Immunodeficiency 10

A number sign (#) is used with this entry because of evidence that primary immunodeficiency-10 (IMD10) is caused by homozygous mutation in the STIM1 gene (605921) on chromosome 11p15.

See IMD9 (612782) for a similar disorder due to mutation in the ORAI1 gene (610277), which acts downstream of the STIM1 gene in the same pathway.

Description

Immunodeficiency-10 is an autosomal recessive primary immunodeficiency characterized by onset of recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta (summary by Parry et al., 2016).

Clinical Features

Picard et al. (2009) reported 3 sibs, born of a consanguineous family from central Europe, who had recurrent infections due to defective T-cell function. Muscle hypotonia and partial iris hypoplasia were noted in the neonatal period. Within a few months, patients developed lymphadenopathy and hepatosplenomegaly associated with autoimmune hemolytic anemia and thrombocytopenia. During the first year of life, all children developed recurrent infections. Defects in enamel dentition were also noted. One died at age 9 years from complications of a bone marrow transplant, whereas another died from the nephrotic syndrome and recurrent infections at age 18 months. The third child had a successful bone marrow transplant at age 15 months. Laboratory studies showed slightly reduced or normal lymphocyte counts, but T cells showed a severely impaired proliferative response to stimulation. Serum immunoglobulin levels were normal, but there were impaired T-cell responses to recall antigens despite immunization. Further studies showed a defect in cellular store-operated calcium entry, which is required for lymphocyte activation. Transfection of wildtype STIM1 corrected the defect in vitro.

Byun et al. (2010) reported a human immunodeficiency virus (HIV)-seronegative Turkish child with STIM1 deficiency who died from disseminated Kaposi sarcoma (KS) at age 2 years. The patient was born to consanguineous parents. At age 2 years, the patient developed the first KS on her lip, followed by rapid dissemination throughout the body. She had lymphadenopathy and hepatosplenomegaly, and she died from severe pulmonary lesions 4 months later. She had no history of other severe infections or tumors, but presented with autoimmune hemolytic anemia. The counts and proportions of blood, T, B, and natural killer cells and subsets were normal, as were serum immunoglobin levels. RT-PCR analysis of Epstein-Barr virus (EBV)-transformed B cell lines from the patient showed significantly reduced STIM1 mRNA expression, and no STIM1 protein was detected by Western blot analysis. Ca(2+) influx was completely abolished in the patient's EBV-B cells, and expression of wildtype STIM1 rescued this defect. Byun et al. (2010) concluded that complete STIM1 deficiency in this patient precipitated the development of lethal classic KS upon infection with human herpesvirus (HHV)-8, the cause of all forms of KS. They noted the similarity of their patient to the patients with STIM1 deficiency reported by Picard et al. (2009). Byun et al. (2010) suggested that the muscular hypotonia, partial iris hypoplasia, and dental enamel defects in the patients reported by Picard et al. (2009) would probably not have been picked up in their patient due to the early onset and fatal outcome of KS.

Fuchs et al. (2012) reported STIM1 deficiency in a 6-year-old Pakistani girl of consanguineous parents. She experienced chronic and recurrent pneumonia, diarrhea, and viremia due to infection with herpesviruses and other pathogens. Additional features included mild muscle hypotonia, anhidrosis with presence of sweat glands, enamel defect of the teeth, and nail dysplasia. Store-operated calcium entry (SOCE) was completely abolished in T cells. The patient's younger sister had a similar history and died at age 21 months. A first cord blood transplant failed in the older girl. Immunologic analysis of the surviving patient showed defects in T-cell proliferation and cytokine production in vitro, as expected, but also the generation of significant antiviral T-cell populations in vivo. The latter cells proliferated in response to viral antigens and showed normal antiviral cytotoxicity. In spite of this apparent antiviral immunity, the patient experienced chronic cytomegalovirus and EBV infections, possibly due to impaired natural killer cell function and absent natural killer T cells. The patient also experienced autoimmune cytopenia, eczema, and intermittent diarrhea, suggesting impaired immune regulation. She possessed FOXP3 (300292)-positive regulatory T (Treg) cells with an abnormal phenotype but normal function. Fuchs et al. (2012) proposed that the sum of these partial defects contribute to the overall pathogenesis of immunodeficiency and autoimmunity in STIM1 deficiency.

