1. Gain-of-Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome.
- Author
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Morin G, Bruechle NO, Singh AR, Knopp C, Jedraszak G, Elbracht M, Brémond-Gignac D, Hartmann K, Sevestre H, Deutz P, Hérent D, Nürnberg P, Roméo B, Konrad K, Mathieu-Dramard M, Oldenburg J, Bourges-Petit E, Shen Y, Zerres K, Ouadid-Ahidouch H, and Rochette J
- Subjects
- Adolescent, Adult, Aged, Blood Platelet Disorders metabolism, Blood Platelet Disorders pathology, Calcium metabolism, Calcium Channels metabolism, Child, Child, Preschool, Dyslexia metabolism, Dyslexia pathology, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum ultrastructure, Erythrocytes, Abnormal metabolism, Erythrocytes, Abnormal pathology, Female, Humans, Ichthyosis metabolism, Ichthyosis pathology, Infant, Infant, Newborn, Male, Membrane Proteins chemistry, Membrane Proteins metabolism, Middle Aged, Migraine Disorders metabolism, Migraine Disorders pathology, Miosis metabolism, Miosis pathology, Muscle Fatigue genetics, Muscle Fibers, Skeletal pathology, Neoplasm Proteins chemistry, Neoplasm Proteins metabolism, Pedigree, Protein Structure, Secondary, Spleen metabolism, Spleen pathology, Stromal Interaction Molecule 1, Blood Platelet Disorders genetics, Dyslexia genetics, Ichthyosis genetics, Membrane Proteins genetics, Migraine Disorders genetics, Miosis genetics, Neoplasm Proteins genetics, Point Mutation, Spleen abnormalities
- Abstract
Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca(2+) sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca(2+) levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance., (© 2014 The Authors. *Human Mutation published by Wiley Periodicals, Inc.)
- Published
- 2014
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