Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome |
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Authors: | Gilles Morin Nadina Ortiz Bruechle Amrathlal Rabbind Singh Cordula Knopp Guillaume Jedraszak Miriam Elbracht Dominique Brémond‐Gignac Kathi Hartmann Henri Sevestre Peter Deutz Didier Hérent Peter Nürnberg Bernard Roméo Kerstin Konrad Michèle Mathieu‐Dramard Johannes Oldenburg Elisabeth Bourges‐Petit Yuequan Shen Klaus Zerres Halima Ouadid‐Ahidouch Jacques Rochette |
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Affiliation: | 1. Department of Molecular and Clinical Genetics, EA 4666, CHU d’Amiens, Université de Picardie Jules Verne, Amiens, France;2. Department of Human Genetics, RWTH University Hospital, Aachen, Germany;3. Department of Ophthalmology, CHU d’Amiens, Amiens, France;4. Department of Ophthalmology, RWTH University Hospital, Aachen, Germany;5. Department of Pathology, Amiens, France;6. Department of Pediatrics, RWTH University Hospital, Aachen, Germany;7. Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany;8. Department of Paediatric Pneumology, Amiens, France;9. Child Neuropsychology Section, Department of Child and Adolescent Psychiatry and Psychotherapy, RWTH University Hospital, Aachen, Germany;10. Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany;11. Department of Paediatric Cardiology, Amiens, France;12. Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) and College of Life Sciences, Nankai University, Tianjin, China;13. Laboratory of Cellular and Molecular Physiology, EA 4667, UFR of Sciences, Amiens, France |
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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 Ca2+ 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 Ca2+ 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. |
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Keywords: | Stormorken syndrome miosis tubular aggregate myopathy stromal interaction molecule 1 (STIM1) calcium homeostasis |
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