Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia

Mayumi Yoshida, Naoyuki Kataoka, Kenjyo Miyauchi, Kenji Ohe, Kei Iida, Suguru Yoshida, Takayuki Nojima, Yukiko Okuno, Hiroshi Onogi, Tomomi Usui, Akihide Takeuchi, Takamitsu Hosoya, Tsutomu Suzuki, Masatoshi Hagiwara

Research output: Contribution to journalArticlepeer-review

83 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2764-2769
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
Publication statusPublished - Mar 3 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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