Interferon receptor gene dosage determines diverse hallmarks of Down syndrome

Abstract

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.

Regulation of human interferon signaling by transposon exonization

“…Second, our work uncovers the relative expression of IFNAR2-L and IFNAR2-S as a potentially key determinant of the severity of immune-mediated diseases. Dysregulated IFN signaling underlies aberrant responses to infection, including severe COVID-19 45,47 , autoimmune diseases including type I interferonopathies such as systemic lupus erythematosus 65 , altered tumor immune phenotypes [66][67][68] and is a hallmark of Down Syndrome 69,70 . Moreover, dysregulated IFN responses also contribute to acquired resistance to recombinant IFN therapy 71 .…”

IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

“…For example, the established link between APP triplication and the high prevalence of AD in this population justifies pursuit of strategies to ameliorate the burden of chronic amyloidosis. 9 Likewise, the demonstration that triplication of IFN receptors contributes to multiple hallmarks of DS in mice 65 , 66 and immune hypersensitivity in human cell types with T21 26 , 27 , 67 , 68 justifies ongoing testing of JAK inhibitors to decrease the burden of autoimmune diseases in DS. 69 , 70 In this context, we report here that individuals with DS display lifelong IGF1 deficiency downstream of GH1 production and that IGF1 deficiency is the top biosignature associated with neurodegeneration and neuroinflammation in DS.…”

Hemophagocytic lymphohistocytosis in trisomy 21: successful treatment with interferon inhibition

“…These monogeneic disorders, some of which include Aicardi-Goutières syndrome (AGS), monogenetic forms of lupus, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE), stimulator of IFN genes (STING)-associated vasculopathy with onset in infancy (SAVI), are caused by a mutation leading to upregulation of type I IFN, which ultimately is involved in the pathogenesis of the diseases [23]. Given trisomy 21 has elevated IFN levels [4][5][6], its proteome has multiple ties to IFN signaling [7], and many of the changes are similar to those observed in type I interferonopathies [10], it is reasonable to think of trisomy 21 similarly to an interferonopathy [8,9,11]. It has often been classified as a 'mild interferonopathy, ' as the interferon activation is milder than that in patients with monogeneic Fig.…”

“…This has prompted some to consider trisomy 21 in a group of disorders termed interferonopathies [10]. Further weight to this concept is supported by evidence that triplication of the IFN receptor in mouse models led to increased expression of all four IFN receptors and an exacerbated immune response, whereas normalization of IFN receptor gene dosage rescued multiple key phenotypic changes associated with trisomy 21 [11].…”