Referenced in: none

Automatically associated channels: TRP

Title: A dominant STIM1 mutation causes Stormorken syndrome.

Authors: Doriana Misceo, Asbjørn Holmgren, William E Louch, Pål A Holme, Masahiro Mizobuchi, Raul J Morales, André Maues De Paula, Asbjørg Stray-Pedersen, Robert Lyle, Bjørn Dalhus, Geir Christensen, Helge Stormorken, Geir E Tjønnfjord, Eirik Frengen

Journal, date & volume: Hum. Mutat., 2014 May , 35, 556-64

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24619930

Abstract
Stormorken syndrome is a rare autosomal-dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca(2+) depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca(2+) release-activated Ca(2+) channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled-coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca(2+) levels were elevated in platelets from the patients compared with controls, and store-operated Ca(2+) entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near-maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.