Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia.

Ajiro, Masahiko, Awaya, Tomonari, Kim, Young Jin, Iida, Kei, Denawa, Masatsugu, Tanaka, Nobuo, Kurosawa, Ryo, Matsushima, Shingo, Shibata, Saiko, Sakamoto, Tetsunori, Studer, Rolenz, Krainer, Adrian R, Hagiwara, Masatoshi (July 2021) Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia. Nature Communications, 12 (1). p. 4507. ISSN 2041-1723

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DOI: 10.1038/s41467-021-24705-5


Approximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5' splice site due to the IVS20 + 6 T > C mutation. Knockdown experiments reveal that exon 20 inclusion is suppressed in the absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20. We show that RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation. Consistently, exon 20 splicing is bidirectionally manipulated by targeting cellular CLK activity with RECTAS versus CLK inhibitors. The therapeutic potential of RECTAS is validated in multiple FD disease models. Our study indicates that small synthetic molecules affecting phosphorylation state of SRSFs is available as a new therapeutic modality for mechanism-oriented precision medicine of splicing diseases.

Item Type: Paper
Subjects: diseases & disorders > congenital hereditary genetic diseases
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing
CSHL Authors:
Communities: CSHL labs > Krainer lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 23 July 2021
Date Deposited: 28 Jul 2021 14:08
Last Modified: 17 Aug 2021 13:07
PMCID: PMC8302731

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