Rare ADAR1 loss-of-function variants alter RNA editing and drive interferon-dependent inflammation in psoriasis

In 4 unrelated pedigrees, we report rare heterozygous loss-of-function ADAR1 mutations cosegregating with autosomal dominant, early onset psoriasis and increased type I interferon (IFN)-stimulated gene (ISG) transcripts in skin lesions and/or blood. We identified 6 additional variants in a psoriasis cohort. Skin single cell transcriptomics identified keratinocytes and melanocytes as key IFN sources. ADAR1 knockdown in keratinocytes and melanocytes, and transduction of ADAR1G1119R and ADAR1P3A alleles in keratinocytes, led to reduced A-to-I RNA editing and upregulation of ISG expression, reversed by JAK1 and TYK2 inhibition, mirroring their clinical benefit in these patients. This set of data defines a new IFN-dependent psoriasis subtype resulting from inborn errors of ADAR1-dependent RNA editing, leading to IFN constitutive dysregulation, and opens new avenues in precision medicine.