Dozens of genetic defects that are important for immune defense

Researchers from the University of Helsinki's Institute of Biotechnology pioneered the discovery of the first patient NFKB1 gene mutation, and they worked with international clinicians to identify and characterize a large number of unreported NFKB1 variants
in patients with immune system-related diseases.

In many cases, the discovery of genetic defects in patients is important for the treatment and prognosis
of patients with rare diseases.

The researchers found two new NFKB1 variants
in two families with common variable immune deficiencies.
Both of these identified NFKB1 variants lead to decreased expression of the NFKB1 protein and lead to altered gene expression and increased
inflammatory responses in patient cells.
Interaction analysis again showed that one of the variants lost the interaction, but the other did not
.

Another group of researchers studied 47 NFKB1 mutation cohorts previously reported in patients, 25 of which appeared to behave indistinguishably from
wild-type NFKB1.
Another 22 mutations were found to have adverse effects on NFKB1, from increasing NFKB1 protein degradation and reducing DNA binding to NFKB1, to reducing NFKB1 function overall by altering the protein structure: this may suggest their possible pathogenicity
.
Analysis of NFKB1 variant protein interactions has shown that the effects vary from the loss of interactions with NFKB family proteins to some mutant protein interactions similar to wild-type NFKB1
.

"These projects are excellent examples of fruitful international multidisciplinary research collaborations between the University of Helsinki and Europe's leading clinical research hospitals and centres
.
Our findings significantly deepen the understanding of the molecular mechanisms of NFKB1 and other autoinflammatory and autoimmune diseases associated with changes in the expression or function of NFKB1," Varjosalo said
.

"In addition, our findings suggest once again that targeted inhibition of certain key NF-kB signaling pathway components is an attractive treatment for these diseases, which can be collectively referred to as NF-kB signaling pathway diseases
.
"

Manfred Fliegauf, Matias Kinnunen, Sara Posadas-Cantera, Nadezhda Camacho-Ordonez, Hassan Abolhassani, Laia Alsina, Faranaz Atschekzei, Delfien J.
Bogaert, Siobhan O.
Burns, Joseph A.
Church, Gregor Dü ckers, Alexandra F.
Freeman, Lennart Hammarströ m, Leif Gunnar Hanitsch, Tessa Kerre, Robin Kobbe, Svetlana O.
Sharapova, Kathrin Siepermann, Carsten Speckmann, Sophie Steiner, Nisha Verma, Jolan E.
Walter, Emma Westermann-Clark, Sigune Goldacker, Klaus Warnatz, Markku Varjosalo, Bodo Grimbacher.
Detrimental NFKB1 missense variants affecting the Rel-homology domain of p105/p50.
Frontiers in Immunology, 2022; 13