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

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.

Therapeutic modulation of inflammasome pathways

“…26,27 A homozygous NLRP1 gain-of-function mutation was recently reported to cause an autosomal recessive form of juvenile-onset recurrent respiratory papillomatosis in two siblings with mild dermatologic abnormalities. 28…”

The NLRP1 and CARD8 inflammasomes

“…69 In addition, a homozygous gain-of-function mutation in NLRP1 (T755N) was found in siblings with a syndromic form of juvenile-onset recurrent respiratory papillomatosis (JRRP). 83 As mentioned above, the P1214R mutation was found to abrogate binding to DPP9. 62 Importantly, these data strongly suggesting that DPP9 binding indeed serves to stabilize the autoinhibited form of NLRP1 and that disruption of this binding interaction leads to inflammasome activation ( Figure 6B).…”

Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

“…In the IFN-I signaling cascade, a homozygous GOF variant has never been reported until this discovery. To our knowledge, there are only two other documented strictly homozygous GOF mutations described in human genetics, one in hypocalcemic hypoparathyroidism caused by homozygous mutations in CASR ( Cavaco et al, 2018 ) and another more recently in recurrent respiratory papillomatosis caused by homozygous mutations in NLRP1 ( Drutman et al, 2019 ). Perhaps the MEFV mutations observed in familial Mediterranean fever may also be considered in this category, albeit with incompletely understood inheritance patterns and molecular mechanisms ( Schnappauf et al, 2019 ).…”