Background Defects in the development or activation of T cells result in immunodeficiency associated with severe infections early in life. T cell activation requires Ca2+ influx through Ca2+-release activated Ca2+ (CRAC) channels encoded by the gene ORAI1. Objective Investigation of the genetic causes and the clinical phenotype of immunodeficiency in patients with impaired Ca2+ influx and CRAC channel function. Methods DNA sequence analysis for mutations in the genes ORAI1, ORAI2, ORAI3, stromal interaction molecules (STIM) 1 and 2 as well as mRNA and protein expression analysis of ORAI1 in immunodeficient patients. Immunohistochemical analysis of ORAI1 tissue distribution in healthy human donors. Results We identified mutations in ORAI1 in patients from two unrelated families. One patient is homozygous for a nonsense mutation in ORAI1 (ORAI1-A88SfsX25) and a second patient is compound heterozygous for two missense mutations in ORAI1 (ORAI1-A103E/L194P). All three mutations abolish ORAI1 expression and impair Ca2+ influx and CRAC channel function. The clinical syndrome associated with ORAI1 deficiency is characterized by immunodeficiency with a defect in the function but not the development of lymphocytes, congenital myopathy and anhydrotic ectodermal dysplasia (EDA) with a defect in dental enamel calcification. In contrast to the limited clinical phenotype, we found ORAI1 protein expression in a wide variety of cell types and organs. Conclusion Ca2+ influx through ORAI1 is crucial for lymphocyte function in vivo. Despite almost ubiquitous ORAI1 expression, the channel has a non-redundant role in only a few cell-types judging from the limited clinical phenotype in ORAI1 deficient patients.

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