Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Nat Genet. 2023 Jun;55(6):1034-1047. doi: 10.1038/s41588-023-01399-7. Epub 2023 Jun 5.
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.
唐氏综合征（DS）是由 21 三体引起的一种遗传性疾病，其特征是认知障碍程度不一、免疫失调、畸形发生以及多种并存病症的发病率增高。导致这些影响的确切机制在很大程度上仍然未知。我们证明，21 号染色体上干扰素受体（IFNR）基因簇的三倍体是 DS 小鼠模型中多种表型所必需的。全血转录组分析表明，IFNR 过表达与 DS 人群中慢性干扰素过度活跃和炎症相关。为了确定该基因座对 DS 表型的贡献，我们使用基因组编辑校正了 DS 小鼠模型中的其拷贝数，从而使抗病毒反应正常化，防止了心脏畸形，改善了发育迟缓，提高了认知能力，并减轻了颅面异常。Ifnr 基因座的三倍体调节了小鼠的 DS 特征，表明 21 三体引发了一种干扰素病，可能适合于治疗干预。
