A Novel De Novo NFKBIA Missense Mutation Associated to Ectodermal Dysplasia with Dysgammaglobulinemia

• Published in: Genes Vol. 13; no. 10; p. 1900
• Main Authors: Chear, Chai Teng, El Farran, Bader Abdul Kader, Sham, Marina, Ramalingam, Kavetha, Noh, Lokman Mohd, Ismail, Intan Hakimah, Chiow, Mei Yee, Baharin, Mohd Farid, Ripen, Adiratna Mat, Mohamad, Saharuddin Bin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.10.2022; MDPI
• Subjects: Bioinformatics; DNA methylation; Dysgammaglobulinemia; Dysplasia; Ectodermal Dysplasia - genetics; Exocrine glands; Genetic disorders; Genomes; Genotype & phenotype; Humans; Hyper-IgM Immunodeficiency Syndrome; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; Immune response; Immunoglobulin M; Immunoglobulins; Immunologic Deficiency Syndromes; Immunology; Kinases; Ligands; Missense mutation; Mutation; Mutation, Missense; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - genetics; NF-κB protein; Patients; Phenotypes; Phosphorylation; Pneumonia; Post-translation; Proteins; Sepsis; Signal transduction; SUMO protein; Translation; United States > US; NFKBIA; NF-κB; post-translational modification; IκBα; hyper IgM-like phenotype
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes13101900

Background: Inborn errors of immunity (IEIs) are comprised of heterogeneous groups of genetic disorders affecting immune function. In this report, a 17-month-old Malay patient suspected of having Hyper IgM syndrome, a type of IEIs, was described. However, the diagnosis of Hyper IgM syndrome was excluded by the normal functional studies and the mild features of ectodermal dysplasia observed from a further clinical phenotype inspection. Methods: Whole-exome sequencing (WES) was performed to unravel the causative mutation in this patient. Results: The variant analysis demonstrated a novel missense mutation in NFKBIA (NM_020529:c.94A > T,NP_065390:p.Ser32Cys) and was predicted as damaging by in silico prediction tools. The NFKBIA gene encodes for IκBα, a member of nuclear factor kappa B (NF-κB) inhibitors, playing an important role in regulating NF-κB activity. The mutation occurred at the six degrons (Asp31-Ser36) in IκBα which were evolutionarily conserved across several species. Prediction analysis suggested that the substitution of Ser32Cys may cause a loss of the phosphorylation site at residue 32 and a gain of the sumoylation site at residue 38, resulting in the alteration of post-translational modifications of IκBα required for NF-κB activation. Conclusion: Our analysis hints that the post-translational modification in the NFKBIA Ser32Cys mutant would alter the signaling pathway of NF-κB. Our findings support the usefulness of WES in diagnosing IEIs and suggest the role of post-translational modification of IκBα.