Nuclear factor κB mutations in human subjects: The devil is in the details

• Published in: Journal of allergy and clinical immunology Vol. 142; no. 4; pp. 1062 - 1065
• Main Authors: Fliegauf, Manfred, Grimbacher, Bodo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2018; Elsevier Limited
• Subjects: Bacterial infections; Common Variable Immunodeficiency; Defects; Deoxyribonucleic acid; Dimerization; DNA; Frameshift mutation; Gene regulation; Genes; Human subjects; Humans; Immune system; Localization; Mutation; NF-kappa B - genetics; NF-kappa B p50 Subunit; NF-κB protein; NFKB1; nuclear factor κB signaling; p50 Protein; Patients; Phenotypes; primary immunodeficiency disease; Proteasomes; Proteins; Signal transduction; Transcription; primary immunodeficiency disease; common variable immunodeficiency; NFKB1; nuclear factor κB signaling
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.06.050

Numerous stimuli can activate p50-containing dimers, which subsequently enter the nucleus and regulate expression of a number of target genes, thereby controlling multiple cellular functions of both the innate and adaptive immune system. [...]nuclear entry and target gene activation are nonautonomous functions of p50 and are dependent on degradation of the inhibitor in response to various stimuli and dimerization with p65, respectively. Three of the variants in the high-effect category comprise frameshift mutations that predict the expression of mutant p50 proteins (with C-terminal extensions compared with p50), thus skipping the precursor stage. Because these mutations typically retain the nuclear localization sequence, the mutant p50-like proteins could potentially enter the nucleus and interfere with target gene regulation (eg, by assembling repressive homodimers or defective or constitutively active heterodimers) if they resist proteasomal degradation. [...]Tuijnenburg et al2 predict a reduced abundance caused by protein destabilization as the main loss-of-function defect for their identified variants. Because the NF-κB signaling pathway plays a central role in many cellular signaling processes, defects leading to immune dysregulation phenotypes might be expected to originate from subtle rather than severely deleterious protein defects. Analyzing IκBα degradation as a surrogate marker for canonical NF-κB signaling activity is clearly not exhaustive because this approach will not uncover mutations that impair nuclear p50 functions, such as translocation, DNA binding, or transcriptional regulation. [...]highly sensitive detection methods might be required, because NFKB1 mutations typically are heterozygous, and due to the presence of wild-type proteins expressed from the nonmutant allele, devastating damage is rather unlikely.