Clinical Variability

Wang et al. (2014) reported a 6-year-old girl, born of consanguineous Turkish parents, who presented with dental enamel abnormalities. The sizes and shapes of the dental crowns were within normal limits, but the enamel was creamy brown and showed rapid attrition that had resulted in loss of the maxillary central incisors. She also had nail dysplasia. She had a history of frequent throat infections, but no immunologic evaluation was performed, and the family was lost to follow-up.

Parry et al. (2016) reported 2 patients, 11 and 18 years of age, from a large consanguineous family who presented with hypomineralized amelogenesis imperfecta and hypohidrosis associated with a homozygous missense mutation in the STIM1 gene (L74P; 605921.0012). Both had asthma; 1 had recurrent chest infections in infancy and spontaneous pneumothoraces as a teenager and was allergic to red food dye, and the other had eczema. Neither had overt features of immunodeficiency, but laboratory studies showed impaired NK cell effector function as well as defective store-operated calcium entry (SOCE) in T cells and NK cells. Only the older patient had stable CD8+ T-cell depletion. T-cell stimulation responses were normal in both patients. Parry et al. (2016) postulated that the relative preservation of T-cell function in these patients may have compensated for NK cell dysfunction, or that the patients may not have encountered a pathogen that would expose an immune system defect. Neither patient had clinical or serologic evidence of a myopathy.

Mapping

Immunodeficiency-10 is caused by mutation in the STIM1 gene, which Parker et al. (1996) mapped to chromosome 11p15.5.

Inheritance

The transmission pattern of STIM1 deficiency in the patients reported by Picard et al. (2009) and Byun et al. (2010) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs with immune dysfunction due to T-cell inactivation, Picard et al. (2009) identified a homozygous truncating mutation in the STIM1 gene (605921.0001).

Using whole-exome sequencing, Byun et al. (2010) identified a homozygous splice site mutation at the -1 position of exon 8 in the STIM1 gene (605921.0002) in an HIV-seronegative Turkish child of consanguineous parents who died at age 2 years from disseminated Kaposi sarcoma associated with complete STIM1 deficiency.

In 2 Pakistani sisters with STIM1 deficiency born to consanguineous parents, Fuchs et al. (2012) identified an arg429-to-cys (R429C; 605921.0003) mutation in the STIM1 gene.

In a 6-year-old girl, born of consanguineous Turkish parents, with IMD10 manifest primarily as amelogenesis imperfecta, Wang et al. (2014) identified a homozygous missense mutation in the STIM1 gene (R426C; 605921.0011). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; each unaffected parent was heterozygous for the mutation. Although functional studies of this variant were not performed, Wang et al. (2014) noted that a previous study (Muik et al., 2011) had demonstrated that a recombinant mutation at the same codon (R426L) prevented STIM1 from interacting with ORAI1 (610277). Wang et al. (2014) concluded that recessive loss-of-function STIM1 mutations, such as R426C, result in failure to induce calcium influx in response to ER calcium store depletion, which results in lower than normal intracellular calcium levels and impaired enamel maturation.

In 2 patients from a consanguineous Pakistani family with IMD10 without overt features of immunodeficiency, Parry et al. (2016) identified a homozygous missense mutation in the STIM1 gene (L74P; 605921.0012) in the EF-hand domain. The mutation, which was found by a combination of autozygosity mapping and exome sequencing, was confirmed by Sanger sequencing, and segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the mutation resulted in altered calcium dynamics that were distinct from both loss of function and constitutive activation. The patients had no clinical or serologic evidence of a myopathy, and 2 heterozygous family members did not report muscle problems, but they were not formally examined.