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.
Patients with Primary Immunodeficiency Diseases (PIDD) are at very high risk for significant morbidity and mortality if undiagnosed correctly and therefore important for public health because this causes significant delays in treatment. To address this problem, understanding the genetic mechanism underlying disease will drive heightened recognition and diagnosis ultimately leading to tailored therapies introduced to the patient earlier in the disease process. Not only is this work pertinent to the goal of the NIH (which is to foster creative discoveries, innovative research strategies, and their applications in order to improve health), it will provide new insight into a novel mechanism for immunodeficiency through the study of a rare PIDD (IL-27RA deficiency) using cutting-edge technologies and innovative investigations, with potential to prevent severe life- threatening disease and reduce the morbidity and mortality for patients.