Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease

  • Nat Genet. 2014 Aug;46(8):812-814. doi: 10.1038/ng.3040.
Sarah E Flanagan  #  1 ,  Emma Haapaniemi  #  2  3 ,  Mark A Russell  #  1 ,  Richard Caswell  1 ,  Hana Lango Allen  1 ,  Elisa De Franco  1 ,  Timothy J McDonald  1 ,  Hanna Rajala  4  5 ,  Anita Ramelius  6  7 ,  John Barton  8 ,  Kaarina Heiskanen  3  9 ,  Tarja Heiskanen-Kosma  10 ,  Merja Kajosaari  9 ,  Nuala P Murphy  11 ,  Tatjana Milenkovic  12 ,  Mikko Seppänen  13 ,  Åke Lernmark  6  7 ,  Satu Mustjoki  4  5 ,  Timo Otonkoski  3  9 ,  Juha Kere  2  3  14  15 ,  Noel G Morgan  1 ,  Sian Ellard  1 ,  Andrew T Hattersley  1
Affiliations
  • 1. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK.
  • 2. Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
  • 3. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
  • 4. Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki.
  • 5. Helsinki University Central Hospital Cancer Center, Helsinki, Finland.
  • 6. Department of Clinical Sciences, Lund University, Lund, Sweden.
  • 7. CRC, Skåne University Hospital SUS, Malmö, Sweden.
  • 8. Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol, BS2 8BJ, UK.
  • 9. Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
  • 10. Department of Pediatrics, Kuopio University Hospital, Helsinki, Finland.
  • 11. Department of Diabetes and Endocrinology, Children's University Hospital, Temple St., Dublin 1, Ireland.
  • 12. Department of Endocrinology, Institute for Mother and Child Health Care of Serbia 'Dr Vukan Cupic', Belgrade, Serbia.
  • 13. Immunodeficiency Unit, Division of Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland.
  • 14. Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovägen 7, 14183 Huddinge, Sweden.
  • 15. Center for Innovative Medicine, Karolinska Institutet, Hälsovägen 7, 14183 Huddinge, Sweden.
  • # Contributed equally.
PMID: 25038750 DOI: 10.1038/ng.3040
Abstract

Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset Autoimmune Disease, including Type 1 Diabetes. These findings emphasize the critical role of STAT3 in Autoimmune Disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.