TY - JOUR
T1 - Lack of IL7Rα expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)
AU - Sanyal, Mrinmoy
AU - Morimoto, Marie
AU - Baradaran-Heravi, Alireza
AU - Choi, Kunho
AU - Kambham, Neeraja
AU - Jensen, Kent
AU - Dutt, Suparna
AU - Dionis-Petersen, Kira Y.
AU - Liu, Lan Xiang
AU - Felix, Katie
AU - Mayfield, Christy
AU - Dekel, Benjamin
AU - Bokenkamp, Arend
AU - Fryssira, Helen
AU - Guillen-Navarro, Encarna
AU - Lama, Giuliana
AU - Brugnara, Milena
AU - Lücke, Thomas
AU - Olney, Ann Haskins
AU - Hunley, Tracy E.
AU - Polat, Ayse Ipek
AU - Yis, Uluc
AU - Bogdanovic, Radovan
AU - Mitrovic, Katarina
AU - Berry, Susan
AU - Najera, Lydia
AU - Najafian, Behzad
AU - Gentile, Mattia
AU - Nur Semerci, C.
AU - Tsimaratos, Michel
AU - Lewis, David B.
AU - Boerkoel, Cornelius F.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
KW - CD127
KW - CpG
KW - IL7Rα
KW - Promoter DNA methylation
KW - SIOD
KW - T-cell immunodeficiency
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U2 - 10.1016/j.clim.2015.10.005
DO - 10.1016/j.clim.2015.10.005
M3 - Article
C2 - 26499378
AN - SCOPUS:84945308414
SN - 1521-6616
VL - 161
SP - 355
EP - 365
JO - Clinical Immunology
JF - Clinical Immunology
IS - 2
ER -