Rare and Novel RELA Variants Contribute to Systemic Autoimmunity

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Autoimmune diseases exhibit diverse phenotypes, posing diagnostic and therapeutic challenges.
• Mutations in RELA (encoding RELA/p65) are implicated in various autoimmune conditions, suggesting diverse underlying mechanisms.
• Understanding RELA variants' functional impact is crucial for elucidating autoimmune disease pathogenesis.

Purpose of the Study:

• To identify and functionally characterize novel/rare RELA variants in patients with autoimmune diseases.
• To investigate the impact of these variants on NF-κB and interferon signaling pathways.
• To correlate genetic findings with observed clinical phenotypes.

Main Methods:

• Whole exome sequencing (WES) to identify RELA variants.
• Luciferase reporter assays to assess NF-κB and interferon-β transcriptional activity.
• Western blot and qPCR to evaluate RELA expression and gene signatures in patient cells.

Main Results:

• Seven novel/rare RELA variants were identified.
• RELA^I250V, RELA^R295H, and RELA^E3* variants showed reduced NF-κB transcriptional activity.
• RELA^I250V and RELA^R295H variants hyperactivated the IFNβ promoter; reduced RELA^I250V protein levels were observed.
• A patient heterozygous for I250V exhibited elevated IFNβ transcripts after TLR7/8 activation.

Conclusions:

• Novel RELA variants with distinct functional effects on NF-κB and IFNβ signaling were identified.
• These findings expand the spectrum of clinical syndromes associated with RELA dysfunction.
• RELA plays a significant role in various autoimmune and autoinflammatory diseases.