Waide Emily H, Dekkers Jack C M, Ross Jason W, Rowland Raymond R R, Wyatt Carol R, Ewen Catherine L, Evans Alyssa B, Thekkoot Dinesh M, Boddicker Nicholas J, Serão Nick V L, Ellinwood N Matthew, Tuggle Christopher K
Department of Animal Sciences, Iowa State University, Ames, IA 50011;
College of Veterinary Medicine, Kansas State University, Manhattan, KS 66502; and.
J Immunol. 2015 Oct 1;195(7):3171-9. doi: 10.4049/jimmunol.1501132. Epub 2015 Aug 28.
Mutations in >30 genes are known to result in impairment of the adaptive immune system, causing a group of disorders collectively known as SCID. SCID disorders are split into groups based on their presence and/or functionality of B, T, and NK cells. Piglets from a line of Yorkshire pigs at Iowa State University were shown to be affected by T(-)B(-)NK(+) SCID, representing, to our knowledge, the first example of naturally occurring SCID in pigs. In this study, we present evidence for two spontaneous mutations as the molecular basis for this SCID phenotype. Flow cytometry analysis of thymocytes showed an increased frequency of immature T cells in SCID pigs. Fibroblasts from these pigs were more sensitive to ionizing radiation than non-SCID piglets, eliminating the RAG1 and RAG2 genes. Genetic and molecular analyses showed that two mutations were present in the Artemis gene, which in the homozygous or compound heterozygous state cause the immunodeficient phenotype. Rescue of SCID fibroblast radiosensitivity by human Artemis protein demonstrated that the identified Artemis mutations are the direct cause of this cellular phenotype. The work presented in the present study reveals two mutations in the Artemis gene that cause T(-)B(-)NK(+) SCID in pigs. The SCID pig can be an important biomedical model, but these mutations would be undesirable in commercial pig populations. The identified mutations and associated genetic tests can be used to address both of these issues.
已知超过30个基因的突变会导致适应性免疫系统受损，引发一组统称为重症联合免疫缺陷（SCID）的疾病。SCID疾病根据B细胞、T细胞和NK细胞的存在情况和/或功能分为不同类别。爱荷华州立大学的一群约克夏猪的仔猪被证明患有T(-)B(-)NK(+) SCID，据我们所知，这是猪自然发生的SCID的首个例子。在本研究中，我们提供了两个自发突变作为这种SCID表型分子基础的证据。对胸腺细胞的流式细胞术分析显示，SCID猪中未成熟T细胞的频率增加。这些猪的成纤维细胞比非SCID仔猪对电离辐射更敏感，RAG1和RAG2基因被消除。遗传和分子分析表明，Artemis基因中存在两个突变，在纯合或复合杂合状态下会导致免疫缺陷表型。人Artemis蛋白对SCID成纤维细胞放射敏感性的挽救表明，所鉴定的Artemis突变是这种细胞表型的直接原因。本研究中的工作揭示了Artemis基因中的两个突变，它们导致猪出现T(-)B(-)NK(+) SCID。SCID猪可以成为一种重要的生物医学模型，但这些突变在商业猪群中是不受欢迎的。所鉴定的突变和相关基因检测可用于解决这两个问题。
