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Related Experiment Video

Updated: May 28, 2026

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

STIM1 GoF Mutants: Genotype-Phenotype Relationships Across the Stormorken/TAM/YPS Spectrum.

Lara Atzgerstorfer¹, Magdalena Prantl¹, Andrea Waldhauser¹

¹Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, 4040 Linz, Austria.

|May 27, 2026

Summary

Gain-of-function mutations in STIM1 disrupt calcium homeostasis, causing overlapping syndromes like Stormorken Syndrome. Understanding these STIM1 mutations reveals a shared disease spectrum with variable clinical presentations.

Keywords:

CRAC channel Ca2+ signaling SOCE STIM1 Stormorken Syndrome York Platelet Syndrome tubular aggregate myopathy

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Area of Science:

Molecular Biology
Genetics
Cellular Physiology

Background:

Store-operated Calcium (Ca2+) entry (SOCE), regulated by STIM1 and Orai1, is crucial for intracellular Ca2+ homeostasis.
Gain-of-function (GoF) mutations in STIM1 are linked to Stormorken Syndrome (STK), tubular aggregate myopathy (TAM), and York Platelet Syndrome (YPS).
These conditions may represent a single disease spectrum due to shared molecular underpinnings.

Purpose of the Study:

To review the molecular mechanisms of STIM1 activation and how GoF mutations disrupt these processes.
To integrate clinical data and mutation information to delineate the spectrum of STIM1-related disorders.
To highlight the variability and incomplete penetrance of clinical manifestations associated with STIM1 mutations.

Main Methods:

Literature review of STIM1 activation mechanisms.
Systematic integration of published case reports and mutation data.
Development of a mutation-phenotype correlation table.

Main Results:

STIM1 activation involves autoinhibitory checkpoints that GoF mutations disrupt, leading to dysregulated SOCE.
Mutations in the EF hand, CC1 domain, and C-terminal regions of STIM1 contribute to the disease spectrum.
Significant variability in clinical manifestations and incomplete penetrance were observed across different STIM1 mutations.

Conclusions:

STIM1 GoF mutations cause a spectrum of disorders previously classified separately, indicating a shared disease entity.
Understanding the molecular impact of specific STIM1 mutations is key to explaining the diverse clinical phenotypes.
Further research is needed to fully elucidate the genotype-phenotype correlations and variable expressivity in STIM1-related diseases.