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

Batsukh Dorjbal, Jeffrey R. Stinson, Chi A. Ma, Michael A. Weinreich, Bahar Miraghazadeh, Julia M. Hartberger, Stefanie Frey-Jakobs, Stephan Weidinger, Lena Moebus, Andre Franke, Alejandro A. Schäffer, Alla Bulashevska, Sebastian Fuchs, Stephan Ehl, Sandhya Limaye, Peter D. Arkwright, Tracy A. Briggs, Claire Langley, Claire Bethune, Andrew F. WhyteHana Alachkar, Sergey Nejentsev, Thomas DiMaggio, Celeste G. Nelson, Kelly D. Stone, Martha Nason, Erica H. Brittain, Andrew J. Oler, Daniel P. Veltri, T. Ronan Leahy, Niall Conlon, Maria C. Poli, Arturo Borzutzky, Jeffrey I. Cohen, Joie Davis, Michele P. Lambert, Neil Romberg, Kathleen E. Sullivan, Kenneth Paris, Alexandra F. Freeman, Laura Lucas, Shanmuganathan Chandrakasan, Sinisa Savic, Sophie Hambleton, Smita Y. Patel, Michael B. Jordan, Amy Theos, Jeffrey Lebensburger, T. Prescott Atkinson, Troy R. Torgerson, Ivan K. Chinn, Joshua D. Milner, Bodo Grimbacher, Matthew C. Cook, Andrew L. Snow*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    110 Citations (Scopus)


    Background: 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.

    Original languageEnglish
    Pages (from-to)1482-1495
    Number of pages14
    JournalJournal of Allergy and Clinical Immunology
    Issue number4
    Publication statusPublished - Apr 2019


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