York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1

Thomas Markello, Dong Chen, Justin Y. Kwan, Iren Horkayne-Szakaly, Alan Morrison, Olga Simakova, Irina Maric, Jay Lozier, Andrew R. Cullinane, Tatjana Kilo, Lynn Meister, Kourosh Pakzad, William Bone, Sanjay Chainani, Elizabeth Lee, Amanda Links, Cornelius Boerkoel, Roxanne Fischer, Camilo Toro, James G. WhiteWilliam A. Gahl, Meral Gunay-Aygun

Research output: Contribution to journalArticle

Abstract

Store-operated Ca2+ entry is the major route of replenishment of intracellular Ca2+ in animal cells in response to the depletion of Ca2+ stores in the endoplasmic reticulum. It is primarily mediated by the Ca2+-selective release-activated Ca2+ (CRAC) channel, which consists of the pore-forming subunits ORAI1-3 and the Ca2+ 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 Ca2+ as a result of store-operated Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)474-482
Number of pages9
JournalMolecular Genetics and Metabolism
Volume114
Issue number3
DOIs
Publication statusPublished - Mar 1 2015
Externally publishedYes

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Keywords

  • STIM1
  • York Platelet syndrome

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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