Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 38, Pages 19055-19063Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1906184116
Keywords
inflammasome; NLRP1; recurrent respiratory papillomatosis; genetics; human papillomavirus
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Funding
- Strategic Positioning Fund on Genetic Orphan Diseases from A* STAR, Singapore
- Jeffrey Modell Foundation
- Bijzonder Onderzoeksfonds-Tenure Grant
- Cure-AID Grant from the European Union ERA-Net for Research Programmes on Rare Diseases
- National Research Foundation
- National Center for Advancing Translational Sciences [UL1TR001866]
- Investissement d'avenir program [ANR-10-IAHU-01]
- Integrative Biology of Emerging Infectious Diseases Laboratoire d'Excellence [ANR-10-LABX-62-IBEID]
- NIH [5 R21 AI107508-02]
- French Cancer Institute [2013-1-PL BIO-11-1]
- St. Giles Foundation
- Rockefeller University
- Institut National de la Sante et de la Recherche Medicale
- Paris Descartes University
- Shapiro-Silverberg Fund for the Advancement of Translational Research
- American Philosophical Society Daland Fellowship in Clinical Investigation
- National Center for Research Resources
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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 papillo-maviruses (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-1 beta secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1 beta 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.
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