Acquired and Innate Immunity Impairment and Severe Disseminated Mycobacterium genavense Infection in a Patient With a NF-κB1 Deficiency

González-Granado, Luis Ignacio; Ruiz‐García, Raquel; Blas-Espada, Javier; Moreno-Villares, José Manuel; Germán-Diaz, Marta; López-Nevado, Marta; Paz‐Artal, Estela; Toldos, Óscar; Rodriguez-Gil, Yolanda; Arocena, Jaime de Inocencio; Domínguez‐Pinilla, Nerea; Allende, Luís M.

doi:10.3389/fimmu.2018.03148

Cited by 17 publications

(12 citation statements)

References 29 publications

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“…Western blotting using isolated PBMCs has successfully been applied to confirm reduced levels of p105 and p50 associated with pathogenic truncating variants, precursor skipping variants and several missense variants ( 12 – 14 , 22 , 23 , 34 ). EBV-transformed B lymphocytes might be used as an alternative ( 12 , 14 ; Supplementary Figure 3 ), e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Variants in additional genes (not listed as "CVID genes" in OMIM), including BLK, CD27, CD70, CTLA4, IL21R, PIK3CD, PIK3R1, PLCG2, PRKCD, RAC2, TNFSF12 and VAV1 have also been associated with CVID (4,(8)(9)(10). Routine mutational analysis, particularly by next generation and whole exome sequencing, has recently enabled the identification of typically heterozygous NFKB1 and NFKB2 variants, which collectively account for the most frequent genetic cause in CVID (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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A Pathogenic Missense Variant in NFKB1 Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage

et al. 2021

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In common variable immunodeficiency (CVID), heterozygous damaging NFKB1 variants represent the most frequent monogenic cause. NFKB1 encodes the precursor p105, which undergoes proteasomal processing to generate the mature NF-κB transcription factor subunit p50. The majority of NFKB1 sequence changes comprises missense variants of uncertain significance (VUS), each requiring functional evaluation to assess causality, particularly in families with multiple affected members presenting with different phenotypes. In four affected members of a German family, all diagnosed with CVID, we identified a previously uncharacterized heterozygous NFKB1 missense variant (c.1049A>G; p.Tyr350Cys). The clinical phenotypes varied markedly regarding onset, frequency and severity of infections. Consistent immunologic findings were hypogammaglobulinemia with normal specific antibody response to protein- and polysaccharide-based vaccinations, reduced switched memory B cells and decreased lymphocyte proliferation upon stimulation with the B cell mitogen SAC. To assess the pathogenicity of the NFKB1 missense variant, we employed immunophenotyping and functional analyses in a routine in vitro cell culture model. Following site-directed mutagenesis to introduce the variant into overexpression vectors encoding EGFP-fused p105 or p50, we analyzed transiently transfected HEK293T cells by confocal imaging and Western blotting. The cytoplasmic p105-Tyr350Cys precursor gained only weak expression levels indicating accelerated decay. The missense change disabled processing of the precursor to prevent the generation of mutant p50. Unlike the wildtype p50, the overexpressed mutant p50-Tyr350Cys was also not sustainable and showed a conspicuous subnuclear mislocalization with accumulation in dense aggregates instead of a homogenous distribution. Electrophoretic mobility shift assays, fluorescence-based reporter gene analyses and co-transfection experiments however demonstrated, that the DNA-binding activity of p50-Tyr350Cys and the interaction with RelA(p65), IκBα and wildtype p50 were preserved. Mutation carriers had reduced p105 and p50 levels, indicating insufficient protein amounts as the most likely primary defect. In conclusion, the missense variant c.1049A>G caused a detrimental defect, preventing the persistent expression of both, the p105-Tyr350Cys precursor and the mature p50-Tyr350Cys. The variable clinical phenotypes among affected family members sharing an identical pathogenic NFKB1 variant support a disease mechanism provoked by a p105/p50 (haplo)insufficient condition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Pathogenic Missense Variant in NFKB1 Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage

et al. 2021

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“…For instance, although we analyze mutant proteins, the primary defect of exonic sequence variants might originate from splicing defects, rather than from amino acid changes. In fact, a recent report described a silent NFKB1 variant (c.705G>A) leading to activation of a cryptic splice site ( 33 ). Three of the single base-pair changes analyzed in our study are located within the first or last codon of the respective exon (c.115A>G, T39A; c.260T>G, I87S; c.406G>A, G136S) and could therefore possibly interfere with the consensus splice sites.…”

Section: Discussionmentioning

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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“…[47][48][49] Rapid WGS at neonatal ICU admission may have been followed by CVID12 diagnosis and treatment with intravenous immunoglobulin and promptly administered broad-spectrum antibiotics. [47][48][49] Infant 183 died of cardiac arrest on DOL 123. CACNA1C long QT syndrome 8 (LQT8; MIM#618447) was identified postmortem.…”

Section: Jama Network Open | Pediatricsmentioning

confidence: 99%

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

et al. 2023

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ImportanceUnderstanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, Setting, and ParticipantsThis cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main Outcomes and MeasuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission.Conclusions and RelevanceIn this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.

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Acquired and Innate Immunity Impairment and Severe Disseminated Mycobacterium genavense Infection in a Patient With a NF-κB1 Deficiency

Cited by 17 publications

References 29 publications

A Pathogenic Missense Variant in NFKB1 Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage

A Pathogenic Missense Variant in NFKB1 Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage

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

Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

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