title: Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis.
abstract: Signaling through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca(2+) homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca(2+) sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca(2+)-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca(2+) entry in the treatment of patients with Stormorken syndrome and related pathologic conditions.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
authors.forename: Vasyl
authors.initials: V
authors.lastname: Nesin
authors.forename: Graham
authors.initials: G
authors.lastname: Wiley
authors.forename: Maria
authors.initials: M
authors.lastname: Kousi
authors.forename: E-Ching
authors.initials: EC
authors.lastname: Ong
authors.forename: Thomas
authors.initials: T
authors.lastname: Lehmann
authors.forename: David J
authors.initials: DJ
authors.lastname: Nicholl
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.forename: Nortina
authors.initials: N
authors.lastname: Shahrizaila
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Klaas J
authors.initials: KJ
authors.lastname: Wierenga
authors.forename: Leonidas
authors.initials: L
authors.lastname: Tsiokas
mesh_terms: D000818:Animals; D001483:Base Sequence; D001791:Blood Platelet Disorders / Q000235:genetics*; D015220:Calcium Channels / Q000235:genetics*; D020013:Calcium Signaling / Q000235:genetics*; D002648:Child; D017931:DNA Primers / Q000235:genetics; D004410:Dyslexia / Q000235:genetics*; D004913:Erythrocytes, Abnormal; D005260:Female; D006801:Humans; D007057:Ichthyosis / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008881:Migraine Disorders / Q000235:genetics*; D015877:Miosis / Q000235:genetics*; D008969:Molecular Sequence Data; D018763:Muscle Fatigue / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D000071740:ORAI1 Protein; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000002:abnormalities*; D000071737:Stromal Interaction Molecule 1; D015027:Zebrafish
chemical_list: D015220:Calcium Channels; D017931:DNA Primers; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1
keywords: calcium signaling; human genetics