Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease

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dc.contributor.authorDorjbal, Batsukh
dc.contributor.authorStinson, Jeffrey R.
dc.contributor.authorMa, Chi A.
dc.contributor.authorWeinreich, Michael A.
dc.contributor.authorMiraghazadeh, Bahar
dc.contributor.authorHartberger, Julia M.
dc.contributor.authorFrey-Jakobs, Stefanie
dc.contributor.authorWeidinger, Stephan
dc.contributor.authorMoebus, Lena
dc.contributor.authorFranke, Andre
dc.contributor.authorSchäffer, Alejandro
dc.contributor.authorBulashevska, Alla
dc.contributor.authorFuchs, Sebastian
dc.contributor.authorEhl, Stephan
dc.contributor.authorLimaye, Sandhya
dc.contributor.authorArkwright, Peter D.
dc.contributor.authorBriggs, Tracy A.
dc.contributor.authorLangley, Claire
dc.contributor.authorBethune, Claire
dc.contributor.authorWhyte, Andrew F
dc.contributor.authorAlachkar, Hana
dc.contributor.authorNejentsev, Sergey
dc.contributor.authorDiMaggio, Thomas
dc.contributor.authorNelson, Celeste G.
dc.contributor.authorStone, Kelly D.
dc.contributor.authorNason, Martha
dc.contributor.authorBrittain, Erica H.
dc.contributor.authorOler, Andrew J.
dc.contributor.authorVeltri, Daniel P.
dc.contributor.authorLeahy, T Ronan
dc.contributor.authorConlon, Niall
dc.contributor.authorPoli, Cecilia
dc.contributor.authorBorzutzky, Arturo
dc.contributor.authorCohen, Jeffrey I.
dc.contributor.authorDavis, Joie
dc.contributor.authorLambert, Michele P.
dc.contributor.authorRomberg, Neil
dc.contributor.authorSullivan, Kathleen E.
dc.contributor.authorParis, Kenneth
dc.contributor.authorFreeman, Alexandra F.
dc.contributor.authorLucas, Laura
dc.contributor.authorChandrakasan, Shanmuganathan
dc.contributor.authorSavic, Sinisa
dc.contributor.authorHambleton, Sophie
dc.contributor.authorPatel, Smita Y.
dc.contributor.authorJordan, Michael B.
dc.contributor.authorTheos, Amy
dc.contributor.authorLebensburger, Jeffrey
dc.contributor.authorAtkinson, Prescott
dc.contributor.authorTorgerson, Troy R.
dc.contributor.authorChinn, Ivan K.
dc.contributor.authorMilner, Joshua D.
dc.contributor.authorGrimbacher, Bodo
dc.contributor.authorCook, Matthew C.
dc.contributor.authorSnow, Andrew L.
dc.date.accessioned2022-06-30T21:24:52Z
dc.date.available2022-06-30T21:24:52Z
dc.date.issued2019
dc.description.abstractBackground: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. Objectives: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. Methods: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. Results: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. Conclusion: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.es
dc.description.versionVersión Publicadaes
dc.identifier.citationorjbal B, Stinson JR, Ma CA, Weinreich MA, Miraghazadeh B, Hartberger JM, Frey-Jakobs S, Weidinger S, Moebus L, Franke A, Schäffer AA, Bulashevska A, Fuchs S, Ehl S, Limaye S, Arkwright PD, Briggs TA, Langley C, Bethune C, Whyte AF, Alachkar H, Nejentsev S, DiMaggio T, Nelson CG, Stone KD, Nason M, Brittain EH, Oler AJ, Veltri DP, Leahy TR, Conlon N, Poli MC, Borzutzky A, Cohen JI, Davis J, Lambert MP, Romberg N, Sullivan KE, Paris K, Freeman AF, Lucas L, Chandrakasan S, Savic S, Hambleton S, Patel SY, Jordan MB, Theos A, Lebensburger J, Atkinson TP, Torgerson TR, Chinn IK, Milner JD, Grimbacher B, Cook MC, Snow AL. Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease. J Allergy Clin Immunol. 2019 Apr;143(4):1482-1495. doi: 10.1016/j.jaci.2018.08.013.es
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2018.08.013 1482es
dc.identifier.urihttp://hdl.handle.net/11447/6283
dc.language.isoenes
dc.subjectCARD11es
dc.subjectAtopic dermatitises
dc.subjectAtopyes
dc.subjectDominant negativees
dc.subjectImmune dysregulationes
dc.subjectPrimary immunodeficiencyes
dc.titleHypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic diseasees
dc.typeArticlees
dcterms.sourceJournal of Allergy and Clinical Immunologyes

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