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SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics 2015 Jun;135(6):e1530-4

Date

05/13/2015

Pubmed ID

25963006

Pubmed Central ID

PMC4444800

DOI

10.1542/peds.2014-3386

Abstract

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 DP

Author

Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Enterocolitis, Necrotizing
Female
Genetic Variation
Humans
Infant, Newborn
Infant, Premature
Male
Mutation
Receptors, Interleukin-1
jenkins-FCD Prod-484 8aa07fc50b7f6d102f3dda2f4c7056ff84294d1d