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Am J Hum Genet. 2014 May 1;94(5):790-7. doi: 10.1016/j.ajhg.2014.04.005.

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

Author information

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: francesca.capon@kcl.ac.uk.

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.

PMID:
24791904
PMCID:
PMC4067562
DOI:
10.1016/j.ajhg.2014.04.005
[Indexed for MEDLINE]
Free PMC Article

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