title: Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia.
abstract: Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by missplicing of exon 20, resulting from an intronic mutation in the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene encoding IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1). A newly established splicing reporter assay allowed us to visualize pathogenic splicing in cells and to screen small chemicals for the ability to correct the aberrant splicing of IKBKAP. Using this splicing reporter, we screened our chemical libraries and identified a compound, rectifier of aberrant splicing (RECTAS), that rectifies the aberrant IKBKAP splicing in cells from patients with FD. Here, we found that the levels of modified uridine at the wobble position in cytoplasmic tRNAs are reduced in cells from patients with FD and that treatment with RECTAS increases the expression of IKAP and recovers the tRNA modifications. These findings suggest that the missplicing of IKBKAP results in reduced tRNA modifications in patients with FD and that RECTAS is a promising therapeutic drug candidate for FD.
authors: Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan;
authors: Mayumi
authors: M
authors: Yoshida
authors: Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; kataoka.naoyuki.6m@kyoto-u.ac.jp hagiwara.masatoshi.8c@kyoto-u.ac.jp.
authors: Naoyuki
authors: N
authors: Kataoka
authors: Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo 113-8510, Japan;
authors: Kenjyo
authors: K
authors: Miyauchi
authors: Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan;
authors: Kenji
authors: K
authors: Ohe
authors: Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Medical Research Support Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan;
authors: Kei
authors: K
authors: Iida
authors: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan;
authors: Suguru
authors: S
authors: Yoshida
authors: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom;
authors: Takayuki
authors: T
authors: Nojima
authors: Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Medical Research Support Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan;
authors: Yukiko
authors: Y
authors: Okuno
authors: Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; KinoPharma, Inc., Tokyo 154-0024, Japan; and.
authors: Hiroshi
authors: H
authors: Onogi
authors: Laboratory of Gene Expression, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Tomomi
authors: T
authors: Usui
authors: Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan;
authors: Akihide
authors: A
authors: Takeuchi
authors: Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan;
authors: Takamitsu
authors: T
authors: Hosoya
authors: Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo 113-8510, Japan;
authors: Tsutomu
authors: T
authors: Suzuki
authors: Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; kataoka.naoyuki.6m@kyoto-u.ac.jp hagiwara.masatoshi.8c@kyoto-u.ac.jp.
authors: Masatoshi
authors: M
authors: Hagiwara
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004402:Dysautonomia, Familial / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007438:Introns; D009154:Mutation; D012326:RNA Splicing / Q000187:drug effects* / Q000235:genetics; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D035602:Transcriptional Elongation Factors
chemical_list: D002352:Carrier Proteins; C114720:Elp1 protein, human; D006575:Heterocyclic Compounds, 3-Ring; D035602:Transcriptional Elongation Factors; D012343:RNA, Transfer
keywords: RNA disease; neurodegenerative disease; small molecules; splicing; tRNA modification