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.
Funder
Branco Weiss Foundation
A*STAR | Institute of Molecular and Cell Biology
National Research Foundation Singapore
European Molecular Biology Organization
Jeffrey Modell Foundation
Ghent University Hospital
E-RARe Program
HHS | NIH | National Center for Research Resources
Agence Nationale de la Recherche
HHS | National Institutes of Health
French Cancer Institute
St. Giles Foundation
Rockefeller University
Institut National de la Santé et de la Recherche Médicale
Université Paris Descartes
Shapiro-Silverberg Fund
American Philosophical Society
Amsterdam Academic Alliance
Publisher
Proceedings of the National Academy of Sciences
Cited by
97 articles.
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