title: York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1.
abstract: Store-operated Ca(2+) entry is the major route of replenishment of intracellular Ca(2+) in animal cells in response to the depletion of Ca(2+) stores in the endoplasmic reticulum. It is primarily mediated by the Ca(2+)-selective release-activated Ca(2+) (CRAC) channel, which consists of the pore-forming subunits ORAI1-3 and the Ca(2+) sensors, STIM1 and STIM2. Recessive loss-of-function mutations in STIM1 or ORAI1 result in immune deficiency and nonprogressive myopathy. Heterozygous gain-of-function mutations in STIM1 cause non-syndromic myopathies as well as syndromic forms of miosis and myopathy with tubular aggregates and Stormorken syndrome; some of these syndromic forms are associated with thrombocytopenia. Increased concentration of Ca(2+) as a result of store-operated Ca(2+) entry is essential for platelet activation. The York Platelet syndrome (YPS) is characterized by thrombocytopenia, striking ultrastructural platelet abnormalities including giant electron-opaque organelles and massive, multilayered target bodies and deficiency of platelet Ca(2+) storage in delta granules. We present clinical and molecular findings in 7 YPS patients from 4 families, demonstrating that YPS patients have a chronic myopathy associated with rimmed vacuoles and heterozygous gain-of-function STIM1 mutations. These findings expand the phenotypic spectrum of STIM1-related human disorders and define the molecular basis of YPS.
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Markello
authors.affiliation: Division of Hematopathology, Department of Laboratory of Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Justin Y
authors.initials: JY
authors.lastname: Kwan
authors.affiliation: Joint Pathology Center, Defense Health Agency, Silver Spring, MD 20910, USA.
authors.forename: Iren
authors.initials: I
authors.lastname: Horkayne-Szakaly
authors.affiliation: Joint Pathology Center, Defense Health Agency, Silver Spring, MD 20910, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Morrison
authors.affiliation: Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Simakova
authors.affiliation: Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Lozier
authors.affiliation: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cullinane
authors.affiliation: Pediatric Hematology, The Children's Hopsital at Westmead, Westmead, NSW 2145, Australia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Kilo
authors.affiliation: Pediatric Hematology, Joe DiMaggio Children's Hospital, Hollywood, FL 33021, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Meister
authors.affiliation: Hematopathology, Pathology Consultants of South Broward, Memorial Healthcare System, Hollywood, FL 33021, USA.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Pakzad
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: William
authors.initials: W
authors.lastname: Bone
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chainani
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lee
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Links
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Boerkoel
authors.affiliation: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Fischer
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.affiliation: Department of Laboratory Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: White
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA; Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: mgaygun@mail.nih.gov.
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
mesh_terms: D000328:Adult; D001791:Blood Platelet Disorders / Q000235:genetics / Q000378:metabolism; D001792:Blood Platelets / Q000473:pathology* / Q000502:physiology / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D053447:Channelopathies / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004410:Dyslexia / Q000235:genetics / Q000378:metabolism; D004913:Erythrocytes, Abnormal / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006801:Humans; D007057:Ichthyosis / Q000235:genetics / Q000378:metabolism; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics / Q000378:metabolism; D015877:Miosis / Q000235:genetics / Q000378:metabolism; D018763:Muscle Fatigue / Q000235:genetics; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000002:abnormalities / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1; D013921:Thrombocytopenia
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: STIM1; York Platelet syndrome