{
  "abstract": "Introduction: Fabry disease (FD) is an X-linked lysosomal storage disorder in which chronic inflammation contributes to disease progression beyond substrate accumulation. Although nuclear factor kappa B (NF-κB) signaling has been implicated in FD pathogenesis, the contribution of alternative NF-κB splicing to immune-inflammatory remodeling remains unknown. Here, we investigated the recently identified NF-κB p65 iso5 splice variants p65 iso5 Δ6/7 and p65 iso5 Δ10 in FD and in individuals carrying GLA variants of uncertain significance (GVUS).\n\nMethods: We characterized p65 iso5 Δ6/7 and p65 iso5 Δ10 in peripheral blood mononuclear cells from 103 patients with FD, including classic and late-onset phenotypes, 30 GVUS subjects, and 30 healthy controls. Isoform expression was assessed at the mRNA and protein levels, and circulating inflammatory mediators were evaluated in selected groups.\n\nResults: Both isoforms were constitutively expressed under physiological conditions and were significantly upregulated at the mRNA level in FD, whereas p65 iso5 Δ6/7 was also increased at the protein level. A similar expression profile was observed in GVUS subjects despite preserved α-galactosidase A activity and normal Lyso-Gb3 levels. In carriers of the p.Ala143Thr (A143T) variant, increased isoform expression was associated with enhanced expression of pro-inflammatory cytokines and elevated circulating inflammatory mediators.\n\nDiscussion: Together with the previously reported downregulation of p65 iso5, these findings indicate that selective NF-κB splice variant redistribution, rather than uniform pathway activation, characterizes immune-inflammatory remodeling in FD. Altered p65 isoforms expression may contribute to immune dysregulation and clinical heterogeneity in FD and GLA variants of uncertain significance.",
  "abstract_shown": true,
  "affiliations": [
    "Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)",
    "Institute for Biomedical Research and Innovation, National Research Council (CNR-IRIB), Section of Catania",
    "Complex Operative Unit of Clinical Pathology, Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico Di Cristina e Benfratelli Hospitals"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Giuseppa Biddeci"
    },
    {
      "affs": [
        0
      ],
      "name": "Paolo Colomba"
    },
    {
      "affs": [
        0
      ],
      "name": "Gaetano Spinelli"
    },
    {
      "affs": [
        0
      ],
      "name": "Monia Anania"
    },
    {
      "affs": [
        0
      ],
      "name": "Irene Giacalone"
    },
    {
      "affs": [
        0
      ],
      "name": "Giovanni Duro"
    },
    {
      "affs": [
        1
      ],
      "name": "Margherita Stefania Rodolico"
    },
    {
      "affs": [
        2
      ],
      "name": "Tommaso Silvano Aronica"
    },
    {
      "affs": [
        0
      ],
      "name": "Francesco Di Blasi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5yzygqxfe6awb.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1922658",
  "fulltext_url": "https://europepmc.org/articles/PMC13680232",
  "id": "5yzygqxfe6awb",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1922658/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Lysosomal Storage Disorders Research"
    ]
  ],
  "openalex": "W7220659036",
  "pdf_url": "https://europepmc.org/articles/PMC13680232?pdf=render",
  "pmcid": "PMC13680232",
  "pmid": "42903206",
  "published": "2026-10-06",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/5yzygqxfe6awb.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:15Z",
      "native_id": "10.3389/fimmu.2026.1922658",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1922658/full"
    },
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42903206",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42903206"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Lysosomal Storage Disorders Research",
      "subfield": "physiology"
    }
  ],
  "title": "NF-κB p65 iso5 Δ6/7 and p65 iso5 Δ10 isoforms drive immune-inflammatory remodeling in Fabry disease and GLA variants of uncertain significance",
  "title_text": "NF-κB p65 iso5 Δ6/7 and p65 iso5 Δ10 isoforms drive immune-inflammatory remodeling in Fabry disease and GLA variants of uncertain significance",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:57Z",
  "url": "https://research.draconitic.com/paper/5yzygqxfe6awb",
  "venue": "Frontiers in Immunology",
  "versions": []
}