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Rescue of recurrent deep intronic mutation underlying cell type–dependent quantitative NEMO deficiency

Lookup NU author(s): Professor Andrew GenneryORCiD



This is the final published version of an article that has been published in its final definitive form by American Society for Clinical Investigation, 2019.

For re-use rights please refer to the publisher's terms and conditions.


© 2018 American Society for Clinical Investigation.All right reserved. X-linked dominant incontinentia pigmenti (IP) and X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) are caused by loss-of-function and hypomorphic IKBKG (also known as NEMO) mutations, respectively. We describe a European mother with mild IP and a Japanese mother without IP, whose 3 boys with EDA-ID died from ID. We identify the same private variant in an intron of IKBKG, IVS4+866 C>T, which was inherited from and occurred de novo in the European mother and Japanese mother, respectively. This mutation creates a new splicing donor site, giving rise to a 44-nucleotide pseudoexon (PE) generating a frameshift. Its leakiness accounts for NF-κB activation being impaired but not abolished in the boys’ cells. However, aberrant splicing rates differ between cell types, with WT NEMO mRNA and protein levels ranging from barely detectable in leukocytes to residual amounts in induced pluripotent stem cell–derived (iPSC-derived) macrophages, and higher levels in fibroblasts and iPSC-derived neuronal precursor cells. Finally, SRSF6 binds to the PE, facilitating its inclusion. Moreover, SRSF6 knockdown or CLK inhibition restores WT NEMO expression and function in mutant cells. A recurrent deep intronic splicing mutation in IKBKG underlies a purely quantitative NEMO defect in males that is most severe in leukocytes and can be rescued by the inhibition of SRSF6 or CLK.

Publication metadata

Author(s): Boisson B, Honda Y, Ajiro M, Bustamante J, Bendavid M, Gennery AR, Kawasaki Y, Ichishima J, Osawa M, Nihira H, Shiba T, Tanaka T, Chrabieh M, Bigio B, Hur H, Itan Y, Liang Y, Okada S, Izawa K, Nishikomori R, Ohara O, Heike T, Abel L, Puel A, Saito MK, Casanova J-L, Hagiwara M, Yasumi T

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2019

Volume: 129

Issue: 2

Pages: 583-597

Print publication date: 01/02/2019

Online publication date: 13/11/2018

Acceptance date: 08/11/2018

Date deposited: 30/03/2020

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI124011

PubMed id: 30422821


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