Immundefizienz 9

Immunodeficiency-9 is an autosomal recessive disorder characterized by early onset of recurrent infections due to defective T-cell activation.

Mutation in the ORAI1 gene. ORAI is a protein-coding gene located on chromosome 12q24.3.

The protein encoded by the ORAI1 gene is a calcium channel subunit (CRAC channels) that is activated by the calcium sensor STIM1 when calcium stores are depleted. CRAC channels are the major pathway for calcium influx into T cells. They promote the immune response to pathogens by activating the transcription factor NFAT.

Feske et al (1996) reported two brothers born to consanguineous Turkish parents with immune dysfunction characterized by intermittent fever and aphthous stomatitis in the neonatal period. Both showed failure to thrive and muscle hypotonia. The older boy developed a protracted rotavirus infection and lymphadenopathy with mycobacterial infection and died of sepsis at 11 months of age (Schlesier et al., 1993). Serum immunoglobulins were elevated, but no specific antibodies were found, and he had no seroconversion after vaccination. Blood lymphocyte counts were normal. However, T cells showed a severely impaired proliferative response and a deficiency in the production of several cytokines, including IL2 (147680), gamma-IFN (147570), IL4 (147780), and TNFA (191160). IL2 and gamma-IFN mRNA could not be detected in patient T cells.

In a follow-up study in these patients, Feske et al (2006) found that the surviving patient had ectodermal dysplasia with anhidrosis (EDA) and congenital nonprogressive myopathy. The authors postulated that the EDA may have been caused by hypoactivation of the transcription factor NFKB due to impaired calcium signaling and the myopathy may have been caused by defective activation of NFAT.

1. Feske S et al. (2007) The duration of nuclear residence of NFAT determines the pattern of cytokine expression in human SCID T cells. J. Immun. 165: 297-305.
2. Feske S et al. (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441: 179-185.
3. Le Deist F et al (1995) A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood 85: 1053-1062.
4. McCarl C-A et al.(2009) ORAI1 deficiency and lack of store-operated Ca(2+) entry cause immunodeficiency, myopathy, and ectodermal dysplasia. J Allergy Clin Immun 124: 1311-1318.
5. Partiseti M et al (1994) The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency. J Biol Chem 269: 32327-32335.
6. Schlesier M et al (1993) Primary severe immunodeficiency due to impaired signal transduction in T cells. Immunodeficiency 4: 133-136.