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A dominant STIM1 mutation causes Stormorken syndrome
Doriana Misceo1, Asbjørn Holmgren, William E Louch
1Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.
Human Mutation
|March 13, 2014
Summary
Stormorken syndrome is linked to a specific STIM1 gene mutation. This mutation causes preactivated platelets and altered calcium signaling, leading to the syndrome's complex symptoms.
Area of Science:
- Genetics
- Molecular Biology
- Cellular Physiology
Background:
- Stormorken syndrome is a rare autosomal-dominant disorder.
- It presents with a complex phenotype including bleeding, thrombocytopathy, thrombocytopenia, anemia, asplenia, myopathy, miosis, headache, and ichthyosis.
Purpose of the Study:
- To identify the genetic cause of Stormorken syndrome.
- To investigate the functional consequences of the identified mutation in STIM1.
Main Methods:
- Genetic analysis of affected families to identify mutations.
- Functional studies on patient-derived platelets to assess calcium signaling and activation state.
Main Results:
- A heterozygous missense mutation (c.910C>T; p.Arg304Trp) in the STIM1 gene was identified and segregated with the disease.
- The mutation is located in the STIM1 coiled-coil 1 domain.
- Patient platelets showed signs of preactivation, elevated resting calcium levels, and impaired store-operated calcium entry, suggesting a gain-of-function mutation.
Conclusions:
- The heterozygous STIM1 mutation c.910C>T is the causative genetic defect in Stormorken syndrome.
- This mutation leads to constitutive activation of STIM1 and ORAI1, explaining the observed platelet abnormalities and clinical phenotype.
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