DECODING IMMUNE MYSTERIES: NUDCD3 MUTATION UNVEILS SCID AND OS SECRETS

The recent discovery in the Mutation in the NUDCD3 gene has shed light on their critical role disrupting V(D)J recombination, leading to Severe Combined Immunodeficiency (SCID) and Omeen Syndrome (OS). SCID and OS are two related in born errors of immunity that result in failure of T-cell development and dysregulation of oligoclonal T-cell. The common cause of SCID and OS is a defect in V(D)J recombination, a crucial process of arranging antigen receptor loci to produce diverse T-cell receptor and immunoglobulin which is governed by a protein Recombination activating genes (RAG1 and RAG2), which are essential for generating diverse T-cell population. NUDCD3 maintains the stability of protein dynein and for cell viability.

A specific mutation, where glycine at 52 is substituted by aspartate (NUDCD3^G52D), a rare variant of NUDCD3 is identified. Unlike typical mutations causing SCID and OS, NUDCD3^G52D uniquely decrease the expression of NUDCD3 gene, decreasing its function and stability as this mutant variant fails to form dimer, which is required for immune system function. Further analysis of pathomechanism suggest that OS is associated either with NUDCD variant or pathogenic defect of RAG1 or RAG2. This leads to lack of immune cells and abnormalities in T-cell and myeloid cells population. RAG1 and RAG2 use T-Cell Recptor (TCRα) to develop the T-cell which are also seen in NUDCD3^G52D, the predominance use of TCRα implies that NUDCD3^G52D T-cell cannot perform repeatedround of V(D )J recombination which creates diverse population of T-cell. Interestingly, NUDCD3^G52D does not affect the production of RAG1 but impairs the transportation of RAG1 from the nucleolus to the RAG2, present outside the nucleolus. This leaves the individual vulnerable to the infections.

Figure 1: Autosomal recessive variant in NUDCD3 causes SCID/OS.

To study the impact of mutation in deeper, Single-cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) repertoire profiling were then conducted to analyze gene expression and immune receptor diversity at the single-cell level. This study use meticulous data analysis pipeline, including doublet detection, quality control, and dimensionality reduction, was implemented to identify distinct immune cell populations. Functional assays, such as KREC assays, were performed to evaluate B cell development and function, while mouse models with specific genetic modifications were utilized for phenotyping experiments and flow cytometry analyses. Through this integrated approach, the study provides valuable insights into immune cell behaviour, advancing our understanding of disease mechanisms and paving the way for targeted immunotherapies.

REFERENCE:

Chen R, Lukianova E, van der Loeff IS, Spegarova JS, Willet JD, James KD, Ryder EJ, Griffin H, IJspeert H, Gajbhiye A, Lamoliatte F. NUDCD3 deficiency disrupts V (D) J recombination to cause SCID and Omenn syndrome. Science Immunology. 2024 May 24;9(95):eade5705.

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