Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis Scott B. Drutman, Filomeen Haerynck, Franklin L. Zhong, David Hum, Nicholas J. Hernandez, Serkan Belkaya, Franck Rapaport, Sarah Jill de Jong, David Creytens, Simon J. Tavernier, Katrien Bonte, Sofie De Schepper, Jutte van der Werff ten Bosch, Lazaro Lorenzo-Diaz, Andy Wullaert, Xavier Bossuyt, Gérard Orth, Vincent R. Bonagura, View ORCID ProfileVivien Béziat, Laurent Abel, Emmanuelle Jouanguy, Bruno Reversade, and Jean-Laurent Casanova https://doi.org/10.1073/pnas.1906184116
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.
We thank David Geneviève for support in investigating the AIADK patient with a JRRPlike phenotype. B.R. is a fellow of the Branco Weiss Foundation, an A*STAR Investigator, a National Research Foundation Singapore and Amsterdam Academic Alliance fellow, and a Young EMBO Investigator and is funded by a Strategic Positioning Fund on Genetic Orphan Diseases from A*STAR, Singapore. F.H. is funded by the Jeffrey Modell Foundation and a Bijzonder Onderzoeksfonds-Tenure Grant. A.W. is funded by the Cure-AID Grant from
the European Union ERA-Net for Research Programmes on Rare Diseases. F.L.Z. is a Nanyang Assistant Professor and is supported by National Research Foundation Fellowship (Class 2019). This work was supported by the National Center for Research Resources and National Center for Advancing Translational Sciences (Grant UL1TR001866), the “Investissement d’avenir” program (Grant ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence (Grant ANR-10-LABX-62-IBEID), the NIH (Grant 5 R21 AI107508-02), the French Cancer Institute (Grant 2013-1-PL BIO-11-1), the St. Giles Foundation, The Rockefeller University, Institut National de la Santé et de la Recherche Médicale, and Paris Descartes University. S.B.D. was supported by the Shapiro–Silverberg Fund for the Advancement of Translational Research and an American Philosophical Society Daland Fellowship in Clinical Investigation.