Interferon receptor gene dosage determines multiple hallmarks of Down syndrome

Trisomy 21 causes Down syndrome, a condition characterized by cognitive impairments, immune dysregulation, and atypical morphogenesis. Using whole blood transcriptome analysis, we demonstrate that specific overexpression of four interferon receptors encoded on chromosome 21 associates with chronic i...

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Bibliographic Details
Published in:bioRxiv 2022-02
Main Authors: Waugh, Katherine A, Minter, Ross, Baxter, Jessica, Chi, Congwu, Tuttle, Kathryn D, Eduthan, Neetha P, Galbraith, Matthew D, 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, Belinda Enriquez Estrada, Rachubinski, Angela L, Lyford, Hannah R, Britton, Eleanor C, Orlicky, David J, Matsuda, Jennifer L, Song, Kunhua, Cox, Timothy C, Sullivan, Kelly D, Espinosa, Joaquin M
Format: Article
Language:English
Subjects:
Chromosome 21
Cognitive ability
Copy number
COVID-19
Dosage
Down syndrome
Down's syndrome
Gene dosage
Hyperactivity
Interferon
Interferon receptors
Morphogenesis
Phenotypes
Transcriptomes
Trisomy
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Summary:Trisomy 21 causes Down syndrome, a condition characterized by cognitive impairments, immune dysregulation, and atypical morphogenesis. Using whole blood transcriptome analysis, we demonstrate that specific overexpression of four interferon receptors encoded on chromosome 21 associates with chronic interferon hyperactivity and systemic inflammation in Down syndrome. To define the contribution of interferon receptor overexpression to Down syndrome phenotypes, we used genome editing to correct interferon receptor gene dosage in mice carrying triplication of a large genomic region orthologous to human chromosome 21. Normalization of interferon receptor copy number attenuated lethal antiviral responses, prevented heart malformations, decreased developmental delays, improved cognition and normalized craniofacial anomalies. Therefore, interferon receptor gene dosage determines major hallmarks of Down syndrome, indicating that trisomy 21 elicits an interferonopathy amenable to therapeutic intervention. Competing Interest Statement JME serves in the COVID19 Scientific Advisory Board for Eli Lilly.
DOI:10.1101/2022.02.03.478982