title: SIGIRR genetic variants in premature infants with necrotizing enterocolitis.
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.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Children's Research Institute, Department of Pediatrics, vsampath@mcw.edu.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Sampath
authors.affiliation: Division of Neonatology, Department of Pediatrics.
authors.forename: Heather
authors.initials: H
authors.lastname: Menden
authors.affiliation: Human Molecular Genetics Center, and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Helbling
authors.affiliation: Developmental Vascular Biology, The Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Keguo
authors.initials: K
authors.lastname: Li
authors.affiliation: Developmental Vascular Biology, The Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Adam
authors.initials: A
authors.lastname: Gastonguay
authors.affiliation: Children's Research Institute, Department of Pediatrics, Developmental Vascular Biology, The Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ramani
authors.initials: R
authors.lastname: Ramchandran
authors.affiliation: Children's Research Institute, Department of Pediatrics, Human Molecular Genetics Center, and.
authors.forename: David P
authors.initials: DP
authors.lastname: Dimmock
mesh_terms: D020345:Enterocolitis, Necrotizing / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D009154:Mutation; D017472:Receptors, Interleukin-1 / Q000235:genetics*
chemical_list: D017472:Receptors, Interleukin-1; C546891:SIGIRR protein, human