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Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis.
Proc Natl Acad Sci U S A. 2014 Mar 18; 111(11):4197-202.PN

Abstract

Signaling through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca(2+) homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca(2+) sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca(2+)-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca(2+) entry in the treatment of patients with Stormorken syndrome and related pathologic conditions.

Authors+Show Affiliations

Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24591628

Citation

Nesin, Vasyl, et al. "Activating Mutations in STIM1 and ORAI1 Cause Overlapping Syndromes of Tubular Myopathy and Congenital Miosis." Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 11, 2014, pp. 4197-202.
Nesin V, Wiley G, Kousi M, et al. Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci USA. 2014;111(11):4197-202.
Nesin, V., Wiley, G., Kousi, M., Ong, E. C., Lehmann, T., Nicholl, D. J., Suri, M., Shahrizaila, N., Katsanis, N., Gaffney, P. M., Wierenga, K. J., & Tsiokas, L. (2014). Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proceedings of the National Academy of Sciences of the United States of America, 111(11), 4197-202. https://doi.org/10.1073/pnas.1312520111
Nesin V, et al. Activating Mutations in STIM1 and ORAI1 Cause Overlapping Syndromes of Tubular Myopathy and Congenital Miosis. Proc Natl Acad Sci USA. 2014 Mar 18;111(11):4197-202. PubMed PMID: 24591628.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. AU - Nesin,Vasyl, AU - Wiley,Graham, AU - Kousi,Maria, AU - Ong,E-Ching, AU - Lehmann,Thomas, AU - Nicholl,David J, AU - Suri,Mohnish, AU - Shahrizaila,Nortina, AU - Katsanis,Nicholas, AU - Gaffney,Patrick M, AU - Wierenga,Klaas J, AU - Tsiokas,Leonidas, Y1 - 2014/03/03/ PY - 2014/3/5/entrez PY - 2014/3/5/pubmed PY - 2014/5/30/medline KW - calcium signaling KW - human genetics SP - 4197 EP - 202 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 111 IS - 11 N2 - Signaling through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca(2+) homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca(2+) sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca(2+)-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca(2+) entry in the treatment of patients with Stormorken syndrome and related pathologic conditions. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/24591628/Activating_mutations_in_STIM1_and_ORAI1_cause_overlapping_syndromes_of_tubular_myopathy_and_congenital_miosis_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=24591628 DB - PRIME DP - Unbound Medicine ER -