The interleukin (IL)-12/interferon(IFN)γ axis plays an important role in the control of mycobacterial diseases as demonstrated by the increased susceptibility to mycobacterial species in patients with an inborn error of the IL-12-dependent IFNγ immunity. Here, we report a novel mutation in the IL-12Rβ1 gene in a female Pakistani patient who was born in a consanguineous marriage and developed severe bacille Calmette-Guérin (BCG) infection and recurrent tuberculosis. After reviewing the patient's clinical records, she was investigated for IL-12/IFNγ defects using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and DNA genetic Sanger sequencing. Quantification of secretory cytokines from the patient's peripheral blood mononuclear cells (PBMCs) revealed significantly reduced IFNγ production. Flow cytometric analysis revealed no surface expression of IL-12Rβ1 on PHA-activated T lymphocytes. In addition, IL-12-induced impaired STAT4 phosphorylation in the patient's lymphocytes when compared with those from five healthy controls. The genetic analysis of IL-12Rβ1 gene identified a novel nonsense mutation c.199G>T/p.E67* within exon 3, which encodes part of the cytokine-binding region (CBR). In silico analysis indicates that this novel nonsense mutation generates a truncated protein with an apparent inactivating effect. Our data expand the genetic spectrum of IL-12Rβ1 deficiency. Moreover, our findings highlight the need for developing newborn screening for patients with primary immunodeficiency associated with mycobacterial infections in areas where BCG vaccination is mandatory in order to improve the treatment of patients, and consequently their quality of life.

中文翻译：

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与复发性结核病相关的新的无意义的IL-12Rβ1突变。

白介素（IL）-12 /干扰素（IFN）γ轴在分枝杆菌疾病的控制中起着重要作用，这是由先天性IL-12依赖的IFNγ免疫缺陷患者对分枝杆菌种类的敏感性增加所证明的。在这里，我们报道了一名女性巴基斯坦患者的IL-12Rβ1基因发生了新的突变，该患者出生于近亲婚姻，并发展为严重的卡介苗-卡格林（BCG）感染并复发了结核病。回顾患者的临床记录后，使用酶联免疫吸附测定（ELISA），流式细胞仪和DNA遗传Sanger测序对她的IL-12 /IFNγ缺陷进行了调查。对患者外周血单核细胞（PBMC）分泌型细胞因子的定量分析显示，IFNγ的产生显着降低。流式细胞仪分析显示在PHA激活的T淋巴细胞上没有IL-12Rβ1的表面表达。此外，与来自五个健康对照组的淋巴细胞相比，IL-12诱导的患者淋巴细胞中的STAT4磷酸化受损。IL-12Rβ1基因的遗传分析在第3外显子中鉴定出一个新的无意义突变c.199G> T / p.E67 *，该突变编码部分细胞因子结合区（CBR）。计算机分析表明，这种新的无意义突变产生具有明显失活作用的截短蛋白。我们的数据扩大了IL-12Rβ1缺乏症的遗传谱。此外，我们的研究结果突显了需要对必须进行BCG疫苗接种的地区的原发性免疫缺陷伴分枝杆菌感染的患者进行新生儿筛查，以改善患者的治疗，