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

Chear, Chai Teng and El Farran, Bader Abdul Kader and Sham, Marina and Ramalingam, Kavetha and Noh, Lokman Mohd and Ismail, Intan Hakimah and Chiow, Mei Yee and Baharin, Mohd Farid and Ripen, Adiratna Mat and Mohamad, Saharuddin (2022) A Novel De Novo NFKBIA missense mutation associated to ectodermal dysplasia with dysgammaglobulinemia. Genes, 13 (10). ISSN 2073-4425, DOI https://doi.org/10.3390/genes13101900.

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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.

Item Type: Article
Funders: Ministry of Health Malaysia [NMRR-16-89231023] [NMRR-20-2387-56356]
Uncontrolled Keywords: Hyper IgM-like phenotype; NFKBIA; I kappa B alpha; NF-kappa B; Post-translational modification
Subjects: Q Science > Q Science (General)
R Medicine
Divisions: Faculty of Science
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 26 Sep 2023 07:00
Last Modified: 26 Sep 2023 07:00
URI: http://eprints.um.edu.my/id/eprint/40841

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