Work

ORAI1 mutation with mixed loss- and gain-of-function properties causes immunodeficiency and HLH

Year: 2025

Type: article

Abstract: Loss-of-function mutations of ORAI1 suppress store-operated Ca2+ entry (SOCE) and cause an immunodeficiency disorder called Ca2+ release–activated Ca2+ channelopathy. Here, we report an infant patient who is compound-heterozygous for p.His134Pro and p.Leu194Pro mutations in ORAI1 and whose T cells have strongly reduced SOCE. Whereas the p.Leu194Pro mutant ORAI1 protein is not expressed at the plasma membrane, the p.His134Pro mutation results in a constitutively open channel that is unresponsive to activation by stromal interaction molecule 1. The patient suffered from a severe form of combined immunodeficiency, hemophagocytic lymphohistiocytosis, and fatal chronic cytomegalovirus infection. His immunodeficiency was characterized by an altered composition of T and NK cell compartments, impaired stimulation-induced cytokine production and signs of CD4+ T cell and NK cell activation, but attenuated CD8+ T effector memory cell function. Our findings demonstrate that small constitutive SOCE through a mutant ORAI1 channel is not sufficient to provide immunity to viral infection.

Source: Journal of Human Immunity

DOI: 10.70962/jhi.20250097