C.F.B.). M.M. was supported by a Four Year Doctoral Fellowship from the University of British Columbia. C.F.B. is a scholar of the Michael Smith Foundation for Health Research and a Clinical Investigator of the Child & Family Research Institute. We would like to thank BioServe (Beltsville, MD) for assistance with recruiting age-matched, sex-matched individuals for the unaffected control blood samples.
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- Promoter DNA methylation
- T-cell immunodeficiency