Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model

• Published in: Nature genetics Vol. 55; no. 6; pp. 1034 - 1047
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-06-2023; Nature Publishing Group
• Subjects: 631/136/2060; 631/208/366; 631/250/248; Agriculture; Alzheimer's disease; Animal Genetics and Genomics; Animals; Anomalies; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chromosome 21; Chromosomes; Cognition; Cognitive ability; Copy number; Cytokines; Disease Models, Animal; Down syndrome; Down Syndrome - genetics; Down's syndrome; Gene expression; Gene Function; Genome editing; Genomes; Heart; Heart Defects, Congenital; Human Genetics; Hyperactivity; Inflammation; Interferon; Interferon receptors; Interferons; Kinases; Lymphatic system; Mice; Phenotype; Phenotypes; Proteins; Receptors; Receptors, Interferon - genetics; Transcriptomes; Trisomy
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-023-01399-7

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.
A mouse model of Down syndrome (DS) highlights the importance of triplication of the
IFNR
gene cluster for a variety of DS-associated traits. Copy number correction resulted in amelioration of multiple phenotypes associated with the condition.