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

Loss of function mutations of ORAI1 suppress store-operated Ca²⁺ entry (SOCE) and cause an immunodeficiency disorder called Ca²⁺ release-activated Ca²⁺ (CRAC) 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 (STIM1). The patient suffered from a severe form of combined immunodeficiency (CID), hemophagocytic lymphohistiocytosis (HLH) 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.