Researchers have discovered dozens of genetic defects important for immune defense and relevant to patients with rare diseases

اكتشف الباحثون العشرات من العيوب الجينية المهمة للدفاع المناعي وذات الصلة بمرضى الأمراض النادرة

Missense variants analyzed in this study and domain structure of p105/p50 (upper panel) Amino acid changes localized to the N-terminal half of p105 affect both precursor and mature p50. blue, variants tested at p105 and p50; Black, variants tested in p50 only. The panel includes all p50 variants recorded in the Tuijnenburg and Lorenzini studies, except for R231H (underlined). The deleterious variant Y350C (23) has previously been described and is included as a model control. (Lower panel) Protein domain structure of the p105 precursor (long horizontal arrow) with the Rel-homology homology domain (RHD; red), glycine-rich region (GRR; blue), Ankyrin repeat domain (ANK; yellow) and death domain (DD, green) . Removal of the C-terminal half by limited proteolysis creates the mature transcription factor p50 subunit (short horizontal arrow). The numbers identify the positions of the amino acids. The nuclear localization sequence (NLS) locus is indicated by an arrow. attributed to him: Frontiers in Immunology (2022). DOI: 10.3389 / fimmu.2022.965326

Researchers from the Institute of Biotechnology at the University of Helsinki, who are pioneers in identifying patient-first mutations on the NFkB1 gene, collaborated with international clinicians to identify and characterize a large number of unreported NFKB1 variants on patients with immune-related diseases.

In many cases, identification of a patient’s genetic defect is of great importance in the treatment of patients with this defect. rare diseases. NFKB1, a transcription factor, causes changes in gene expression It is activated by stress and immune-related signaling pathways. Mutations in NFkB1 have been previously linked to common variable immunodeficiency (CVID).

Two new studies have been published in Frontiers in Immunology It may bring more relief to patients with hereditary genetic defects in their immune system.

“These studies have significantly expanded the associations of NFKB1 variants to immune system Dysfunction — links we first reported in 2017,” says Director of Research Marko Vargosalo of the University of Helsinki’s Institute of Biotechnology.

The researchers identified two variants of NFKB1 in two families with common variable immunodeficiency. Both specific NFKB1 variants reduced expression of the NFKB1 protein and led to altered gene expression and increased inflammatory response in the patient’s cells. Interaction analysis again showed a loss of interactions for one variable without the other.

Another group of investigators studied a group of 47 NFKB1 mutations previously reported in patients, of which 25 did not appear to behave differently from wild-type NFKB1. Another 22 mutations were found to have deleterious effects on NFKB1 which ranged from increased NFKB1 proteolysis, reduced DNA binding of NFKB1 to decreased overall NFKB1 function through alteration. Protein Structure: This may indicate its potential pathogenicity. NFKB1 تحليل Analysis alternative protein The interactions showed varying effects from loss of interaction with NFKB family proteins to some interactions of variants that appear similar to wild type NFKB1.

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

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

Researchers solved regulation of human transcription factor (TF)

more information:
Manfred Fliegauf et al, deleterious NFKB1 missense variants affecting the Rel-homology domain of p105/p50, Frontiers in Immunology (2022). DOI: 10.3389 / fimmu.2022.965326

Friedrich Stiles et al, Common variable immunodeficiency in two species with heterogeneous phenotypes caused by novel heterozygous NFKB1 mutations, Frontiers in Immunology (2022). DOI: 10.3389 / fimmu.2022.973543

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