Germline hypomorphic CARD11 mutations in severe atopic disease

  • Nat Genet. 2017 Aug;49(8):1192-1201. doi: 10.1038/ng.3898.
Chi A Ma  1 ,  Jeffrey R Stinson  2 ,  Yuan Zhang  1 ,  Jordan K Abbott  3 ,  Michael A Weinreich  1 ,  Pia J Hauk  3 ,  Paul R Reynolds  3 ,  Jonathan J Lyons  1 ,  Celeste G Nelson  1 ,  Elisa Ruffo  2  4 ,  Batsukh Dorjbal  2 ,  Salomé Glauzy  5 ,  Natsuko Yamakawa  5 ,  Swadhinya Arjunaraja  2 ,  Kelsey Voss  2 ,  Jennifer Stoddard  6 ,  Julie Niemela  6 ,  Yu Zhang  7 ,  Sergio D Rosenzweig  6 ,  Joshua J McElwee  8 ,  Thomas DiMaggio  1 ,  Helen F Matthews  7 ,  Nina Jones  9 ,  Kelly D Stone  1 ,  Alejandro Palma  10 ,  Matías Oleastro  10 ,  Emma Prieto  10 ,  Andrea R Bernasconi  10 ,  Geronimo Dubra  10 ,  Silvia Danielian  10 ,  Jonathan Zaiat  10 ,  Marcelo A Marti  10 ,  Brian Kim  11 ,  Megan A Cooper  12 ,  Neil Romberg  13 ,  Eric Meffre  5 ,  Erwin W Gelfand  3 ,  Andrew L Snow  2 ,  Joshua D Milner  1
Affiliations
  • 1. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • 2. Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
  • 3. Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
  • 4. Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
  • 5. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
  • 6. Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
  • 7. Human Immunological Disease Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • 8. Merck Research Laboratories, Merck and Co., Inc., Boston, Massachusetts, USA.
  • 9. Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland, USA.
  • 10. Servicio de Immunología y Reumatología, Hospital Nacional de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina.
  • 11. Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 12. Department of Pediatrics, Division of Rheumatology and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
  • 13. Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
PMID: 28628108 DOI: 10.1038/ng.3898
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.