A mutation in ORAI1, the gene encoding the pore-forming subunit of the Ca²⁺-release–activated Ca²⁺ (CRAC) channel, abrogates the store-operated entry of Ca²⁺ into cells and impairs lymphocyte activation. Stromal interaction molecule 1 (STIM1) in the endoplasmic reticulum activates ORAI1–CRAC channels. We report on three siblings from one kindred with a clinical syndrome of immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, thrombocytopenia, muscular hypotonia, and defective enamel dentition. Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca²⁺ influx.