Contributing to the Functional Classification of Missense Variants in RAG1 Protein from Structural Perspective

Year 2025, Volume: 15 Issue: 1, 31 - 40, 16.04.2025

Aslı Kutlu , Begüm Işıkgil , Sinem Firtina

https://doi.org/10.26650/experimed.1562959

Abstract

Objective: Primary immune deficiencies (PIDs) are syndromic diseases characterized by severe clinical f indings in early childhood. The diagnosis and treatment of PID are challenging due to its genetic and clinical heterogeneity. Severe combined immune deficiency (SCID) is one of its most severe and fatal forms and is characterized by the absence of T lymphocytes and either the presence of B and/or natural killer (NK) cells. The failures in variable, diversity, joining (V(D)J) recombination, which are also controlled by the recombination activating gene (RAG) 1/2 complex, result in the deficiency of B- and T-cells, and these failures are associated with SCID or its alternative forms. Due to complete defect in RAG1 function, the SCID phenotype occurs, but OMENN syndrome (OS) and atypic SCID (AS) occur if defects in RAG1 function are partially tolerated.

Materials and Methods: By using in-silico computational tools, the structural differences are revealed and then variants are prioritized according to how degree the existing structural alterations are tolerated or not.

Results: These promising ones are Arg474Cys, Arg778Gln & Arg975Trp in AS, Arg396His, Arg396Leu, Arg624Cys, Trp552Cys, Val433Met & Met435Val in OS, and Arg474His and Glu722Lys in SCID.

Conclusions: The utilization of in-silico computational tools provides a great advantage to gain insight about variant specific molecular mechanisms of diseases to boost existing knowledge about RAG1/2 failures.

Keywords

Primer immune deficiency, Severe combined immunodeficiency, Omenn syndrome, Atypical SCID, RAG1 gene, Structural alterations

Project Number

Herhangi bir proje kapsamında gerçekleştirilmemiştir.

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