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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Dorjbal, Batsukh¹  Stinson, Jeffrey R.¹  Ma, Chi A.²  Weinreich, Michael A.²  Miraghazadeh, Bahar^7,8  Hartberger, Julia M.⁹  Frey-Jakobs, Stefanie⁹  Weidinger, Stephan¹⁰  Moebus, Lena¹⁰  Franke, Andre¹¹  Schaffer, Alejandro A.¹²  Bulashevska, Alla⁹  Fuchs, Sebastian⁹  Ehl, Stephan⁹  Limaye, Sandhya¹³  Arkwright, Peter D.¹⁴  Briggs, Tracy A.¹⁴  Langley, Claire¹⁴  Bethune, Claire¹⁵  Whyte, Andrew F.¹⁵  Alachkar, Hana¹⁶  Nejentsev, Sergey¹⁷  DiMaggio, Thomas²  Nelson, Celeste G.²  Stone, Kelly D.²  Nason, Martha³  Brittain, Erica H.³  Oler, Andrew J.⁴  Veltri, Daniel P.⁴  Leahy, T. Ronan^18,19  Conlon, Niall²⁰  Poli, Maria C.^21,22  Borzutzky, Arturo²³  Cohen, Jeffrey I.⁵  Davis, Joie⁶  Lambert, Michele P.^24,25  Romberg, Neil^24,25  Sullivan, Kathleen E.^24,25  Paris, Kenneth^26,27  Freeman, Alexandra F.⁶  Lucas, Laura²⁸  Chandrakasan, Shanmuganathan²⁸  Savic, Sinisa²⁹  Hambleton, Sophie³⁰  Patel, Smita Y.^31,32  Jordan, Michael B.³³  Theos, Amy³⁴  Lebensburger, Jeffrey³⁵  Atkinson, T. Prescott³⁶  Torgerson, Troy R.³⁷  Chinn, Ivan K.^21,22  Milner, Joshua D.²  Grimbacher, Bodo⁹  Cook, Matthew C.^7,8  Snow, Andrew L.¹ 

[1] Uniformed Serv Univ Hlth Sci, Dept Pharmacol & Mol Therapeut, 4301 Jones Bridge Rd,C-2013, Bethesda, MD 20814 USA

[2] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[3] NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[4] NIAID, Bioinformat & Computat Sci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[5] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA

[6] NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[7] Australian Natl Univ, Canberra Hosp, Dept Immunol, Canberra, ACT, Australia

[8] Australian Natl Univ, Ctr Personalised Immunol, John Curtin Sch Med Res, Canberra, ACT, Australia

[9] Univ Freiburg, Fac Med, Med Ctr, CCI, Freiburg, Germany

[10] Univ Hosp Schleswig Holstein, Dept Dermatol Venereol & Allergol, Campus Kiel, Kiel, Germany

[11] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[12] NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA

[13] Repatriat & Gen Hosp, Concord, NSW, Australia

[14] Univ Manchester, Paediat Allergy & Immunol & Manchester Ctr Genom, Manchester, Lancs, England

[15] Plymouth Hosp NHS Trust, Dept Clin Immunol, Plymouth, Devon, England

[16] Salford Royal Fdn Trust, Immunol, Manchester, Lancs, England

[17] Univ Cambridge, Dept Med, Cambridge, England

[18] Our Ladys Childrens Hosp, Dept Paediat Immunol, Dublin, Ireland

[19] Our Ladys Childrens Hosp, ID, Dublin, Ireland

[20] St James Hosp, Dept Immunol, Dublin, Ireland

[21] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[22] Texas Childrens Hosp, Sect Immunol Allergy & Rheumatol, Houston, TX 77030 USA

[23] Pontificia Univ Catolica Chile, Sch Med, Dept Pediat, Santiago, Chile

[24] Univ Penn, Childrens Hosp Philadelphia, Div Immunol & Allergy, Philadelphia, PA 19104 USA

[25] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

[26] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA

[27] Childrens Hosp, New Orleans, LA USA

[28] Emory Univ, Sch Med, Div Bone Marrow Transplant, Childrens Healthcare Atlanta, Atlanta, GA USA

[29] St James Univ Hosp, Leeds Inst Rheumat & Musculoskeletal Med, Leeds, W Yorkshire, England

[30] Newcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne, Tyne & Wear, England

[31] Oxford Univ Hosp NHS Trust, Oxford, England

[32] NIHR Oxford Biomed Res Ctr, Oxford, England

[33] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45221 USA

[34] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA

[35] Univ Alabama Birmingham, Dept Pediat Hematol Oncol, Birmingham, AL USA

[36] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA

[37] Univ Washington, Sch Med, Seattle, WA USA

关键词: CARD11;    atopy;    atopic dermatitis;    dominant negative;    primary immunodeficiency;    immune dysregulation;   

DOI  :  10.1016/j.jaci.2018.08.013

来源: Elsevier

【 摘 要 】

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 kappa 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 kappa 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.

【 授权许可】

Free