Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis.
Proc Natl Acad Sci U S A
; 116(38): 19055-19063, 2019 09 17.
Article
en En
| MEDLINE
| ID: mdl-31484767
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-1ß secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1ß 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.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Infecciones del Sistema Respiratorio
/
Infecciones por Papillomavirus
/
Proteínas Adaptadoras Transductoras de Señales
/
Proteínas Reguladoras de la Apoptosis
/
Mutación con Ganancia de Función
/
Homocigoto
Límite:
Child, preschool
/
Female
/
Humans
/
Infant
/
Male
Idioma:
En
Año:
2019
Tipo del documento:
Article