A novel inhibitor of nuclear factor kappa-B kinase subunit gamma mutation identified in an incontinentia pigmenti patient with syndromic tooth agenesis.

OBJECTIVE: To explore the gene mutation in an incontinentia pigmenti (IP) patient with syndromic tooth agenesis. METHODS: Long-range polymerase chain reaction (PCR) and Sanger sequencing were used to detect inhibitor of nuclear factor kappa-B kinase subunit gamma (IKBKG) mutation in the IP patient. We used the nuclear factor kappa B (NF-kappaB) reporter gene to assess activation of NF-kappaB, after transfecting an empty vector, wild-type, or mutant NF-kappaB essential modulator (NEMO) plasmid into IKBKG-deficient HEK293T cells, respectively. Furthermore, we performed immunoprecipitation and immunoblotting to describe the polyubiquitination of NEMO. Lastly, we detected the interactions between mutant NEMO and I kappa B kinase alpha (IKKalpha), I kappa B kinase beta (IKKbeta), TNF receptor associated factor 6 (TRAF6), HOIL-1-interacting protein (HOIP), hemo-oxidized iron regulatory protein 2 ligase 1 (HOIL-1), and SHANK-associated RH domain interactor (SHARPIN). RESULTS: A de novo nonsense mutation in IKBKG (c.924C > G; p.Tyr308*) was observed. The Tyr308* mutation inhibited activation of the NF-kappaB pathway by reducing K63-linked polyubiquitination and linear polyubiquitination. The mutant NEMO was not able to interact with TRAF6, HOIL-1, or SHARPIN. CONCLUSIONS: We identified a novel nonsense IKBKG mutation (c.924C > G; p.Tyr308*) in an IP patient with syndromic tooth agenesis. This research enriches the mutation spectrum of the IKBKG gene.