ORAI1 – Stormorken syndrome

ORAI1 encodes the pore-forming subunit of the Ca2+ release–activated Ca2+ (CRAC) channel, a key component of store-operated Ca2+ entry (SOCE) in excitable and non-excitable cells. SOCE initiated by endoplasmic reticulum Ca2+ depletion via STIM1 sensors leads to ORAI1-mediated Ca2+ influx critical for lymphocyte activation, muscle function, and platelet activation. Precise regulation of CRAC channels ensures Ca2+ homeostasis under physiological conditions. Dominant gain-of-function (GOF) mutations in ORAI1 cause excessive Ca2+ entry and underlie the spectrum of tubular aggregate myopathy and Stormorken syndrome. Loss-of-function mutations instead trigger immunodeficiency phenotypes, highlighting ORAI1’s pivotal role in human disease. This summary focuses on ORAI1’s association with Stormorken syndrome, a rare multisystemic GOF disorder.

Stormorken syndrome manifests as a multisystem disorder characterized by proximal muscle weakness, tubular aggregate formation on muscle histology, and congenital miosis. Patients frequently exhibit thrombocytopenia with bleeding diathesis, hyposplenism, ichthyosis, dyslexia, and short stature. Platelet functional assays reveal preactivated platelets with elevated resting Ca2+ levels and diminished Ca2+ influx attenuation. The phenotype spectrum overlaps with tubular aggregate myopathy, indicating a continuum of severity. Clinical heterogeneity and overlapping myopathic signs pose diagnostic challenges. Recognition of this phenotype spectrum is essential for targeted genetic testing.

The inheritance of ORAI1-related Stormorken syndrome is autosomal dominant. To date, 47 unrelated families with heterozygous gain-of-function ORAI1 variants have been reported, establishing a robust genotype–phenotype correlation (PMID:31448844). Segregation analyses confirm variant co-segregation with disease in multiple pedigrees. Most reported ORAI1 mutations are missense substitutions affecting transmembrane segments or cytosolic loops, which alter channel gating. Variant classes include missense gain-of-function variants without truncating alleles. Recurrent and private alleles suggest no prevalent founder variant in diverse populations.

A representative ORAI1 variant associated with Stormorken syndrome is c.551C>T (p.Thr184Met) detected in patients presenting with late-onset tubular aggregate myopathy and congenital miosis (PMID:28058752). Functional characterization in HEK cells shows that p.Thr184Met induces constitutive channel opening. Similar GOF variants such as p.Pro245Leu have been shown to suppress slow Ca2+-dependent inactivation and prolong Ca2+ influx. Other variants, including p.Gly98Ser, increase basal Ca2+ currents independent of store depletion. These missense alleles underscore a mutation-dependent pathomechanism correlating with clinical severity. Prevalence of carrier frequency remains unknown.

Functional assays demonstrate that ORAI1 GOF variants yield constitutive Ca2+ influx at resting potentials and heightened SOCE upon store depletion (PMID:24591628). Electrophysiological recordings in HEK293T and muscle cells reveal increased basal Ca2+ entry and delayed channel closure. Cellular studies show that constitutive Ca2+ entry leads to platelet preactivation, contributing to thrombocytopenia and bleeding diathesis. In vitro rescue experiments using CRAC channel inhibitors normalize Ca2+ homeostasis, indicating therapeutic potential. The pathomechanism involves impaired slow Ca2+-dependent inactivation of the ORAI1 pore. Collectively, these data support a direct link between GOF variant biophysics and clinical manifestations.

The convergence of genetic, electrophysiological, and cellular data confirms ORAI1 gain-of-function as the central mechanism in Stormorken syndrome. Autosomal dominant inheritance combined with consistent co-segregation in 47 families supports a “Strong” ClinGen gene–disease validity classification. Genetic evidence reaches a “Strong” score with a significant number of independent probands and variant functionality, while functional evidence is rated “Moderate” due to multiple concordant assays. No conflicting reports have disputed ORAI1’s role in this syndrome. Additional studies exploring genotype–phenotype correlations and variant-specific phenotypic modifiers may further refine risk assessment. Clinically, ORAI1 genetic testing is recommended in patients with Stormorken spectrum features to inform management and genetic counseling.

In summary, heterozygous gain-of-function ORAI1 variants cause a dominant form of Stormorken syndrome characterized by multisystemic Ca2+ dysregulation. Molecular diagnosis of ORAI1 mutations enables timely therapeutic interventions, including CRAC channel modulators. This association underscores the importance of calcium channelopathies in muscle and hematologic disorders. Genetic and functional findings form the basis for commercial testing platforms and guide personalized treatment strategies. Early identification of ORAI1 variants can improve diagnostic accuracy and patient outcomes. Screening ORAI1 expands the clinical utility of gene panels for myopathy and bleeding diathesis. Targeted CRAC channel inhibition represents a promising therapeutic avenue in Stormorken syndrome.

References

• Human Mutation • 2020 • Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation. PMID:31448844
• Human Mutation • 2017 • ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. PMID:28058752
• Proceedings of the National Academy of Sciences of the United States of America • 2014 • Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. PMID:24591628

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