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 (IL7R alpha) 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 IL7R alpha expression, associated with
hypermethylation of the IL7R promoter, in T cells and possibly their
earlier progenitors, restricts T-cell development in SIOD patients. (C)
2015 Elsevier Inc. All rights reserved