SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics 2015 Jun;135(6):e1530-4
Date
05/13/2015Pubmed ID
25963006Pubmed Central ID
PMC4444800DOI
10.1542/peds.2014-3386Scopus ID
2-s2.0-84930607947 (requires institutional sign-in at Scopus site) 69 CitationsAbstract
Necrotizing enterocolitis (NEC) is a severe form of bowel disease that develops in premature infants. Although animal data and human studies suggest that aberrant activation of the intestinal immune system contributes to NEC, the pathogenesis remains unclear. We hypothesized that inherited defects in the regulation of Toll-like receptor signaling can contribute to NEC susceptibility in premature infants. A forward genetic screen done in an infant with lethal NEC using exome sequencing identified a novel stop mutation (p.Y168X) and a rare missense variant (p.S80Y) in SIGIRR, a gene that inhibits intestinal Toll-like receptor signaling. Functional studies carried out in human embryonic kidney cells and intestinal epithelial cells demonstrated that SIGIRR inhibited inflammation induced by lipopolysaccharide, a cell wall component of Gram-negative bacteria implicated in NEC. The genetic variants identified in the infant with NEC resulted in loss of SIGIRR function and exaggerated inflammation in response to lipopolysaccharide. Additionally, Sanger sequencing identified missense, stop, or splice region SIGIRR variants in 10 of 17 premature infants with stage II+ NEC. To the best of our knowledge, this is one of the first reports of a phenotype associated with SIGIRR in humans. Our data provide novel mechanistic insight into the probable causation of NEC and support additional investigation of the hypothesis that inherited defects in the regulation of innate immune signaling can contribute to NEC susceptibility in premature infants.
Author List
Sampath V, Menden H, Helbling D, Li K, Gastonguay A, Ramchandran R, Dimmock DPAuthors
Keguo Li MD, PhD Research Scientist I in the Surgery department at Medical College of WisconsinRamani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Enterocolitis, NecrotizingFemale
Genetic Variation
Humans
Infant, Newborn
Infant, Premature
Male
Mutation
Receptors, Interleukin-1
