Abstract
BackgroundTransient receptor potential melastatin subfamily member 4 (TRPM4) is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically however, partial loss or gain of function mutations in TRPM4 lead to arrythmia and heart disease, with no documentation of immunological disorders. ObjectiveTo characterize the functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated trpm4 gene. MethodsWe employ a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches. ResultsWe report the first human cases with complete loss of the TRPM4 channel leading to immune dysregulation with frequent bacterial and fungal infections. Single cell and bulk RNAseq point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP1 monocyte cell line reduces migration. More importantly primary T cells and monocytes from the TRPM4 patients migrate poorly. Finally, CRISPR knockout of TRPM4 in THP1 cells greatly reduces their migration potential. ConclusionOur results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections.
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