Explaining the different forms of primer immunodeficiency (PID) caused by missense variants in RAG1 gene from structural perspective

Işıkgil, Begüm
Fırtına, Sinem
Kutlu, Aslı
Severe combined immunodeficiency (SCID) is a primary immunodeficiency disease characterized by T cell deficiency or dysfunction and associated with the presence or absence of B and NK (natural killer) cells. Up to now, several genes are associated with SCID and one of them is RAG1 gene (Uniprot ID: P15918). RAG1 protein has a recombinase activity together with RAG2, and it is involved in the rearrangement of immunoglobulin and T-cell receptor genes required for the development of B and T-cells. Besides SCID, atypical SCID and Omenn’s syndrome (OS) are also associated with missense mutations in RAG1 gene. Within the scope of this study, we identify 37 total missense mutations in RAG1 gene via text-mining from Uniprot database, and these variants were counted as 9 in SCID, 6 in atypical SCID and 22 in OS. Here, we were questioning how these missense mutations affect the structural features of RAG1 protein that altered the disease mechanisms by causing different clinical outcomes. The second question was either same clinical outputs were associated with same or similar structural changes in RAG1 protein dynamics or not. To explain more about it, we used different computational tools used to visualize changes in protein structure, to predict impacts of mutations on protein thermodynamics via calculating intramolecular interactions (salt bridges & disulfide bonds) or assessing change in ∆G, and so on. We also paid special attention to case(s) in which different missense variants at same position caused to different clinical outcomes, e.g. Arg474Cys-atypic SCID but Arg474His-SCID and Arg624Cys-OS but Arg624His SCID. Indeed, we provided a theoretical structural background about RAG1 protein to explain the associations between changes in RAG1 protein dynamics via combination of different computational tools. We demonstrated that the different structural features of RAG1 protein have caused to varied clinical inputs associated with altered disease etiology.


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Citation Formats
B. Işıkgil, S. Fırtına, and A. Kutlu, “Explaining the different forms of primer immunodeficiency (PID) caused by missense variants in RAG1 gene from structural perspective,” Erdemli, Mersin, TÜRKİYE, 2022, p. 3047, Accessed: 00, 2023. [Online]. Available: https://hibit2022.ims.metu.edu.tr.