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The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition.
J Biol Chem. 2009 Mar 13; 284(11):6620-6.JB

Abstract

Homozygous expression of Orai1 bearing the R91W mutation results in the complete abrogation of currents through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels, resulting in a form of hereditary severe combined immune deficiency (SCID) syndrome (Feske, S., Gwack, Y., Prakriya, M., Srikanth, S., Puppel, S. H., Tanasa, B., Hogan, P. G., Lewis, R. S., Daly, M., and Rao, A. (2006) Nature 441, 179-185). Although heterozygous carriers of the mutation show no clinical symptoms of immunodeficiency, store-operated Ca(2+) entry in their T cells is impaired, suggesting a gene-dosage effect of the mutation. We have recently demonstrated that the functional CRAC channel pore is composed of a tetrameric assembly of Orai1 subunits (Mignen, O., Thompson, J. L., and Shuttleworth, T. J. (2008) J. Physiol. 586, 419-425). Therefore, to directly quantify the effect of the SCID mutant in the heterozygous situation, we generated a series of concatenated tetramers of Orai1 that included different numbers and arrangements of the R91W Orai1 subunits. The data obtained show that inclusion of increasing numbers of mutant subunits results in a graded reduction in CRAC channel currents and that this effect is independent of the spatial arrangement or order of the mutant subunits in the tetramer. Macroscopic biophysical properties of the channels were unchanged by inclusion of the mutant subunits, although the rate at which the current activates on store depletion was slowed. We conclude that incorporation of R91W mutant Orai1 subunits in the CRAC channel pore affects the overall magnitude of its conductance and that this effect is related solely to the number of mutant subunits incorporated. Predictions based on the tetrameric channel structure indicate that the graded effect of incorporation of SCID mutant subunits into such an assembly is quantitatively consistent with the previously demonstrated impaired effects on Ca(2+) entry recorded in the heterozygous carriers.

Authors+Show Affiliations

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, USA.No 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

19075015

Citation

Thompson, Jill L., et al. "The Orai1 Severe Combined Immune Deficiency Mutation and Calcium Release-activated Ca2+ Channel Function in the Heterozygous Condition." The Journal of Biological Chemistry, vol. 284, no. 11, 2009, pp. 6620-6.
Thompson JL, Mignen O, Shuttleworth TJ. The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition. J Biol Chem. 2009;284(11):6620-6.
Thompson, J. L., Mignen, O., & Shuttleworth, T. J. (2009). The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition. The Journal of Biological Chemistry, 284(11), 6620-6. https://doi.org/10.1074/jbc.M808346200
Thompson JL, Mignen O, Shuttleworth TJ. The Orai1 Severe Combined Immune Deficiency Mutation and Calcium Release-activated Ca2+ Channel Function in the Heterozygous Condition. J Biol Chem. 2009 Mar 13;284(11):6620-6. PubMed PMID: 19075015.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition. AU - Thompson,Jill L, AU - Mignen,Olivier, AU - Shuttleworth,Trevor J, Y1 - 2008/12/15/ PY - 2008/12/17/entrez PY - 2008/12/17/pubmed PY - 2009/5/5/medline SP - 6620 EP - 6 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 284 IS - 11 N2 - Homozygous expression of Orai1 bearing the R91W mutation results in the complete abrogation of currents through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels, resulting in a form of hereditary severe combined immune deficiency (SCID) syndrome (Feske, S., Gwack, Y., Prakriya, M., Srikanth, S., Puppel, S. H., Tanasa, B., Hogan, P. G., Lewis, R. S., Daly, M., and Rao, A. (2006) Nature 441, 179-185). Although heterozygous carriers of the mutation show no clinical symptoms of immunodeficiency, store-operated Ca(2+) entry in their T cells is impaired, suggesting a gene-dosage effect of the mutation. We have recently demonstrated that the functional CRAC channel pore is composed of a tetrameric assembly of Orai1 subunits (Mignen, O., Thompson, J. L., and Shuttleworth, T. J. (2008) J. Physiol. 586, 419-425). Therefore, to directly quantify the effect of the SCID mutant in the heterozygous situation, we generated a series of concatenated tetramers of Orai1 that included different numbers and arrangements of the R91W Orai1 subunits. The data obtained show that inclusion of increasing numbers of mutant subunits results in a graded reduction in CRAC channel currents and that this effect is independent of the spatial arrangement or order of the mutant subunits in the tetramer. Macroscopic biophysical properties of the channels were unchanged by inclusion of the mutant subunits, although the rate at which the current activates on store depletion was slowed. We conclude that incorporation of R91W mutant Orai1 subunits in the CRAC channel pore affects the overall magnitude of its conductance and that this effect is related solely to the number of mutant subunits incorporated. Predictions based on the tetrameric channel structure indicate that the graded effect of incorporation of SCID mutant subunits into such an assembly is quantitatively consistent with the previously demonstrated impaired effects on Ca(2+) entry recorded in the heterozygous carriers. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/19075015/The_Orai1_severe_combined_immune_deficiency_mutation_and_calcium_release_activated_Ca2+_channel_function_in_the_heterozygous_condition_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=19075015 DB - PRIME DP - Unbound Medicine ER -