Unlocking Cellular Secrets: Charting Proteomic Frontiers in LRBA Deficiency Through the Lens of Readthrough Promoters

Inborn Errors of Immunity (IEI) occur when certain genes are born with glitches, leading to issues like loss of function or gain of function of the proteins they encode. This can result in a higher susceptibility to infections, autoimmune problems, inflammation, allergies, and even cancer. About one-third of these errors fall under the category of Primary Immune Regulatory Disorders (PIRDs), where the normal immune system regulation goes haywire, causing problems like inflammation, autoimmunity, and excessive lymphocyte production. LRBA deficiency is one of these PIRDs and it messes with crucial cellular functions like vesicular trafficking, autophagy, and apoptosis. Among the different genetic mutations causing LRBA deficiency, we focused on a specific nonsense mutation (c.5047C > T). Our study takes a dive into potential solutions, using small molecules, oxadiazole derivatives, known to act as readthrough promoters, to observe how they influence the regulation of proteins on human fibroblasts harbouring the mutation. In our pursuit, we harness the power of mass spectrometry (MS) techniques for precise protein analysis. The result gives us new, first insights on the possible proteomic impact of the readthrough promoters.