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

ABSTRACT: 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 ?B, 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 ?B 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.

SUBMITTER: Dorjbal B

PROVIDER: S-EPMC6395549 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Dorjbal Batsukh B Stinson Jeffrey R JR Ma Chi A CA Weinreich Michael A MA Miraghazadeh Bahar B Hartberger Julia M JM Frey-Jakobs Stefanie S Weidinger Stephan S Moebus Lena L Franke Andre A Schäffer Alejandro A AA Bulashevska Alla A Fuchs Sebastian S Ehl Stephan S Limaye Sandhya S Arkwright Peter D PD Briggs Tracy A TA Langley Claire C Bethune Claire C Whyte Andrew F AF Alachkar Hana H Nejentsev Sergey S DiMaggio Thomas T Nelson Celeste G CG Stone Kelly D KD Nason Martha M Brittain Erica H EH Oler Andrew J AJ Veltri Daniel P DP Leahy T Ronan TR Conlon Niall N Poli Maria C MC Borzutzky Arturo A Cohen Jeffrey I JI Davis Joie J Lambert Michele P MP Romberg Neil N Sullivan Kathleen E KE Paris Kenneth K Freeman Alexandra F AF Lucas Laura L Chandrakasan Shanmuganathan S Savic Sinisa S Hambleton Sophie S Patel Smita Y SY Jordan Michael B MB Theos Amy A Lebensburger Jeffrey J Atkinson T Prescott TP Torgerson Troy R TR Chinn Ivan K IK Milner Joshua D JD Grimbacher Bodo B Cook Matthew C MC Snow Andrew L AL

The Journal of allergy and clinical immunology 20180828 4

<h4>Background</h4>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 (he ...[more]

PMID: 30170123

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Project description:BackgroundHuman hypomorphic nuclear factor-kappaB essential modulator (NEMO) mutations cause diverse clinical and immunologic phenotypes, but understanding of their scope and mechanistic links to immune function and genotype is incomplete.ObjectiveWe created and analyzed a database of hypomorphic NEMO mutations to determine the spectrum of phenotypes and their associated genotypes and sought to establish a standardized NEMO reconstitution system to obtain mechanistic insights.MethodsPhenotypes of 72 individuals with NEMO mutations were compiled. NEMO L153R and C417R were investigated further in a reconstitution system. TNF-alpha or Toll-like receptor (TLR)-5 signals were evaluated for nuclear factor-kappaB activation, programmed cell death, and A20 gene expression.ResultsThirty-two different mutations were identified; 53% affect the zinc finger domain. Seventy-seven percent were associated with ectodermal dysplasia, 86% with serious pyogenic infection, 39% with mycobacterial infection, 19% with serious viral infection, and 23% with inflammatory diseases. Thirty-six percent of individuals died at a mean age of 6.4 years. CD40, IL-1, TNF-alpha, TLR, and T-cell receptor signals were impaired in 15 of 16 (94%), 6 of 7 (86%), 9 of 11 (82%), 9 of 14 (64%), and 7 of 18 (39%), respectively. Hypomorphism-reconstituted NEMO-deficient cells demonstrated partial restoration of NEMO functions. Although both L153R and C417R impaired TLR and TNF-alpha-induced NF-kappaB activation, L153R also increased TNF-alpha-induced programmed cell death with decreased A20 expression.ConclusionDistinct NEMO hypomorphs define specific disease and genetic characteristics. A reconstitution system can identify attributes of hypomorphisms independent of an individual's genetic background. Apoptosis susceptibility in L153R reconstituted cells defines a specific phenotype of this mutation that likely contributes to the excessive inflammation with which it is clinically associated.

Dataset Information

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

Publications

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

Similar Datasets

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