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Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model.
Waugh, Katherine A; Minter, Ross; Baxter, Jessica; Chi, Congwu; Galbraith, Matthew D; Tuttle, Kathryn D; Eduthan, Neetha P; Kinning, Kohl T; Andrysik, Zdenek; Araya, Paula; Dougherty, Hannah; Dunn, Lauren N; Ludwig, Michael; Schade, Kyndal A; Tracy, Dayna; Smith, Keith P; Granrath, Ross E; Busquet, Nicolas; Khanal, Santosh; Anderson, Ryan D; Cox, Liza L; Estrada, Belinda Enriquez; Rachubinski, Angela L; Lyford, Hannah R; Britton, Eleanor C; Fantauzzo, Katherine A; Orlicky, David J; Matsuda, Jennifer L; Song, Kunhua; Cox, Timothy C; Sullivan, Kelly D; Espinosa, Joaquin M.
Afiliación
  • Waugh KA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Minter R; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Baxter J; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Chi C; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Galbraith MD; Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Tuttle KD; Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Eduthan NP; The Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Kinning KT; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Andrysik Z; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Araya P; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Dougherty H; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Dunn LN; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Ludwig M; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Schade KA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Tracy D; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Smith KP; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Granrath RE; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Busquet N; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Khanal S; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Anderson RD; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Cox LL; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Estrada BE; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Rachubinski AL; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Lyford HR; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Britton EC; Animal Behavior Core, NeuroTechnology Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Fantauzzo KA; Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Orlicky DJ; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Matsuda JL; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Song K; Department of Oral and Craniofacial Sciences, University of Missouri-Kansas City, Kansas City, MO, USA.
  • Cox TC; Department of Oral and Craniofacial Sciences, University of Missouri-Kansas City, Kansas City, MO, USA.
  • Sullivan KD; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Espinosa JM; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Nat Genet ; 55(6): 1034-1047, 2023 06.
Article en En | MEDLINE | ID: mdl-37277650
ABSTRACT
Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndrome de Down / Cardiopatías Congénitas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndrome de Down / Cardiopatías Congénitas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos