NEW YORK – Researchers have found that overexpression of interferon receptor (IFNR) genes in patients with Down's syndrome (DS) could be responsible for some of the traits associated with the condition.
The findings, published in Nature Genetics on Monday, could help in the development of new therapeutics for DS or trisomy 21 that occurs when babies are born with an extra copy of chromosome 21.
These patients experience an array of health problems such as developmental delays, cognitive impairments and craniofacial abnormalities, congenital heart defects (CHD), autoimmune disorders, and neurological conditions, including Alzheimer’s disease.
"Despite many efforts, the mechanisms by which trisomy 21 causes the developmental and clinical hallmarks of DS remain poorly understood," corresponding authors Kelly Sullivan, an assistant professor of pediatrics-developmental biology, and Joaquin Espinosa, a professor in the department of pharmacology at the University of Colorado, wrote in the paper.
For their study, Espinosa and colleagues conducted an analysis of the transcriptomes and plasma immune markers in blood from 304 individuals with DS and 96 control subjects with normal chromosome numbers. The researchers noted that among the top 10 gene sets substantially enriched in trisomy 21, seven were linked to interferon (IFN) signaling and inflammatory pathways, with a few having consistently significant positive correlations, including the four IFNRs and IFN-stimulated genes encoded on human chromosome 21 (HSA21). Since the 1970s, researchers have noted hyperactive IFN signaling in cells with trisomy. However, it largely remained unknown as to how IFN hyperactivity led to different DS phenotypes. The researchers also defined correlations between circulating levels of the inflammatory marker C-reactive protein and the pro-inflammatory cytokine interleukin 6 against the expression of HSA21 genes in trisomy 21 individuals. They found that expression of only a few HSA21 genes correlated positively with CRP and IL6, including the four IFNRs.
The authors then turned to Dp16, a mouse model of DS which has three copies of mouse chromosome 16 (MMU16). This causes triplication of several genes similar to those on human chromosome 21, including the IFNR cluster. Dp16 mice display key phenotypes of DS including hyperactive IFN signaling, a dysregulated antiviral response, increased prevalence of heart defects, developmental delays, cognitive impairments, and craniofacial anomalies, the authors noted.
Using genome editing techniques, the researchers removed the third copy of the IFNR gene cluster in Dp16 mice and saw a reduction in hyperactive immune response that was previously noted in these mice.
Further tests also revealed that the removal of the extra IFNR gene cluster in mice also lead to improvements of the mouse traits of Down's syndrome, including cognitive defects and improper development of the skull, cranial base, mandible, and heart.
"These results expand the evidence for harmful effects of aberrant IFN signaling in development, while supporting the notion that DS can be understood in part as an interferonopathy," the authors concluded.
However, despite the improvements in cardiac abnormalities, the researchers said that the findings do not show that IFNR triplication is the sole cause of congenital heart defects in mice. They further cautioned that the improvements in DS traits among mice should not be solely attributed to the changes in IFNR gene cluster. Other factors also need to be considered, including contributions from noncoding RNAs and cis-regulatory elements, the authors wrote.
According to the authors, IFN signaling can be attenuated with agents approved for the treatment of diverse autoinflammatory conditions, such as JAK inhibitors, which block the immune hypersensitivity phenotype observed in Dp16 mice. A clinical trial for JAK inhibition in DS is already underway.
Meanwhile, the transcriptome analysis also revealed that multiple pathways related to INFR, such as synaptogenesis, SNARE signaling, and dopamine signaling, could be affected, which likely leads to some of the cognitive impairments in DS.
Highlighting a major limitation of their study, the authors wrote that the contribution of the INFR locus was defined in a single mouse model of DS, and therefore, the findings should be extrapolated to the human condition with extreme caution.