Tcf4 CTG Repeat Expansion Induces RNA Toxicity and MBNL-Associated Splicing Dysregulation in a Mouse Model of Fuchs Endothelial Corneal Dystrophy.

Authors

Taichi Yuasa, Hayato Tsutsumi, Naoyuki Ueda, Itsuki Matsuoka, Daiya Nemoto, Suguru Ito, Ayaka Izumi, Yoshinori Oie, Motokazu Tsujikawa, Yuki Oyama, Masahito Ikawa, Noriko Koizumi, Naoki Okumura

Published in

Investigative ophthalmology & visual science. Volume 67. Issue 11. Pages 53. Sep 01, 2026.

Abstract

To determine whether a Tcf4 CTG repeat knock-in mouse model of Fuchs endothelial corneal dystrophy (FECD) recapitulates molecular features of repeat RNA toxicity and MBNL-associated splicing dysregulation in corneal endothelial cells in vivo.
Corneal endothelial tissues from 20-, 40-, and 60-week-old wild-type and Tcf4(CTG)100/(CTG)100 mice were examined by contact specular microscopy and CUG-repeat RNA FISH with MBNL1 immunostaining. At 60 weeks, we used RT-PCR, quantitative PCR, Western blotting, and RNA-Seq analysis to assess Mbnl autoregulatory splicing, genome-wide alternative splicing, RNA-binding protein motif enrichment, and Tcf4 isoform composition; selected splicing events were compared with human FECD data.
Tcf4(CTG)100/(CTG)100 mice showed neither obvious guttae-like abnormalities nor nuclear RNA foci at 20 weeks; both were detected at 40 and 60 weeks, whereas wild-type mice showed neither at any age. Foci-positive nuclei and RNA foci-MBNL1 colocalization did not differ between 40 and 60 weeks. Although Mbnl1 and Mbnl2 transcript levels and MBNL1 and MBNL2 protein levels were unchanged, Mbnl2 exon 6 inclusion was reduced. RNA-Seq reanalysis identified 645 differential alternative splicing events, predominantly skipped exons, with MBNL1 motif enrichment among events with increased exon skipping. Representative MBNL-regulated events were only partially conserved between the mouse model and human FECD. Total Tcf4 expression was unchanged, whereas Tcf4-225 was selectively upregulated.
This model provides in vivo evidence that Tcf4 CTG repeat expansion can induce molecular hallmarks of repeat RNA toxicity and downstream MBNL-associated splicing dysregulation, together with selective Tcf4 isoform alteration. It offers an in vivo platform for mechanistic and therapeutic studies.

PMID:
42813922
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.