ORAI1 – Tubular Aggregate Myopathy

Store-operated Ca2+ entry (SOCE) is mediated by the interaction of the ER Ca2+ sensor STIM1 and the plasma membrane Ca2+ channel ORAI1, with ORAI1 forming the ion-selective pore (PMID:16921385). Loss-of-function ORAI1 mutations cause severe combined immunodeficiency, whereas dominant gain-of-function variants underlie tubular aggregate myopathy (TAM) (MONDO:0008051).

A heterozygous c.290C>G (p.Ser97Cys) ORAI1 variant was identified in three members of an Italian family with late-onset TAM and congenital miosis; the variant segregated with disease in two generations (3 probands) (PMID:27882542). Additional dominant ORAI1 TAM mutations including p.Gly98Ser and p.Thr184Met have been reported in at least 3 unrelated probands, expanding the mutational spectrum (PMID:28058752).

Clinically, affected individuals exhibit mild proximal muscle weakness, asymptomatic creatine kinase elevation, and congenital miosis without bleeding diathesis. Muscle biopsies show classical tubular aggregates, and MRI reveals a pattern of lower limb involvement correlating with clinical severity consistent with a Stormorken-like phenotype.

Functional assays in HEK cells and patient myotubes demonstrated constitutive CRAC channel activation for p.Ser97Cys, p.Gly98Ser, and p.Thr184Met variants, with increased basal Ca2+ entry and altered ion selectivity, confirming a gain-of-function mechanism (PMID:27882542; PMID:28058752).

Mechanistically, TAM-associated ORAI1 variants disrupt slow Ca2+-dependent inactivation and widen the channel pore, leading to excessive Ca2+ influx and downstream muscle pathology. Pharmacological blockade with CRAC inhibitor GSK-7975A normalizes basal currents in vitro, suggesting therapeutic potential (PMID:30382595).

No studies have refuted the association of ORAI1 gain-of-function variants with TAM. However, further longitudinal studies are needed to assess variable expressivity and potential modifier genes.

In summary, dominant gain-of-function ORAI1 mutations cause TAM via constitutive CRAC channel activation, supporting genetic testing for ORAI1 in adult-onset myopathy with miosis and informing potential targeted therapy.

Key Take-home: ORAI1 gain-of-function variants should be considered in adults presenting with late-onset tubular aggregate myopathy and congenital miosis, enabling precise diagnosis and potential CRAC channel–directed interventions.

References

• Nature • 2006 • Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. PMID:16921385
• Clinical Genetics • 2017 • A novel gain-of-function mutation in ORAI1 causes late-onset tubular aggregate myopathy and congenital miosis. PMID:27882542
• Human Mutation • 2017 • ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. PMID:28058752
• The Journal of Physiology • 2019 • ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain. PMID:30382595
• Proceedings of the National Academy of Sciences of the United States of America • 2006 • Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. PMID:16921385

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