Vulnerability to Meningococcal Disease in Immunodeficiency Due to a Novel Pathogenic Missense Variant in NFKB1

Anim, Manfred; Sogkas, Georgios; Schmidt, Gunnar; Dubrowinskaja, Natalia; Witte, Torsten; Schmidt, Reinhold; Atschekzei, Faranaz

doi:10.3389/fimmu.2021.767188

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…NF-κB1 gene polymorphism contributes to a spectrum of other diseases as well. Within a family afflicted by antibody deficiency, a detrimental missense variation in NF-κB1 (691 C>T, p.R230C) was identified, confirmed through Sanger sequencing, and predicted to have deleterious effects through computational analyses [82]. The single nucleotide polymorphism (SNP) rs4648068, a functionally significant site that significantly affects cell motility and proliferation, has been linked to the transcriptional activity of NF-B1.…”

Section: Other Diseasesmentioning

confidence: 96%

Exploring the Impact of NF- KB1 Gene Polymorphism

N K Lasitha,

Mahendra Jaideep,

Selvaraj J

et al. 2023

J. Adv. Zool.

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This review article extensively explores the influence of NF-κB1 gene polymorphism on a diverse range of health issues. The NF-κB pathway, a crucial controller of immune response, is closely associated with numerous disease mechanisms. The NF-kB1 gene has undergone significant genetic changes, and these changes have shown strong connections with the onset and development of numerous disorders. This article investigates the intricate relationship between mutations in the NF-kB1 gene and a wide range of disorders through a thorough study of the literature. These conditions encompass inflammatory disorders, cancer, cardiovascular diseases (CVD), and various other medical ailments. The notable discoveries emphasized within this review underscore the essential role of NF-κB1 gene polymorphism in the development of a range of diseases. Furthermore, these discoveries have important ramifications that could help develop more specialized, successful treatment approaches. To sum up, this work sheds light on the different ways in which NF-kB1 gene variation influences the progression of disorders and highlights the urgent need for more research in this area.

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Section: Other Diseasesmentioning

confidence: 96%

Exploring the Impact of NF- KB1 Gene Polymorphism

N K Lasitha,

Mahendra Jaideep,

Selvaraj J

et al. 2023

J. Adv. Zool.

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“…In the current study, we assessed 47 distinct N-terminal p50 missense alterations, including 39 variants from the Tuijnenburg and Lorenzini cohorts, four variants described elsewhere ( 6 – 8 , 10 , 11 , 18 , 24 – 28 ) and four previously uncharacterized variants. We found nine single amino acid substitutions within the Rel-homology domain causing protein-decaying defects.…”

Section: Introductionmentioning

confidence: 99%

Detrimental NFKB1 missense variants affecting the Rel-homology domain of p105/p50

et al. 2022

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Most of the currently known heterozygous pathogenic NFKB1 (Nuclear factor kappa B subunit 1) variants comprise deleterious defects such as severe truncations, internal deletions, and frameshift variants. Collectively, these represent the most frequent monogenic cause of common variable immunodeficiency (CVID) identified so far. NFKB1 encodes the transcription factor precursor p105 which undergoes limited proteasomal processing of its C-terminal half to generate the mature NF-κB subunit p50. Whereas p105/p50 haploinsufficiency due to devastating genetic damages and protein loss is a well-known disease mechanism, the pathogenic significance of numerous NFKB1 missense variants still remains uncertain and/or unexplored, due to the unavailability of accurate test procedures to confirm causality. In this study we functionally characterized 47 distinct missense variants residing within the N-terminal domains, thus affecting both proteins, the p105 precursor and the processed p50. Following transient overexpression of EGFP-fused mutant p105 and p50 in HEK293T cells, we used fluorescence microscopy, Western blotting, electrophoretic mobility shift assays (EMSA), and reporter assays to analyze their effects on subcellular localization, protein stability and precursor processing, DNA binding, and on the RelA-dependent target promoter activation, respectively. We found nine missense variants to cause harmful damage with intensified protein decay, while two variants left protein stability unaffected but caused a loss of the DNA-binding activity. Seven of the analyzed single amino acid changes caused ambiguous protein defects and four variants were associated with only minor adverse effects. For 25 variants, test results were indistinguishable from those of the wildtype controls, hence, their pathogenic impact remained elusive. In summary, we show that pathogenic missense variants affecting the Rel-homology domain may cause protein-decaying defects, thus resembling the disease-mechanisms of p105/p50 haploinsufficiency or may cause DNA-binding deficiency. However, rare variants (with a population frequency of less than 0.01%) with minor abnormalities or with neutral tests should still be considered as potentially pathogenic, until suitable tests have approved them being benign.

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