Researchers discover dozens of genetic defects important for immune defence - relevant for patients with rare diseases

Researchers from the Institute of Biotechnology, University of Helsinki, pioneers in identifying the first patient mutations on the NFkB1-gene, cooperated with international clinicians to identify and characterise a plethora of unreported NFKB1 variants on patients with immune system related illnesses.

In many cases, the identification of a genetic defect in a patient is of great importance 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 the NFkB1 have previously been linked to common variable immune deficiency (CVID). 

Two new studies may bring further relief for patients with hereditary gene defect in immune system

“These studies have significantly expanded the associations of NFKB1 variants to immune system dysfunction – the connections which we first reportedin 2017, “ says research director Markku Varjosalo from the Institute of Biotechnology, University of Helsinki

Researchers identified two new NFKB1 variants in two families suffering from common variable immune deficiency. Both identified NFKB1 variants caused reduced expression of the NFKB1 protein and lead to an altered gene expression and increased inflammation response in patient cells. Interaction analysis again showed loss of interactions for one of the variants but not the other. 

Another group of researchers studied a cohort of 47 NFKB1 mutations previously reported in patients, out of which 25 did not appear to behave differently from wild type NFKB1. The other 22 mutations were found to have adverse effects on NFKB1 which ranged from increased NFKB1 protein degradation, reduced DNA binding of NFKB1 to overall reduced NFKB1 function through altered protein structure: This may hint towards their likely pathogenicity. Analysis of NFKB1 variant protein interactions showed varied effects from loss of interaction with NFKB family proteins to some variants interactions appearing similar to wild type NFKB1. 

 “These projects are excellent examples of fruitful international multidisciplinary research collaborations between the University of Helsinki and the leading clinical research hospitals and centers in Europe. Our findings significantly deepen the understanding of the molecular mechanisms underlying NFKB1, and other autoinflammatory and autoimmune diseases associated with altered NFkB1 expression or function,” says Varjosalo.

“Also, our results yet again suggest that targeted inhibition of certain key NFkB signaling pathway components is an attractive therapeutic approach for treating these diseases which could be collectively paraphrased as diseases of NF-kB signaling”.

Original articles:


This research is basic research, which is the foundation of all scientific research at the university. Basic research is the study of the phenomenon or activity of something, and therefore increases scientific understanding of the subject. Basic research does not lead directly to an application in everyday life, but it can lead to a scientific breakthrough. 

CVI, a common variable immunodeficiency disease

Finland has the highest prevalence of CVI in the world. There are probably hundreds of carriers. In the capital area (7.7 : 100 000). And up to half of the CVI cases are caused by NFKB1 mutations.

CVI is very diverse, but follows the general pattern of congenital immune deficiencies. Patients typically present with recurrent invasive bacterial infections, prolonged or fluctuating lymphatic tissue hyperplasia, susceptibility to lymphoma, inflammatory diseases of various organs and often bronchiectasis. The most common inflammatory diseases are interstitial lung diseases, inflammatory bowel diseases and haematological autoimmune diseases. This study was able to identify which allelic variants are the key determinants of severe disease.

Rare diseases affect 300-500 million people globally.