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Rescue of recurrent deep intronic mutation underlying cell type–dependent quantitative NEMO deficiency
Bertrand Boisson, … , Masatoshi Hagiwara, Takahiro Yasumi
Bertrand Boisson, … , Masatoshi Hagiwara, Takahiro Yasumi
Published November 13, 2018
Citation Information: J Clin Invest. 2019;129(2):583-597. https://doi.org/10.1172/JCI124011.
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Research Article Genetics Infectious disease

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

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Abstract

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.

Authors

Bertrand Boisson, Yoshitaka Honda, Masahiko Ajiro, Jacinta Bustamante, Matthieu Bendavid, Andrew R. Gennery, Yuri Kawasaki, Jose Ichishima, Mitsujiro Osawa, Hiroshi Nihira, Takeshi Shiba, Takayuki Tanaka, Maya Chrabieh, Benedetta Bigio, Hong Hur, Yuval Itan, Yupu Liang, Satoshi Okada, Kazushi Izawa, Ryuta Nishikomori, Osamu Ohara, Toshio Heike, Laurent Abel, Anne Puel, Megumu K. Saito, Jean-Laurent Casanova, Masatoshi Hagiwara, Takahiro Yasumi

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Figure 3

Reanalysis of the IKBKG locus with 1kG Project data.

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Reanalysis of the IKBKG locus with 1kG Project data.
(A) Correlation bet...
(A) Correlation between the MAF of each variant in this study and the MAF reported in the 1kG Project. Plots show all the variants except for the IKBKG locus and the correlation for variants of FAM3 and GAB3, respectively. (B) Magnification of the IKBKG locus, for a comparison of the variants identified in this study (blue circles) with those reported in the various databases (red, orange, and green circles correspond to 1kG, ExAC, and ESP6500 databases, respectively). IKBKG exons are depicted by red bars and G6PD by gray bars.
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ISSN: 0021-9738 (print), 1558-8238 (online)

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