Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Molecular genetics and metabolism, 2015-03, Vol.114 (3), p.474-482

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

ScienceDirect

Beschreibungen/Notizen

• 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.