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J Clin Invest. 2019 Feb 1;129(2):583-597. doi: 10.1172/JCI124011. Epub 2018 Dec 18.

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

Author information

1
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.
2
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
3
Paris Descartes University, Imagine Institute, Paris, France.
4
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
5
Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
6
Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
7
Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
8
Institute of Cellular Medicine, Newcastle University and Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.
9
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
10
Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
11
The Charles Bronfman Institute for Personalized Medicine, and.
12
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
13
Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan.
14
Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
15
Kazusa DNA Research Institute, Kisarazu, Japan.
16
Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan.
17
Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
18
Howard Hughes Medical Institute (HHMI), New York, New York, USA.

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.

KEYWORDS:

Genetics; Infectious disease; Molecular diagnosis; NF-kappaB

PMID:
30422821
PMCID:
PMC6355244
DOI:
10.1172/JCI124011
[Indexed for MEDLINE]
Free PMC Article

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