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

Thumbnail Image

Departments

Organizational Unit

School / College / Institute

Organizational Unit
SCHOOL OF MEDICINE
Upper Org Unit

Program

KU Authors

Co-Authors

Drutman, Scott B.
Haerynck, Filomeen
Zhong, Franklin L.
Hum, David
Hernandez, Nicholas J.
Belkaya, Serkan
Rapaport, Franck
de Jong, Sarah Jill
Creytens, David
Tavernier, Simon J.

Publication Date

Language

Embargo Status

NO

Journal Title

Journal ISSN

Volume Title

Alternative Title

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.

Source

Publisher

National Academy of Sciences

Subject

Medicine, Medical genetics

Citation

Has Part

Source

Proceedings of the National Academy of Sciences of the United States of America

Book Series Title

Edition

DOI

10.1073/pnas.1906184116

item.page.datauri

Link

Rights

Copyrights Note

Endorsement

Review

Supplemented By

Referenced By

0

Views

3

Downloads

View PlumX Details