• A Corrigendum to this article was published on 27 October 2017

This article has been updated

Abstract

Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor–induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.

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Change history

  • 14 July 2017

    In the version of this article initially published online, the name of author Neil Romberg appeared incorrectly as Neil D Romberg, and the affiliation of author Nina Jones was incorrect and should have appeared as Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland, USA. In addition, the following sentences were omitted from the Acknowledgments: "This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government." These errors have been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank W. Tsai, M. Gadina and C. Malinverni for technical assistance. We thank the patients and their families for participating in this research. The patients were enrolled on an IRB-approved protocol and provided informed consent. CARD11-deficient Jurkat cells (JPM50.6) were originally provided by X. Lin (MD Anderson Cancer Center). This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, the NIAID Clinical Genomics Program and grants from the National Institutes of Health (1R21AI109187 to A.L.S. and AI061093 to E.M.), the Henry M. Jackson Foundation (Val Hemming Fellowship to J.R.S.), Telethon (GGP13254 to E.R.), and the Joanne Siegel Fund (to E.W.G.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

Author information

Author notes

    • Chi A Ma
    • , Jeffrey R Stinson
    •  & Yuan Zhang

    These authors contributed equally to this work.

    • Erwin W Gelfand
    • , Andrew L Snow
    •  & Joshua D Milner

    These authors jointly directed this work.

Affiliations

  1. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Chi A Ma
    • , Yuan Zhang
    • , Michael A Weinreich
    • , Jonathan J Lyons
    • , Celeste G Nelson
    • , Thomas DiMaggio
    • , Kelly D Stone
    •  & Joshua D Milner
  2. Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.

    • Jeffrey R Stinson
    • , Elisa Ruffo
    • , Batsukh Dorjbal
    • , Swadhinya Arjunaraja
    • , Kelsey Voss
    •  & Andrew L Snow
  3. Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.

    • Jordan K Abbott
    • , Pia J Hauk
    • , Paul R Reynolds
    •  & Erwin W Gelfand
  4. Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

    • Elisa Ruffo
  5. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Salomé Glauzy
    • , Natsuko Yamakawa
    •  & Eric Meffre
  6. Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.

    • Jennifer Stoddard
    • , Julie Niemela
    •  & Sergio D Rosenzweig
  7. Human Immunological Disease Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Yu Zhang
    •  & Helen F Matthews
  8. Merck Research Laboratories, Merck and Co., Inc., Boston, Massachusetts, USA.

    • Joshua J McElwee
  9. Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland, USA.

    • Nina Jones
  10. Servicio de Immunología y Reumatología, Hospital Nacional de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina.

    • Alejandro Palma
    • , Matías Oleastro
    • , Emma Prieto
    • , Andrea R Bernasconi
    • , Geronimo Dubra
    • , Silvia Danielian
    • , Jonathan Zaiat
    •  & Marcelo A Marti
  11. Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Brian Kim
  12. Department of Pediatrics, Division of Rheumatology and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Megan A Cooper
  13. Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Neil Romberg

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Contributions

C.A.M., Yuan Zhang, M.A.W. and S.G. performed experiments with primary patient cells. J.R.S. and B.D. produced all CARD11 mutant constructs. J.R.S., E.R., S.A., K.V. and B.D. conducted cell transfection experiments. J.J.L., C.G.N., T.D., K.D.S., H.F.M. and J.D.M. were involved in clinical workup of patient A.-I. J.S., J.N. and S.D.R. performed sequence analysis on patient A.-I. J.K.A., P.J.H., P.R.R. and E.W.G. were involved in clinical care and sequence analysis of family B. Yu Zhang, B.K., M.A.C., N.R., S.G. and E.M. were involved in clinical workup of family C. A.P., M.O., E.P., A.R.B., G.D. and S.D. were involved in clinical care and workup of family D. J.Z. and M.A.M. performed sequence analysis of family D. N.Y. performed regulatory T cell experiments. J.J.M. provided sequencing resources and data. N.J. provided patient care and information. C.A.M., M.A.W., J.R.S., A.L.S. and J.D.M. co-wrote the manuscript. E.W.G., A.L.S. and J.D.M. supervised the project. All authors discussed the results and contributed to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joshua D Milner.

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https://doi.org/10.1038/ng.3898

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