Novel Primary Immunodeficiency Disease Due to IL27RA Deficiency

超过400个基因的缺陷已被确定为原发性免疫缺陷疾病的原因。的 然而，许多原发性免疫缺陷疾病的分子病因学仍然未知。中的这一空白 知识削弱了我们诊断和适当治疗受影响患者的能力。因此， 提高对原发性免疫缺陷疾病的遗传基础和机制的认识。的 本申请的目的是使用尖端的基因组和分子技术来研究一种新的 原发性免疫缺陷病，[肉芽肿、低T细胞和身材矮小（GRALTS）]，与 IL 27 RA的双等位基因致病性变体。本申请的中心假设是IL 27 RA缺乏 导致GRALTS。该假设将通过3个具体目标进行检验：1）确定变量的影响 2）为了确定变体对T细胞中IL 27 RA功能的影响， 和3）阐明受损的IL-27信号传导的下游结果。建议的工作是创新的 因为IL-27信号传导的缺陷以前没有被证明会导致人类疾病。具有重要意义 因为它将证实IL 27 RA缺陷是人类原发性免疫缺陷的新的潜在原因 疾病因此，预计该项目将产生重要的积极影响，因为它将增强我们的能力， 适当识别和治疗患有IL 27 RA缺陷的原发性免疫缺陷病患者。 预计获得的信息将提高我们功能评估和验证双等位基因变体的能力 在IL 27 RA中的意义尚不确定，并增强了我们对IL-27信号传导在 人T细胞功能。因此，拟议的研究与NIH和RFA的使命相关 因为它的重点是调查人类疾病的新原因， 这将有助于减轻疾病和残疾的负担，改善 有这种情况和相关的原发性免疫缺陷疾病。

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.