IL23R Missense Variants Disrupt N-Glycosylation Sites and Destabilize Receptor Structure: A Multi-Tool In Silico Study with Implications for Colorectal Cancer Immunobiology

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Altıntaş Kazar G.

XI. Multidisciplinary Cancer Research Congress, İstanbul, Türkiye, 2 - 05 Temmuz 2026, ss.42, (Özet Bildiri)

  • Yayın Türü: Bildiri / Özet Bildiri
  • Basıldığı Şehir: İstanbul
  • Basıldığı Ülke: Türkiye
  • Sayfa Sayıları: ss.42
  • Açık Arşiv Koleksiyonu: AVESİS Açık Erişim Koleksiyonu
  • Trakya Üniversitesi Adresli: Evet

Özet

Introduction and Aim: Interleukin-23 receptor (IL23R) mediates IL-23/JAK2-STAT3 signaling and promotes colorectal cancer (CRC) tumor growth, with elevated IL-23 expression correlating with poor prognosis. The IL23R 3'UTR variant rs10889677 confers an odds ratio of 3.10 for CRC. Despite these associations, the functional impact of IL23R missense variants on glycosylation sites remains unexamined. This study characterizes high-risk IL23R missense variants through a multi-tool in silico pipeline, focusing on glycosylation site disruption.

Materials and Methods: Missense SNVs were retrieved from gnomAD v4.1.1. Pathogenicity, conservation, PTM disruption, and stability were assessed using PredictSNP2, ConSurf, MusiteDeep (against confirmed IL-23R glycosylation sites), DynaMut2, and MuPro, respectively. PPI networks used STRING; structural mapping used AlphaFold2.

Results: Of 694 missense SNVs, 87 were deleterious and 39 were high-risk (score ≥7). Three Asn81 variants disrupted an N-glycosylation site (score=0.908) between confirmed Asn58 and Asn118 positions. p.Gly122Arg (ΔΔG: −0.92/−1.05; REVEL=0.665) and p.Cys52Tyr (ΔΔG: −1.08/−0.96; REVEL=0.838) showed concordant destabilization, both achieving maximum risk score 9 within the IL-23A binding interface.

Discussion: This study identifies disruption of experimentally validated IL-23R glycosylation sites as a novel mechanistic consequence of coding missense variation. p.Gly122Arg and p.Cys52Tyr emerge as top-priority candidates for experimental validation in CRC models.

Key words: IL23R; missense variant; N-glycosylation; PTM disruption; colorectal cancer; JAK-STAT signaling