Researchers find dozens of genetic defects important for immune defense
Newswise — Researchers at the Institute of Biotechnology, University of Helsinki, who pioneered the identification of the first patient mutations in the NFkB1 gene, collaborated with international clinicians to identify and characterize numerous unreported NFKB1 variants in patients with immune-related diseases.
In many cases, the identification of a patient’s genetic defect is very important for the treatment and prognosis of patients with rare diseases. NFKB1, a transcription factor, causes changes in gene expression and is activated by stress- and immune-related signaling pathways. Mutations in NFkB1 have previously been associated with common variable immunodeficiency (CVID).
Two new studies may bring more relief to patients with an inherited genetic defect in the immune system
“These studies have significantly expanded the associations of NFKB1 variants with immune system dysfunction – links we first reported in 2017,” says the study director. Markku Varjosalo from the Institute of Biotechnology, University of Helsinki
Researchers identified two new NFKB1 variants in two families with common variable immunodeficiency. Both identified NFKB1 variants caused reduced expression of NFKB1 protein and led to altered gene expression and increased inflammatory response in patient cells. Interaction analysis again showed a loss of interactions for one variant but not the other.
Another group of researchers studied a cohort of 47 NFKB1 mutations previously reported in patients, of which 25 did not appear to behave differently from wild-type NFKB1. A further 22 mutations were found to have deleterious effects on NFKB1, ranging from increased NFKB1 protein degradation, decreased NFKB1 DNA binding to overall decreased function of NFKB1 through altered protein structure: This may indicate their likely pathogenicity. Analysis of NFKB1 variant protein interactions showed variable effects, from loss of interaction with NFKB family proteins to interactions of some variants that appeared similar to wild-type NFKB1.
“These projects are excellent examples of fruitful international multidisciplinary research collaboration between the University of Helsinki and Europe’s leading clinical research hospitals and centers. Our discovery significantly deepens the understanding of the molecular mechanisms behind NFKB1 and other autoinflammatory and autoimmune diseases that are associated with altered NFkB1 expression or function,” says Varjosalo.
“Furthermore, the results again suggest that targeted inhibition of certain key components of the NFkB signaling pathway is an attractive therapeutic approach for the treatment of these diseases, which could be collectively termed NF-kB signaling diseases.”