AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking

  • Am J Hum Genet. 2014 May 1;94(5):790-7. doi: 10.1016/j.ajhg.2014.04.005.
Niovi Setta-Kaffetzi  1 ,  Michael A Simpson  1 ,  Alexander A Navarini  1 ,  Varsha M Patel  1 ,  Hui-Chun Lu  2 ,  Michael H Allen  1 ,  Michael Duckworth  1 ,  Hervé Bachelez  3 ,  A David Burden  4 ,  Siew-Eng Choon  5 ,  Christopher E M Griffiths  6 ,  Brian Kirby  7 ,  Antonios Kolios  8 ,  Marieke M B Seyger  9 ,  Christa Prins  10 ,  Asma Smahi  11 ,  Richard C Trembath  12 ,  Franca Fraternali  2 ,  Catherine H Smith  1 ,  Jonathan N Barker  1 ,  Francesca Capon  13
Affiliations
  • 1. Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
  • 2. Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 9RT, UK.
  • 3. Institut National de la Santé et de la Recherche Médicale Unité 781, Institut Imagine, Hopital Necker - Enfant Malades, Paris 75015, France; Department of Dermatology, Sorbonne Paris Cité Université Paris Diderot and Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Paris 75010, France.
  • 4. Department of Dermatology, University of Glasgow, Glasgow G11 6NT, UK.
  • 5. Department of Dermatology, Hospital Sultanah Aminah, Johor Bahru 80100, Malaysia.
  • 6. Department of Dermatology, University of Manchester, Manchester M6 8HD, UK.
  • 7. Department of Dermatology, St. Vincent University Hospital, Dublin 4, Ireland.
  • 8. Department of Dermatology, Zurich University Hospital, Zurich 8091, Switzerland.
  • 9. Department of Dermatology, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, the Netherlands.
  • 10. Dermatology Service, Geneva University Hospital, 1211 Geneva 14, Switzerland.
  • 11. Institut National de la Santé et de la Recherche Médicale Unité 781, Institut Imagine, Hopital Necker - Enfant Malades, Paris 75015, France.
  • 12. Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK; Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London EC1M 6QB, UK.
  • 13. Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK. Electronic address: [email protected].
PMID: 24791904 DOI: 10.1016/j.ajhg.2014.04.005
Abstract

Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like Receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like Receptor homeostasis.