NF-κB p65 iso5 Δ6/7 and p65 iso5 Δ10 isoforms drive immune-inflammatory remodeling in Fabry disease and GLA variants of uncertain significance
- 1Institute for Biomedical Research and Innovation, National Research Council of Italy (CNR-IRIB)
- 2Institute for Biomedical Research and Innovation, National Research Council (CNR-IRIB), Section of Catania
- 3Complex Operative Unit of Clinical Pathology, Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico Di Cristina e Benfratelli Hospitals
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).
Methods: 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.
Results: 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.
Discussion: 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.
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BibTeX
@article{biddeci2026nfκb,
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}},
author = {Giuseppa Biddeci and Paolo Colomba and Gaetano Spinelli and Monia Anania and Irene Giacalone and Giovanni Duro and Margherita Stefania Rodolico and Tommaso Silvano Aronica and Francesco Di Blasi},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1922658},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1922658/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - NF-κB p65 iso5 Δ6/7 and p65 iso5 Δ10 isoforms drive immune-inflammatory remodeling in Fabry disease and GLA variants of uncertain significance
AU - Giuseppa Biddeci
AU - Paolo Colomba
AU - Gaetano Spinelli
AU - Monia Anania
AU - Irene Giacalone
AU - Giovanni Duro
AU - Margherita Stefania Rodolico
AU - Tommaso Silvano Aronica
AU - Francesco Di Blasi
PY - 2026
DA - 2026/10/06
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1922658
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1922658/full
AB - 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). Methods: 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. Results: 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. Discussion: 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.
SN - 1664-3224
ER -