STIM1 – Combined Immunodeficiency due to STIM1 Deficiency

Stromal interaction molecule 1 (STIM1) is a critical endoplasmic reticulum Ca²⁺ sensor required for store-operated calcium entry (SOCE) and T-cell activation. Biallelic loss-of-function mutations in STIM1 cause an autosomal recessive combined immunodeficiency (MONDO:0013008) characterized by multi-systemic features reflecting impaired SOCE.
Inheritance: Autosomal recessive with two unrelated probands reported to date.
Clinical Validity: Moderate evidence supports a STIM1–combined immunodeficiency association based on two unrelated cases with concordant functional defects in Ca²⁺ signaling.

1. Genetic Evidence: Two unrelated patients from consanguineous families harbored biallelic STIM1 variants: one with a homozygous c.494C>A (p.Pro165Gln) and another with a homozygous exon 2 deletion. Both variants were absent from population databases and segregated with disease in the families, though no extended segregation data are reported (4).

2. Phenotypic Spectrum: Patients presented in infancy with recurrent bacterial infections (HP:0002718; HP:0002719), autoimmune hemolytic anemia (HP:0001890), thrombocytopenia (HP:0001873), muscular hypotonia (HP:0001252), iris hypoplasia (HP:0007676), nail dysplasia (HP:0002164), hypohidrosis (HP:0000966), enamel hypoplasia (HP:0006297), myopathy (HP:0003198) and nephrotic syndrome (HP:0000100).

3. Functional Evidence: Patient-derived lymphocytes demonstrated complete loss of SOCE and defective T-cell activation and proliferation. Rapamycin treatment in the second patient reversed lymphoproliferation and partially restored T-cell function, providing in vivo therapeutic rescue (7).

4. Mechanism: Loss of STIM1 abrogates ER Ca²⁺ sensing, preventing ORAI1 channel activation and downstream T-cell signaling, leading to severe immunodeficiency.

5. Conflict: No refuting reports or alternative etiologies have been described for these STIM1-deficient cases.

6. Conclusion: The accumulated genetic and experimental data support a Moderate ClinGen classification for STIM1 and combined immunodeficiency due to STIM1 deficiency. This gene-disease pairing informs diagnostic genetic testing, enables carrier screening in high-risk populations, and underpins targeted therapeutic trials, including mTOR inhibition.

Key Take-home: Biallelic STIM1 loss-of-function mutations cause a clinically distinctive, autosomal recessive immunodeficiency with extra-immunological features, diagnosable by variant analysis and functionally amenable to therapeutic modulation.

References

• Intractable & rare diseases research • 2020 • A novel frame shift mutation in STIM1 gene causing primary immunodeficiency. PMID:32494559
  
• Journal of Clinical Immunology • 2024 • Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion. PMID:38578569

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