Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Cell Culture, Keratinocyte

SUBMITTER: Chiara guerrera

LAB HEAD: Ida Chiara Guerrera

PROVIDER: PXD065122 | Pride | 2026-04-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	230825_HeBA_Evo_DIA_ADAR1_n1-9_scr-highCa-1_S1-B1_1_593.d.7z	Other
	230825_HeBA_Evo_DIA_ADAR1_n1-9_scr-highCa-2_S1-B2_1_594.d.7z	Other
	230825_HeBA_Evo_DIA_ADAR1_n1-9_scr-highCa-3_S1-B3_1_595.d.7z	Other
	230825_HeBA_Evo_DIA_ADAR1_n1-9_scr-highCa-4_S1-B4_1_596.d.7z	Other
	230825_HeBA_Evo_DIA_ADAR1_n1-9_scr-highCa-5_S1-B5_1_597.d.7z	Other

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Project description:The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments. We used Affymetrix microarrays to evaluate genome-wide expression in primary human keratinocytes exposed to cytokines. Cytokine activity signatures were used to interpret the shifts in gene expression that occur in psoriasis plaques relative to normal uninvolved skin. Primary keratinocytes from three donors (subjects 1, 2, and 3) were obtained and were either untreated (control) or exposed to cytokines (IL-4, IL-13, IFN-alpha, IFN-gamma and TNF). For the IL17A samples, primary keratinocytes were obtained from six donors, with cells derived from three donors treated with IL-17A and cells derived from the other three donors left untreated (i.e., unpaired control samples).

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

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