ZFIN ID: ZDB-PUB-140513-425
Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis
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.
Date: 2014
Source: Proceedings of the National Academy of Sciences of the United States of America   111: 4197-202 (Journal)
Registered Authors: Katsanis, Nicholas
Keywords: calcium signaling, human genetics
MeSH Terms:
  • Animals
  • Base Sequence
  • Blood Platelet Disorders/genetics*
  • Calcium Channels/genetics*
  • Calcium Signaling/genetics*
  • Child
  • DNA Primers/genetics
  • Dyslexia/genetics*
  • Erythrocytes, Abnormal
  • Female
  • Humans
  • Ichthyosis/genetics*
  • Membrane Proteins/genetics*
  • Migraine Disorders/genetics*
  • Miosis/genetics*
  • Molecular Sequence Data
  • Muscle Fatigue/genetics
  • Mutagenesis, Site-Directed
  • Mutation/genetics
  • Myopathies, Structural, Congenital/genetics*
  • Neoplasm Proteins/genetics*
  • Patch-Clamp Techniques
  • Pedigree
  • Sequence Analysis, DNA
  • Spleen/abnormalities*
  • Zebrafish
PubMed: 24591628 Full text @ Proc. Natl. Acad. Sci. USA
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.