Khan Taj Ali, Iqbal Asif, Rahman Hazir, Cabral-Marques Otavio, Ishfaq Muhammad, Muhammad Noor
Department of Microbiology, Kohat University of Science and Technology, Kohat, Pakistan.
Laboratory of Biochemistry and Biophysics, Butantan Institute, Sao Paulo, Brazil.
Microb Pathog. 2017 Aug;109:114-119. doi: 10.1016/j.micpath.2017.05.033. Epub 2017 May 25.
Severe combined immunodeficiency (SCID) is a potentially fatal primary immunodeficiency (PID) that is caused by mutations in genes such as IL2RG, JAK3, IL7RA, RAG1, RAG2, and ADA. The products of these genes are involved in the development of several immune cells such as T, B and natural killer (NK) cells. Most of the SCID forms are autosomal recessive with the exception of IL2RG defects that cause an X-linked SCID. Among the different SCID types, there is a rare SCID form called leaky SCID, which is less severe when compared to the other classical SCID phenotypes. Leaky SCID can be caused by hypomorphic mutations in RAG1 and RAG2 that result in only partial loss of enzymatic function of the proteins respectively encoded by these genes. Here we report a novel missense mutation (c. 307C > T/p.H103Y) in the RAG1 gene in a patient with leaky SCID. In addition, we characterize the clinical and immunological features of this patient that developed along with other severe and recurrent infections such as mycobacterial diseases (BCGitis and pulmonary tuberculosis), the first occurrence of Chromobacterium violaceum in a patient with SCID. Understanding the increased susceptibility to mycobacteria presented by the patient, in which a functional investigation of IL-12/IFN-γ axis was performed, which demonstrated reduced production of IFN-γ in the supernatans of peripheral blood mononuclear cell cultures from the patient compared with those from healthy subjects. In conclusion, our data expands the molecular and clinical spectrum associated with the leaky SCID phenotype.
重症联合免疫缺陷（SCID）是一种潜在致命的原发性免疫缺陷（PID），由IL2RG、JAK3、IL7RA、RAG1、RAG2和ADA等基因的突变引起。这些基因的产物参与多种免疫细胞的发育，如T细胞、B细胞和自然杀伤（NK）细胞。除了导致X连锁SCID的IL2RG缺陷外，大多数SCID形式为常染色体隐性遗传。在不同类型的SCID中，有一种罕见的SCID形式称为渗漏型SCID，与其他经典SCID表型相比，其病情较轻。渗漏型SCID可能由RAG1和RAG2中的亚效突变引起，这些突变分别导致这些基因编码的蛋白质的酶功能仅部分丧失。在此，我们报告了一名渗漏型SCID患者RAG1基因中的一个新的错义突变（c.307C>T/p.H103Y）。此外，我们还描述了该患者的临床和免疫学特征，该患者同时出现了其他严重和反复感染，如分枝杆菌病（卡介苗感染和肺结核），这是SCID患者首次出现紫色色杆菌感染。了解该患者对分枝杆菌易感性增加的情况，我们对其进行了IL-12/IFN-γ轴的功能研究，结果显示该患者外周血单个核细胞培养上清液中IFN-γ的产生与健康受试者相比有所减少。总之，我们的数据扩展了与渗漏型SCID表型相关的分子和临床谱。
