What is the clinical evidence from this study?

Study design: Review. Population: Orai1 dysfunction (SCID, TAM, STRMK). Intervention: Orai1 mutations.

What does this research mean for the field?

Mutations distributed across all transmembrane domains of the Orai1 calcium channel disrupt its complex activation mechanism, leading to severe diseases such as SCID, TAM, and STRMK through either loss-of-function or gain-of-function alterations. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To comprehensively review known disease-associated Orai1 mutations, define how they perturb the channel activation cascade, and establish their clinical significance.

September 1, 2026The Journal of General Physiology

The many faces of Orai1 dysfunction: Molecular mechanisms and clinical manifestations

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Why the study?

Disruption of Orai1-mediated store-operated calcium entry is associated with human diseases, but the mechanisms by which disease-associated mutations interfere with the activation cascade required comprehensive compilation.

Design

Review

Key result

Orai1 mutations cause severe combined immunodeficiency via loss-of-function, and tubular aggregate myopathy and Stormorken syndrome via gain-of-function alterations.

Authors

MPMagdalena Prantl LALara Atzgerstorfer TRTamara Radiskovic

Discussion

Member takes

Overview

Catalogs Orai1 mutation mechanisms across channelopathies; leaves open targeted CRAC therapies pending functional validation.

Key Points

To comprehensively review known disease-associated Orai1 mutations, define how they perturb the channel activation cascade, and establish their clinical significance.
Synthesized findings on structural and functional alterations across all four transmembrane domains of the Orai1 channel.
Evaluated molecular mechanisms linking loss-of-function and gain-of-function mutations to store-operated calcium entry disruption.
Loss-of-function Orai1 mutations prevent channel opening, leading to severe combined immunodeficiency.
Gain-of-function mutations cause constitutive or excessive calcium permeation, resulting in tubular aggregate myopathy and Stormorken syndrome.
Disease-causing mutations span all four transmembrane domains, demonstrating that disruptions at multiple domain interfaces can fundamentally impair channel gating.

PICO

Population

Orai1 dysfunction (SCID, TAM, STRMK)

Exposure / Comparator

Orai1 mutations

This review highlights how Orai1 mutations disrupt intracellular calcium homeostasis, leading to severe diseases like SCID, TAM, and STRMK.

Cite This Study

Prantl et al. (2026) conducted a review in Orai1 dysfunction (SCID, TAM, STRMK). Orai1 mutations was evaluated. Orai1 mutations cause severe combined immunodeficiency via loss-of-function, and tubular aggregate myopathy and Stormorken syndrome via gain-of-function alterations.

synapsesocial.com/papers/6a969a7f535111e2d4ce8ce4 https://doi.org/10.1085/jgp.202614031

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September 1, 2026The Journal of General Physiology

The many faces of Orai1 dysfunction: Molecular mechanisms and clinical manifestations

View Full Paper

Ask AI

Bookmark

Why the study?

Design

Review

Key result

Orai1 mutations cause severe combined immunodeficiency via loss-of-function, and tubular aggregate myopathy and Stormorken syndrome via gain-of-function alterations.

Authors

MPMagdalena Prantl LALara Atzgerstorfer TRTamara Radiskovic

Discussion

Member takes

Overview

Catalogs Orai1 mutation mechanisms across channelopathies; leaves open targeted CRAC therapies pending functional validation.

Key Points

To comprehensively review known disease-associated Orai1 mutations, define how they perturb the channel activation cascade, and establish their clinical significance.
Synthesized findings on structural and functional alterations across all four transmembrane domains of the Orai1 channel.
Evaluated molecular mechanisms linking loss-of-function and gain-of-function mutations to store-operated calcium entry disruption.
Loss-of-function Orai1 mutations prevent channel opening, leading to severe combined immunodeficiency.
Gain-of-function mutations cause constitutive or excessive calcium permeation, resulting in tubular aggregate myopathy and Stormorken syndrome.
Disease-causing mutations span all four transmembrane domains, demonstrating that disruptions at multiple domain interfaces can fundamentally impair channel gating.

PICO

Population

Orai1 dysfunction (SCID, TAM, STRMK)

Exposure / Comparator

Orai1 mutations

This review highlights how Orai1 mutations disrupt intracellular calcium homeostasis, leading to severe diseases like SCID, TAM, and STRMK.

Cite This Study

synapsesocial.com/papers/6a969a7f535111e2d4ce8ce4 https://doi.org/10.1085/jgp.202614031

Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

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