title: A novel gain-of-function mutation in ORAI1 causes late-onset tubular aggregate myopathy and congenital miosis.
abstract: We present three members of an Italian family affected by tubular aggregate myopathy (TAM) and congenital miosis harboring a novel missense mutation in ORAI1. All patients had a mild, late onset TAM revealed by asymptomatic creatine kinase (CK) elevation and congenital miosis consistent with a Stormorken-like Syndrome, in the absence of thrombocytopathy. Muscle biopsies showed classical histological findings but ultrastructural analysis revealed atypical tubular aggregates (TAs). The whole body muscle magnetic resonance imaging (MRI) showed a similar pattern of muscle involvement that correlated with clinical severity. The lower limbs were more severely affected than the scapular girdle, and thighs were more affected than legs. Molecular analysis revealed a novel c.290C>G (p.S97C) mutation in ORAI1 in all affected patients. Functional assays in both human embryonic kidney (HEK) cells and myotubes showed an increased rate of Ca2+entry due to a constitutive activation of the CRAC channel, consistent with a 'gain-of-function' mutation. In conclusion, we describe an Italian family harboring a novel heterozygous c.290C>G (p.S97C) mutation in ORAI1 causing a mild- and late-onset TAM and congenital miosis via constitutive activation of the CRAC channel. Our findings extend the clinical and genetic spectrum of the ORAI1-related TAM.
authors.affiliation: Unit of Neuromuscular Diseases, Department of Neurology Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.|Neuromuscular Diseases Centre, Department of Clinical Neurosciences, University Hospital of Nice, Nice, France.
authors.forename: M
authors.initials: M
authors.lastname: Garibaldi
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Research Hospital, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fattori
authors.affiliation: Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Riva
authors.affiliation: Neuromuscular Morphology Unit, Myology Institute, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Labasse
authors.affiliation: Neuromuscular Morphology Unit, Myology Institute, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Brochier
authors.affiliation: Department of Radiology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ottaviani
authors.affiliation: Neuromuscular Diseases Centre, Department of Clinical Neurosciences, University Hospital of Nice, Nice, France.
authors.forename: S
authors.initials: S
authors.lastname: Sacconi
authors.affiliation: Unit of Neuromuscular Diseases, Department of Neurology Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Vizzaccaro
authors.affiliation: Department of Radiology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Laschena
authors.affiliation: Neuromuscular Morphology Unit, Myology Institute, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France.
authors.forename: N B
authors.initials: NB
authors.lastname: Romero
authors.affiliation: Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Genazzani
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Research Hospital, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Unit of Neuromuscular Diseases, Department of Neurology Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Antonini
mesh_terms: D017668:Age of Onset; D000071739:Calcium Release Activated Calcium Channels / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000503:physiopathology; D000071740:ORAI1 Protein / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011681:Pupil Disorders / Q000151:congenital* / Q000235:genetics
chemical_list: D000071739:Calcium Release Activated Calcium Channels; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human
keywords: CRAC channel; ORAI1; Stormorken syndrome; congenital miosis; muscle MRI; tubular aggregate myopathy