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

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.