Mendelian disease caused by variants affecting recognition of Z-DNA and Z-RNA by the Za domain of the double-stranded RNA editing enzyme ADAR

摘要

Variants in the human double-stranded RNA editing enzyme ADAR produce three well-characterized rare Mendelian Diseases: Dyschromatosis Symmetrica Hereditaria (OMIM: 127400), Aicardi-Goutieres syndrome (OMIM: 615010) and Bilateral Striatal Necrosis/Dystonia. ADAR encodes p150 and p110 protein isoforms. p150 incorporates the Za domain that binds left-handed Z-DNA and Z-RNA with high affinity through contact of highly conserved residues with the DNA and RNA double helix. In certain individuals, frameshift variants on one parental chromosome in the second exon of ADAR produce haploinsufficiency of p150 while maintaining normal expression of p110. In other individuals, loss of p150 expression from one chromosome allows mapping of Z alpha p150 variants from the other parental chromosome directly to phenotype. The analysis reveals that loss of function Z alpha variants cause dysregulation of innate interferon responses to double-stranded RNA. This approach confirms a biological role for the left-handed conformation in human disease, further validating the power of Mendelian genetics to deliver unambiguous answers to difficult questions. The findings reveal that the human genome encodes genetic information using both shape and sequence.