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

Abstract

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.

Genetic analysis and characterization of reproductive control genes in Belgian and Qinchuan cattle population structure

“…Inhibition of IKBA phosphorylation signi cantly enhances sperm motility [20]. Mutations in the NFKBIA gene result in bracketed ectodermal dysplasia [21] So the expression of NFKBIA gene may affect the reproductive performance of the population (Fig. 5).…”

Compound heterozygous WNT10A missense variations exacerbated the tooth agenesis caused by hypohidrotic ectodermal dysplasia

“…Compared to HED cases caused by EDA variations, the clinical phenotype of HED caused by WNT10A variations is milder, exhibiting abnormal hair and sweat glands but no facial deformities [ 18 ]. And the remaining 10% of hypohidrotic/anhidrotic ED cases caused by rarer genetic variations, such as NFKBIA [ 24 – 26 ], and NEMO / IKBKG [ 27 – 29 ]. However, the molecular mechanisms and signalling pathways underlying HED with WNT10A variations have not been fully elucidated and the correlation between the number and location of missing teeth in HED and the pathogenic genes has not yet been fully elucidated.…”