Sanyal Mrinmoy, Morimoto Marie, Baradaran-Heravi Alireza, Choi Kunho, Kambham Neeraja, Jensen Kent, Dutt Suparna, Dionis-Petersen Kira Y, Liu Lan Xiang, Felix Katie, Mayfield Christy, Dekel Benjamin, Bokenkamp Arend, Fryssira Helen, Guillen-Navarro Encarna, Lama Giuliana, Brugnara Milena, Lücke Thomas, Olney Ann Haskins, Hunley Tracy E, Polat Ayse Ipek, Yis Uluc, Bogdanovic Radovan, Mitrovic Katarina, Berry Susan, Najera Lydia, Najafian Behzad, Gentile Mattia, Nur Semerci C, Tsimaratos Michel, Lewis David B, Boerkoel Cornelius F
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medical Genetics and Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Clin Immunol. 2015 Dec;161(2):355-65. doi: 10.1016/j.clim.2015.10.005. Epub 2015 Oct 21.
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.
施姆克免疫性骨发育不良（SIOD）是一种常染色体隐性遗传的致命性儿童疾病，与骨骼发育不良、肾功能障碍及T细胞免疫缺陷相关。该疾病与SMARCAL1基因的双等位基因功能丧失突变有关。尽管由于T细胞缺陷导致的反复感染是发病和死亡的主要原因，但T细胞免疫缺陷的病因尚不清楚。在此，我们证明SIOD患者的T细胞中白细胞介素7受体α链（IL7Rα）的蛋白质和mRNA水平检测不到，且对IL-7刺激无反应，表明功能性受体缺失。在这些患者的IL7R外显子中未检测到致病突变；然而，IL7R启动子中的CpG位点在SIOD T细胞中发生了高度甲基化。因此，我们提出，T细胞及其早期祖细胞中与IL7R启动子高度甲基化相关的IL7Rα表达缺失，限制了SIOD患者的T细胞发育。
