Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model
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Open Access
- 5 June 2023
- journal article
- editorial
- Published by Springer Nature in Nature Genetics
- Vol. 55 (6) , 1034-1047
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01AI150305, R01AI145988)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30CA046934, T32CA190216)
- Global Down Syndrome Foundation (N/A)
- Human Immunology and Immunotherapy Initiative, GI & Liver Innate Immune Program
- U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (2T32AR007411)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R01HL133230)
- University of Colorado Department of Medicine Outstanding Early Career Scholar Program; The Gates Frontiers Fund.
- Stowers Family Endowed Chair in Dental and Mineralized Tissue Research
- Boettcher Foundation (N/A)
- U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (K02DE028572, R01DE030864)
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