ADAR1 loss-of-function variants altering RNA editing define a new interferon-dependent psoriasis subtype.

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• Altered RNA editing and type I interferon (IFN) signaling are implicated in immune-mediated diseases like psoriasis.
• The specific genetic underpinnings of these alterations in psoriasis remain largely unknown.

Purpose of the Study:

• To investigate the genetic basis of early-onset plaque psoriasis with a strong IFN signature.
• To identify genetic defects causing a monogenic form of psoriasis linked to IFN dysregulation.

Main Methods:

• Whole-exome sequencing in multiplex families with early-onset psoriasis.
• Analysis of rare ADAR1 variants in an independent psoriasis cohort.
• Single-cell transcriptomics to identify IFN-producing cells.
• Functional studies assessing RNA editing and IFN responses.

Main Results:

• Four rare heterozygous loss-of-function mutations in ADAR1 were identified, cosegregating with psoriasis and elevated IFN-stimulated genes.
• ADAR1 knockdown or expression of pathogenic variants reduced RNA editing and increased IFN and inflammatory cytokines.
• Keratinocytes and melanocytes were identified as key sources of type I IFN.

Conclusions:

• A novel subtype of IFN-dependent psoriasis is caused by inborn defects in ADAR1-mediated RNA editing.
• These findings highlight the critical role of RNA editing in immune homeostasis.
• Therapeutic strategies targeting IFN signaling, like upadacitinib and deucravacitinib, may be effective for this subtype.