Novel Primary Immunodeficiency Disease Due to IL27RA Deficiency

400多个基因的缺陷已被确定为原发免疫缺陷性疾病的原因。这个 然而，许多原发免疫缺陷疾病的分子病因仍不清楚。这一差距在 知识削弱了我们诊断和适当治疗受影响患者的能力。因此，存在一种迫切的需求 以加强对原发免疫缺陷疾病的遗传基础和机制的了解。这个 这项应用的目的是利用尖端的基因组和分子技术来研究一种新的 原发免疫缺陷病[肉芽肿、T细胞减少和身材矮小(GRALTS)]，与 IL27RA双等位致病变异体。这一应用的中心假设是IL27RA缺乏 导致GRALTS。这一假设将以3个具体目标进行检验：1)定义变种的影响 对T细胞中IL27RA表达的影响，2)为了确定突变体对T细胞中IL27RA功能的影响， 3)阐明IL-27信号受损的下游转归。建议的工作具有创新性。 因为此前还没有证据表明IL-27信号的缺陷会导致人类疾病。这一点意义重大 因为它将证实IL27RA缺陷是人类原发免疫缺陷的一个新的潜在原因 疾病。因此，这个项目预计将产生重要的积极影响，因为它将增强我们的能力 正确认识和治疗IL27RA缺乏的原发免疫缺陷病患者。 所获得的信息有望提高我们从功能上评估和验证双等位基因变异的能力 在IL-27RA中的不确定意义，并加强我们对IL-27信号在 人类T细胞功能。因此，这项拟议的研究与美国国立卫生研究院和该RFA的使命有关。 因为它专注于对一种新的人类疾病病因的调查，以获得基础知识 这将有助于减轻疾病和残疾的负担，并改善以下患者的生活 有这种情况和相关的原发免疫缺陷疾病。

Defects in over 400 genes have been identified as causes of primary immunodeficiency diseases. The molecular etiologies of many primary immunodeficiency diseases nevertheless remain unknown. This gap in knowledge impairs our ability to diagnose and properly treat affected patients. A critical need therefore exists for enhanced understanding of the genetic basis and mechanisms of primary immunodeficiency diseases. The objective of this application is to use cutting-edge genomic and molecular technologies to investigate a novel primary immunodeficiency disease, [GRAnulomas, Low T cells, and Short stature (GRALTS)], associated with biallelic pathogenic variants in IL27RA. The central hypothesis of this application is that IL27RA deficiency causes GRALTS. This hypothesis will be tested with 3 specific aims: 1) To define the effect of the variants on IL27RA expression in T cells, 2) To determine the impact of the variants on IL27RA function in T cells, and 3) Elucidate the downstream outcomes of impaired IL-27 signaling. The proposed work is innovative because defects in IL-27 signaling have not previously been shown to cause human disease. It is significant because it will validate IL27RA deficiency as a novel underlying cause of human primary immunodeficiency disease. Thus, this project is expected to have an important positive impact because it will augment our ability to appropriately recognize and treat primary immunodeficiency disease patients who have IL27RA deficiency. The information gained is anticipated to improve our ability to functionally assess and validate biallelic variants of uncertain significance in IL27RA and enhance our understanding of the importance of IL-27 signaling in human T cell function. The proposed research is therefore relevant to the mission of the NIH and this RFA because it focuses upon the investigation of a novel cause of human disease to gain fundamental knowledge that will facilitate reduction in the burden of illness and disability and improvement in the lives of patients who have this condition and related primary immunodeficiency diseases.