title: Gain-of-Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome.
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.
authors.affiliation: Department of Molecular and Clinical Genetics, EA 4666, CHU d'Amiens, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Morin
authors.forename: Nadina Ortiz
authors.initials: NO
authors.lastname: Bruechle
authors.forename: Amrathlal Rabbind
authors.initials: AR
authors.lastname: Singh
authors.forename: Cordula
authors.initials: C
authors.lastname: Knopp
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jedraszak
authors.forename: Miriam
authors.initials: M
authors.lastname: Elbracht
authors.forename: Dominique
authors.initials: D
authors.lastname: Brémond-Gignac
authors.forename: Kathi
authors.initials: K
authors.lastname: Hartmann
authors.forename: Henri
authors.initials: H
authors.lastname: Sevestre
authors.forename: Peter
authors.initials: P
authors.lastname: Deutz
authors.forename: Didier
authors.initials: D
authors.lastname: Hérent
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Bernard
authors.initials: B
authors.lastname: Roméo
authors.forename: Kerstin
authors.initials: K
authors.lastname: Konrad
authors.forename: Michèle
authors.initials: M
authors.lastname: Mathieu-Dramard
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bourges-Petit
authors.forename: Yuequan
authors.initials: Y
authors.lastname: Shen
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.forename: Halima
authors.initials: H
authors.lastname: Ouadid-Ahidouch
authors.forename: Jacques
authors.initials: J
authors.lastname: Rochette
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001791:Blood Platelet Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004410:Dyslexia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D004913:Erythrocytes, Abnormal / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015877:Miosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018763:Muscle Fatigue / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D017433:Protein Structure, Secondary; D013154:Spleen / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: Stormorken syndrome; calcium homeostasis; miosis; stromal interaction molecule 1 (STIM1); tubular aggregate myopathy