Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient's clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as protein-protein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.

中文翻译：

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新型半合子 IL2RG p.(Pro58Ser) 突变损害淋巴细胞上的 IL-2 受体复合物表达，导致 X 连锁联合免疫缺陷。

Hypomorphic IL2RG 突变可能导致比 X-SCID 更温和的表型，不同地命名为非典型 X-SCID 或 X-CID。我们报告了一个 11 岁男孩的小说 c。IL2RG 中的 172C>T;p.(Pro58Ser) 突变，呈现非典型 X-SCID 表型。我们还回顾了越来越多的导致非典型 X-SCID 的亚形 IL2RG 突变。我们研究了患者的临床表型、B、T、NK 和树突细胞表型、IL2RG 和 CD25 细胞表面表达以及 IL-2 靶基因表达、STAT 酪氨酸磷酸化、PBMC 增殖和响应 IL-2 刺激的胚细胞形成，以及通过 BioID 邻近标记突变的 IL2RG 的蛋白质-蛋白质相互作用。患者患有反复上呼吸道和下呼吸道感染、支气管扩张和反应性关节炎。尽管 T 和 B 细胞亚群偏斜，且浆细胞样树突状细胞数量非常少，但他的总淋巴细胞计数仍保持正常。他的淋巴细胞上 IL2RG 的表面表达降低。这导致响应 IL-2 和 IL-21 的 STAT 酪氨酸磷酸化受损，降低患者 CD4+ T 细胞中 IL-2 靶基因的表达，并降低响应 IL-2 刺激的细胞增殖。BioID 邻近标记显示突变的 IL2RG 和 ER/高尔基体蛋白之间的异常相互作用导致突变的 IL2RG 错误定位到 ER/高尔基体界面。总之，IL2RG p.(Pro58Ser) 导致 X-CID。IL2RG 质膜靶向失败可能导致非典型 X-SCID。我们进一步从新生儿 SCID 筛查中发现了这种突变的另一个携带者，但在更仔细的审查中丢失了。