期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 38, 页码 19055-19063出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1906184116
关键词
inflammasome; NLRP1; recurrent respiratory papillomatosis; genetics; human papillomavirus
资金
- Strategic Positioning Fund on Genetic Orphan Diseases from A* STAR, Singapore
- Jeffrey Modell Foundation
- Bijzonder Onderzoeksfonds-Tenure Grant
- Cure-AID Grant from the European Union ERA-Net for Research Programmes on Rare Diseases
- National Research Foundation
- National Center for Advancing Translational Sciences [UL1TR001866]
- Investissement d'avenir program [ANR-10-IAHU-01]
- Integrative Biology of Emerging Infectious Diseases Laboratoire d'Excellence [ANR-10-LABX-62-IBEID]
- NIH [5 R21 AI107508-02]
- French Cancer Institute [2013-1-PL BIO-11-1]
- St. Giles Foundation
- Rockefeller University
- Institut National de la Sante et de la Recherche Medicale
- Paris Descartes University
- Shapiro-Silverberg Fund for the Advancement of Translational Research
- American Philosophical Society Daland Fellowship in Clinical Investigation
- National Center for Research Resources
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 papillo-maviruses (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-1 beta secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1 beta 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据