Selective NF-κB splice variant redistribution, rather than uniform pathway activation, characterizes immune-inflammatory remodeling in Fabry disease and GLA variants of uncertain significance, with p65 iso5 Δ6/7 and Δ10 upregulated at the mRNA level (and Δ6/7 also at the protein level).
NF-κB p65 iso5 Δ6/7 and p65 iso5 Δ10 are constitutively expressed in PBMCs under physiological conditions.
Both p65 iso5 Δ6/7 and p65 iso5 Δ10 are significantly upregulated at the mRNA level in Fabry disease, while only p65 iso5 Δ6/7 is also increased at the protein level.
GLA variants of uncertain significance (GVUS) subjects show an isoform expression profile similar to Fabry disease despite preserved α-galactosidase A activity and normal Lyso-Gb3 levels.
In carriers of the p.Ala143Thr (A143T) variant, increased p65 isoform expression is associated with enhanced pro-inflammatory cytokine expression and elevated circulating inflammatory mediators.
Combined with previously reported downregulation of p65 iso5, the data indicate selective redistribution of NF-κB splice variants rather than uniform pathway activation in Fabry disease.
Fabry disease is an inherited disorder in which a missing enzyme causes fatty substances to build up in the body. Chronic inflammation is thought to make the disease worse beyond this buildup. This study looked at two recently discovered variants of a key inflammation-regulating protein, NF-κB p65, in blood immune cells from 103 people with Fabry disease, 30 people with genetic variants of uncertain significance in the Fabry gene (GLA), and 30 healthy controls. Both variants were present in healthy people but were higher in Fabry disease at the mRNA level, and one (Δ6/7) was also higher at the protein level. People with uncertain-significance variants showed a similar pattern even though their enzyme activity and Lyso-Gb3 (a disease marker) were normal. In carriers of the A143T variant, higher isoform levels went along with more pro-inflammatory cytokines and higher inflammatory markers in the blood. This research suggests that Fabry-related inflammation involves a reshuffling of which NF-κB forms are produced, rather than a simple switching on of the whole pathway. It also raises the possibility that some people with uncertain-significance variants have immune changes despite normal standard tests, though this study does not show how this affects their health outcomes.
Biddeci G, Colomba P, Spinelli G, Anania M, Giacalone I, Duro G, et al.. (2026). NF-κB p65 iso5 Δ6/7 and p65 iso5 Δ10 isoforms drive immune-inflammatory remodeling in Fabry disease and GLA variants of uncertain significance.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1922658