{
  "abstract": "Background The pathogenesis of Crohn’s disease (CD) is closely associated with genetic factors and an imbalance of intestinal neuro-immune crosstalk. However, the functions of genes maintaining the enteric nervous system (ENS) structure remain poorly understood. This study aimed to identify novel genetic susceptibility loci for CD and to investigate the functional impact of a candidate missense mutation in the neural adhesion molecule NFASC.Methods Whole-exome sequencing (WES) was performed on a pair of monozygotic twins with CD to identify disease-associated mutations. Evolutionary conservation of the mutated residue was assessed through multiple sequence alignment, and structural alterations were predicted using AlphaFold 3.0. Clinical correlation was assessed using three independent GEO transcriptomic datasets. Localization of NFASC protein in ENS was examined by immunofluorescence staining of murine colon tissue. The functional impact of the NFASC mutation was assessed using: (1) primary mouse enteric neurons to evaluate neuronal excitability via patch clamp recordings; and (2) enteric neuron–macrophage co-cultures to investigate neuro-immune communication.Results A novel and evolutionarily conserved NFASC mutation was identified in CD-discordant monozygotic twins. Multiple independent datasets revealed significant downregulation of NFASC mRNA in the intestinal mucosa of CD patients (IDDF2026-ABS-0153 Figure 1. Multi-cohort GEO dataset validation). AlphaFold 3.0 structural modeling predicted that the mutation disrupts the hydrogen bond network within the FnIII domain, leading to local conformational instability. NFASC protein was specifically and highly expressed in colonic myenteric plexus neurons and was markedly downregulated during intestinal inflammation in DSS-treated mice (IDDF2026-ABS-0153 Figure 2. Histological localization and expression of NFASC in Inflammation). Although the mutation did not affect intestinal epithelial cell function, it significantly reduced the excitability of primary mouse enteric neurons in vitro. In neuron–macrophage co-cultures, neurons expressing mutant NFASC failed to suppress LPS-induced pro-inflammatory cytokine production and M1 macrophage polarization. These findings implicate a mechanistic cascade in which NFASC mutation compromises enteric neuronal activity, thereby driving intestinal immune dysregulation and chronic inflammation.Conclusions NFASC is a novel susceptibility gene for CD. The mutation likely contributes to CD pathogenesis by impairing the excitability of enteric neurons rather than directly damaging the intestinal epithelium. These findings highlight the potential role of neuro-immune axis dysfunction in the development of CD.Abstract IDDF2026-ABS-0153 Figure 1Abstract IDDF2026-ABS-0153 Figure 2",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China"
      ],
      "name": "Junhui Lin"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China"
      ],
      "name": "Xianling Zhao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China"
      ],
      "name": "Mi Peng"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China"
      ],
      "name": "Zhenyu Ye"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China"
      ],
      "name": "Guleng Bayasi"
    }
  ],
  "title": "IDDF2026-ABS-0153 The mechanism of NFASC missense mutation leading to imbalance of intestinal neuro-immune crosstalk and promotes the occurrence of crohn’s disease",
  "uid": "e7d81d6d-fc08-5fe8-aaed-1112092a071d"
}