ArticleThe Journal of clinical investigation2019
Rescue of recurrent deep intronic mutation underlying cell type-dependent quantitative NEMO deficiency.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 52 citations in OpenAlex.
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- Revisiting X-linked agammaglobulinemia.Journal of human immunity · 2025Review
- Invention of an oral medication for cardiac Fabry disease caused by RNA mis-splicing.Science advances · 2025Article
- Reliable genetic diagnosis ofFrontiers in immunology · 2025Article
- Development of a biomarker signature associated with anoikis to predict prognosis and immunotherapy response in melanoma.Archives of dermatological research · 2024Article
- A deep intronic BTK variant underlies X-linked agammaglobulinemia.Journal of clinical immunology · 2024Article
- Cryptotanshinone is a candidate therapeutic agent for interstitial lung disease associated with a BRICHOS-domain mutation ofiScience · 2023Article
- PDIVAS: Pathogenicity predictor for Deep-Intronic Variants causing Aberrant Splicing.BMC genomics · 2023Article
- Branchpoints as potential targets of exon-skipping therapies for genetic disorders.Molecular therapy. Nucleic acids · 2023Article
- A multilocus approach for accurate variant calling in low-copy repeats using whole-genome sequencing.Bioinformatics (Oxford, England) · 2023Article
- The nexus between RNA-binding proteins and their effectors.Nature reviews. Genetics · 2023Review
- Critical Roles of NF-κB Signaling Molecules in Bone Metabolism Revealed by Genetic Mutations in Osteopetrosis.International journal of molecular sciences · 2022Review
- A novel risk model based on anoikis: Predicting prognosis and immune infiltration in cutaneous melanoma.Frontiers in pharmacology · 2022Article
- Hyper-IgE Syndrome due to an Elusive Novel Intronic Homozygous Variant in DOCK8.Journal of clinical immunology · 2022Article
- Induced Pluripotent Stem Cell-Derived Monocytes/Macrophages in Autoinflammatory Diseases.Frontiers in immunology · 2022Review
- Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance.The Journal of experimental medicine · 2021Article
- Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia.Nature communications · 2021Article
- EDA-ID: a Severe Clinical Presentation Associated with a New IKBKG Mutation.Journal of clinical immunology · 2021Article
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Authors and funding
28 authors at 7 institutions in 4 countries.
Funding
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.
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