ORAI1 deficiency and lack of store-operated Ca²⁺ entry cause immunodeficiency, myopathy, and ectodermal dysplasia

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, and stromal interaction molecule (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 2 unrelated families. One patient is homozygous for a frameshift nonsense mutation in ORAI1 (ORAI1-A88SfsX25), and a second patient is compound heterozygous for 2 missense mutations in ORAI1 (ORAI1-A103E/L194P). All 3 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 in the development of lymphocytes, congenital myopathy, and anhydrotic ectodermal dysplasia with a defect in dental enamel calcification. In contrast with 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 nonredundant role in only a few cell types judging from the limited clinical phenotype in ORAI1-deficient patients.

Key words: ORAI1, STIM1, CRAC, calcium channel, Ca²⁺, store-operated Ca²⁺ entry, T cells, immunodeficiency, signal transduction, congenital myopathy, anhydrotic ectodermal dysplasia, dental enamel, amelogenesis imperfecta

Abbreviations used: CRAC, Ca²⁺ release activated Ca²⁺, EDA, Ectodermal dysplasia with anhydrosis, HSCT, Hematopoietic stem cell transplantation, NK, Natural killer, SCID, Severe combined immunodeficiency, SNP, Single nucleotide polymorphism, SOCE, Store-operated Ca²⁺ entry, STIM, Stromal interaction molecule