Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
29
04
2022
accepted:
14
04
2023
medline:
14
6
2023
pubmed:
6
6
2023
entrez:
5
6
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37277650
doi: 10.1038/s41588-023-01399-7
pii: 10.1038/s41588-023-01399-7
pmc: PMC10260402
doi:
Substances chimiques
Receptors, Interferon
0
Interferons
9008-11-1
Banques de données
figshare
['10.6084/m9.figshare.22317835', '10.6084/m9.figshare.22317922', '10.6084/m9.figshare.22320661']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1034-1047Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK116073
Pays : United States
Organisme : NIDCR NIH HHS
ID : K02 DE028572
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL159086
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI150305
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI145988
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR007411
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002535
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE030864
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA190216
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE027689
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133230
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s).
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