Journal Article

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

Zhong, Franklin L., Bonagura, Vincent R., Tavernier, Simon J., de Jong, Sarah Jill, Haerynck, Filomeen, Orth, Gérard, Hum, David, Wullaert, Andy, Lorenzo-Diaz, Lazaro, Reversade, Bruno, Hernandez, Nicholas J., van der Werff ten Bosch, Jutte, Rapaport, Franck, Belkaya, Serkan, Jouanguy, Emmanuelle, Bossuyt, Xavier, Abel, Laurent, Casanova, Jean-Laurent, Béziat, Vivien, Creytens, David, De Schepper, Sofie, Drutman, Scott B., Bonte, Katrien

2019

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Abnormalities / Adaptor Proteins, Signal Transducing - genetics / Apoptosis Regulatory Proteins - genetics / Biological Sciences / Child, Preschool / Children / Cytokines / Cytokines - metabolism / Female / Gain of Function Mutation / Genetics / Heredity / Homozygote / Human papillomavirus / Humans / IL-1β / Infant / Inflammasomes / Keratinocytes / Keratinocytes - cytology / Keratinocytes - immunology / Keratinocytes - metabolism / Leucine / Male / Mutation / Nucleotides / Oligomerization / Papilloma / Papillomaviridae / Papillomavirus Infections - genetics / Papillomavirus Infections - pathology / Pedigree / Phenotypes / Pyrin protein / Respiratory tract / Respiratory Tract Infections - genetics / Respiratory Tract Infections - pathology / Siblings / Syndrome