iScience (Jun 2023)
Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes
- Bergithe E. Oftedal,
- Kristian Assing,
- Safa Baris,
- Stephanie L. Safgren,
- Isik S. Johansen,
- Marianne Antonius Jakobsen,
- Dusica Babovic-Vuksanovic,
- Katherine Agre,
- Eric W. Klee,
- Emina Majcic,
- Elise M.N. Ferré,
- Monica M. Schmitt,
- Tom DiMaggio,
- Lindsey B. Rosen,
- Muhammad Obaidur Rahman,
- Dionisios Chrysis,
- Aristeidis Giannakopoulos,
- Maria Tallon Garcia,
- Luis Ignacio González-Granado,
- Katherine Stanley,
- Jessica Galant-Swafford,
- Pim Suwannarat,
- Isabelle Meyts,
- Michail S. Lionakis,
- Eystein S. Husebye
Affiliations
- Bergithe E. Oftedal
- Department of Clinical Science, University of Bergen and Department of Medicine, Haukeland University Hospital, Bergen, Norway; Corresponding author
- Kristian Assing
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
- Safa Baris
- Marmara University, Faculty of Medicine, Pediatric Allergy and Immunology, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- Stephanie L. Safgren
- Center for Individualized Medicine, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- Isik S. Johansen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
- Marianne Antonius Jakobsen
- Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
- Dusica Babovic-Vuksanovic
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
- Katherine Agre
- Invitae, San Francisco, CA, USA
- Eric W. Klee
- Mayo Clinic, Department of Quantitative Health Sciences, Rochester, MN, USA
- Emina Majcic
- Department of Clinical Science, University of Bergen and Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Elise M.N. Ferré
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
- Monica M. Schmitt
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
- Tom DiMaggio
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
- Lindsey B. Rosen
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
- Muhammad Obaidur Rahman
- Department of Clinical Science, University of Bergen and Department of Medicine, Haukeland University Hospital, Bergen, Norway
- Dionisios Chrysis
- Department of Pediatrics, Division of Pediatric Endocrinology, Medical School, University of Patras, Rion, Greece
- Aristeidis Giannakopoulos
- Department of Pediatrics, Division of Pediatric Endocrinology, Medical School, University of Patras, Rion, Greece
- Maria Tallon Garcia
- Pediatric Hematology and Oncology Department, Hospital Álvaro Cunqueiro, Vigo, Spain
- Luis Ignacio González-Granado
- Unidad de Inmunodeficiencias, Pediatría, Instituto de Investigación Hospital 12 de Octubre, Facultad de Medicina, Universidad Complutense, Madrid, Spain
- Katherine Stanley
- Mid-Atlantic Permanente Medical Group, Kaiser Permanente MidAtlantic, Rockville, MD, USA
- Jessica Galant-Swafford
- Division of Allergy & Clinical Immunology, National Jewish Health, Denver, CO, USA
- Pim Suwannarat
- Mid-Atlantic Permanente Medical Group, Kaiser Permanente MidAtlantic, Rockville, MD, USA
- Isabelle Meyts
- Department of Pediatrics, University Hospital Leuven, Laboratory for Inborn Errors of Immunity, Department of Microbiology Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Michail S. Lionakis
- Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
- Eystein S. Husebye
- Department of Clinical Science, University of Bergen and Department of Medicine, Haukeland University Hospital, Bergen, Norway; Corresponding author
- Journal volume & issue
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Vol. 26,
no. 6
p. 106818
Abstract
Summary: Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.
