A Novel De Novo NFKBIA missense mutation associated to ectodermal dysplasia with dysgammaglobulinemia

Document Type

Article

Publication Date

10-1-2022

Abstract

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 I kappa B alpha, a member of nuclear factor kappa B (NF-kappa B) inhibitors, playing an important role in regulating NF-kappa B activity. The mutation occurred at the six degrons (Asp31-Ser36) in I kappa B alpha 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 I kappa B alpha required for NF-kappa B activation. Conclusion: Our analysis hints that the post-translational modification in the NFKBIA Ser32Cys mutant would alter the signaling pathway of NF-kappa B. Our findings support the usefulness of WES in diagnosing IEIs and suggest the role of post-translational modification of I kappa B alpha.

Keywords

Hyper IgM-like phenotype, NFKBIA, I kappa B alpha, NF-kappa B, Post-translational modification

Divisions

Science

Funders

Ministry of Health Malaysia [NMRR-16-89231023] [NMRR-20-2387-56356]

Publication Title

Genes

Volume

13

Issue

10

Publisher

MDPI

Publisher Location

ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND

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