title: A dominant STIM1 mutation causes Stormorken syndrome.
abstract: Stormorken syndrome is a rare autosomal-dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca(2+) depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca(2+) release-activated Ca(2+) channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled-coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca(2+) levels were elevated in platelets from the patients compared with controls, and store-operated Ca(2+) entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near-maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.
authors.affiliation: Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Doriana
authors.initials: D
authors.lastname: Misceo
authors.forename: Asbjørn
authors.initials: A
authors.lastname: Holmgren
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
authors.forename: Pål A
authors.initials: PA
authors.lastname: Holme
authors.forename: Masahiro
authors.initials: M
authors.lastname: Mizobuchi
authors.forename: Raul J
authors.initials: RJ
authors.lastname: Morales
authors.forename: André Maues
authors.initials: AM
authors.lastname: De Paula
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.forename: Bjørn
authors.initials: B
authors.lastname: Dalhus
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Helge
authors.initials: H
authors.lastname: Stormorken
authors.forename: Geir E
authors.initials: GE
authors.lastname: Tjønnfjord
authors.forename: Eirik
authors.initials: E
authors.lastname: Frengen
mesh_terms: D000328:Adult; D001791:Blood Platelet Disorders / Q000235:genetics* / Q000473:pathology; D015220:Calcium Channels / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004410:Dyslexia / Q000235:genetics* / Q000473:pathology; D004913:Erythrocytes, Abnormal / Q000473:pathology; D059472:Exome / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008881:Migraine Disorders / Q000235:genetics* / Q000473:pathology; D015877:Miosis / Q000235:genetics* / Q000473:pathology; D018763:Muscle Fatigue / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D000071740:ORAI1 Protein; D010375:Pedigree; D013154:Spleen / Q000002:abnormalities* / Q000473:pathology; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1
keywords: CRAC; SOCE; STIM1; Stormorken syndrome; whole-exome sequencing