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

TitleHypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease.
Publication TypeJournal Article
Year of Publication2019
AuthorsDorjbal, 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, T Leahy, R, 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, T Atkinson, P, Torgerson, TR, Chinn, IK, Milner, JD, Grimbacher, B, Cook, MC, Snow, AL
JournalJ Allergy Clin Immunol
Date Published2019 Apr

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.

Alternate JournalJ. Allergy Clin. Immunol.
PubMed ID30170123
PubMed Central IDPMC6395549
Grant ListR21 AI109187 / AI / NIAID NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
ZIA AI001183-04 / / Intramural NIH HHS / United States