Immunodeficiency 9

A number sign (#) is used with this entry because of evidence that primary immunodeficiency-9 (IMD9) is caused by homozygous or compound heterozygous mutation in the ORAI1 gene (610277), which encodes a subunit of the plasma membrane calcium channel CRAC, on chromosome 12q24.

See IMD10 (612783) for a similar disorder due to mutation in the STIM1 gene (605921), which acts upstream of the ORAI1 gene in the same pathway.

Description

Immunodeficiency-9 is an autosomal recessive disorder characterized by early onset of recurrent infections due to defective T-cell activation. Affected individuals also have congenital myopathy resulting in muscle weakness as well as features of ectodermal dysplasia, including soft dental enamel (summary by McCarl et al., 2009).

Clinical Features

Feske et al. (1996) reported 2 brothers, born to consanguineous Turkish parents, with an immune disorder characterized by intermittent fever and aphthous stomatitis from the neonatal period. Both showed failure to thrive and muscular hypotonia. The older boy developed a prolonged rotavirus infection and lymphadenopathy with mycobacteria infection, and died from sepsis at age 11 months (Schlesier et al., 1993). Serum immunoglobulins were increased, but no specific antibodies were found, and he had no seroconversion after vaccination. Blood lymphocyte counts were normal, but the T cells showed severely impaired proliferative responses and a deficiency in the production of multiple 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. The second child showed a similar phenotype to his brother and received a bone marrow transplant from his aunt. Feske et al. (1996) concluded that the cause for the multiple cytokine deficiency was a defect in signal transduction events leading to cytokine gene expression within T cells, and postulated a defect in the propagation of distal calcium-dependent signaling within T cells. In a follow-up, Feske et al. (2006) noted that the surviving patient had ectodermal dysplasia and anhidrosis (EDA) and a congenital nonprogressive myopathy. The authors postulated that EDA may have resulted from hypoactivation of the transcription factor NFKB (164011) due to impaired calcium signaling, and the myopathy from defective activation of NFAT (see 600490).

Partiseti et al. (1994) reported a patient with primary immunodeficiency characterized by lack of T-cell proliferation. Detailed studies of patient lymphocytes showed absence of calcium influx in response to activation of the T-cell receptor (TCR) compared to control lymphocytes. Intracellular calcium release in patient cells was similar to controls. McCarl et al. (2009) reported detailed clinical features of the patient (P4) reported by Partiseti et al. (1994) and his similarly affected brother (P3). The proband presented at birth with facial dysmorphism, clubfoot, and hypocalcemia. During the first year of life, he had failure to thrive and recurrent infections, including chronic diarrhea, chronic candidiasis, pneumonia, and pyelonephritis. He had a small thymus with normal numbers of lymphocytes, but T-cell proliferation was severely impaired in response to stimuli. At age 7 months, he developed neutropenia and thrombocytopenia. Additional features included developmental delay, congenital muscular hypotonia, spasticity, and encephalopathy. The child died at age 11 months from progressive encephalopathy and seizures. His older, similarly affected brother died of pneumonia at age 5 months.

Le Deist et al. (1995) reported 2 brothers with primary immunodeficiency apparent since the neonatal period. The proband had normal lymphocyte numbers, but T-cell proliferation in response to stimulus was defective. Patient cells showed a defect in nuclear localization of NFAT resulting from a defect in extracellular calcium influx, although intracellular calcium release was normal. The proband received a bone marrow transplant; his older brother died at age 8 months of protracted diarrhea, cytomegalovirus infection, and toxoplasmic encephalitis. McCarl et al. (2009) reported clinical features of the brothers (P5 and P6) reported by Le Deist et al. (1995). They were born of unrelated German parents and presented in early infancy with failure to thrive, immunodeficiency, and hypotonia. The younger brother had a successful bone marrow transplant at age 4 months. At age 16 years, he had myopathy with loss of independent ambulation around age 15 years, pectus excavatum, and respiratory muscle insufficiency resulting in chronic pulmonary disease. He also had features of ectodermal dysplasia, including severely dysplastic tooth enamel due to hypocalcified amelogenesis imperfecta, dry skin with anhidrosis, and heat intolerance; hair was normal. Neurologic and mental development was normal.

Inheritance

The transmission pattern of IMD9 in the families reported by Feske et al. (1996) and McCarl et al. (2009) was consistent with autosomal recessive inheritance.

Molecular Genetics

Feske et al. (2006) showed that the patients with immune dysfunction due to impaired T-cell activation described by Feske et al. (1996) were homozygous for a mutation in the ORAI1 gene (610277.0001). Lack of a functional CRAC current resulted in impaired calcium influx and lack of normal T-cell activation. Expression of wildtype ORAI1 in SCID T cells restored store-operated calcium ion influx and the CRAC current (I-CRAC).

In the probands of the families with IMD9 reported by Partiseti et al. (1994) and Le Deist et al. (1995), McCarl et al. (2009) identified homozygous or compound heterozygous mutations in the ORAI1 gene (610277.0005-610277.0007). In vitro functional expression studies showed that the mutations resulted in a loss of function.

Pathogenesis

Feske et al. (2000) found that T lymphocytes derived from the Turkish patients with IMD9 reported by Feske et al. (1996) had impaired expression of NFAT-dependent genes, including multiple cytokines. Patient cells had no expression of NFAT3 (602699), whereas NFAT1 (600490), NFAT2 (600489), and NFAT4 (602698) were expressed normally. These NFAT proteins showed only transient dephosphorylation when stimulated with ionomycin compared to controls, and this was associated with impaired nuclear import and localization of the transcription factors. Limiting the time of NFAT activation in normal control cells mimicked the cytokine expression pattern in IMD9 T cells, suggesting that the expression of different cytokine genes is differentially regulated by the duration of NFAT residence in the nucleus. The findings indicated that abnormal regulation of the NFAT transcription factors in patients with IMD9 underlies the defect in cytokine production.