2. Academic Validation
  3. Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

  • Proc Natl Acad Sci U S A. 2019 Sep 17;116(38):19055-19063. doi: 10.1073/pnas.1906184116.
Scott B Drutman 1,  Filomeen Haerynck 2,  Franklin L Zhong 3 4 5 6,  David Hum 1,  Nicholas J Hernandez 1,  Serkan Belkaya 1,  Franck Rapaport 1,  Sarah Jill de Jong 1,  David Creytens 7 8,  Simon J Tavernier 2 9 10,  Katrien Bonte 11,  Sofie De Schepper 12,  Jutte van der Werff Ten Bosch 13,  Lazaro Lorenzo-Diaz 14 15,  Andy Wullaert 10 16 17,  Xavier Bossuyt 18 19,  Gérard Orth 20,  Vincent R Bonagura 21 22,  Vivien Béziat 1 14 15,  Laurent Abel 1 14 15,  Emmanuelle Jouanguy 1 14 15,  Bruno Reversade 3 4 23 24,  Jean-Laurent Casanova 25 14 15 26 27
Affiliations

Affiliations

  • 1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065.
  • 2 Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, 9000 Ghent, Belgium.
  • 3 Institute of Molecular and Cell Biology, A*STAR, 138673 Proteos, Singapore.
  • 4 Laboratory of Human Embryology and Genetics, Institute of Medical Biology, A*STAR, 138648 Immunos, Singapore.
  • 5 Skin Research Institute of Singapore, 138648 Immunos, Singapore.
  • 6 Lee Kong Chian School of Medicine, Nanyang Technological University, 636921 Singapore.
  • 7 Department of Pathology, Ghent University Hospital, 9000 Ghent, Belgium.
  • 8 Cancer Research Institute Ghent, Ghent University, 9000 Ghent, Belgium.
  • 9 Center for Inflammation Research, Unit of Molecular Signal Transduction in Inflammation, Flanders Institute for Biotechnology, 9052 Ghent, Belgium.
  • 10 Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
  • 11 Department of Otorhinolaryngology, Head and Neck Surgery, Craniofacial Team, Gent University Hospital, 9000 Ghent, Belgium.
  • 12 Department of Dermatology, Ghent University Hospital, 9000 Ghent, Belgium.
  • 13 Department of Pediatrics, Universitair Ziekenhuis Brussel, 1090 Jette, Belgium.
  • 14 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France.
  • 15 Imagine Institute, Paris Descartes University, 75006 Paris, France.
  • 16 Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium.
  • 17 Center for Inflammation Research, Flanders Institute for Biotechnology, 9052 Ghent, Belgium.
  • 18 Department of Microbiology and Immunology, KU Leuven, 3000 Leuven, Belgium.
  • 19 Department of Laboratory Medicine, University Hospitals Leuven, 3000 Leuven, Belgium.
  • 20 Department of Virology, Pasteur Institute, 75015 Paris, France.
  • 21 Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY 11030.
  • 22 Division of Allergy and Immunology, Department of Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY 11549.
  • 23 Medical Genetics Department, Koç University School of Medicine, 34450 Istanbul, Turkey.
  • 24 Reproductive Biology Laboratory, Amsterdam UMC Netherlands, 1105 AZ Amsterdam, The Netherlands.
  • 25 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065; [email protected].
  • 26 Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, 75015 Paris, France.
  • 27 HHMI, The Rockefeller University, New York, NY 10065.
PMID: 31484767 DOI: 10.1073/pnas.1906184116
Abstract

Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.

Keywords

NLRP1; genetics; human papillomavirus; inflammasome; recurrent respiratory papillomatosis.

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