Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Edwin H A Allen
  • ,
  • David G Courtney
  • ,
  • Sarah D Atkinson
  • ,
  • Johnny E Moore
  • ,
  • Laura Mairs
  • ,
  • Ebbe Toftgaard Poulsen
  • Davide Schiroli
  • ,
  • Eleonora Maurizi
  • ,
  • Christian Cole
  • ,
  • Robyn P Hickerson
  • ,
  • John James
  • ,
  • Helen Murgatroyd
  • ,
  • Francis J D Smith
  • ,
  • Carrie MacEwen
  • ,
  • Jan J Enghild
  • M Andrew Nesbit
  • ,
  • Deena M Leslie Pedrioli
  • ,
  • W H Irwin McLean
  • ,
  • C B Tara Moore

Meesmann epithelial corneal dystrophy (MECD) is a rare autosomal dominant disorder caused by dominant-negative mutations within the KRT3 or KRT12 genes, which encode the cytoskeletal proteins keratin K3 and K12, respectively. To investigate the pathomechanism of this disease we generated and phenotypically characterized a novel knock-in humanised mouse model carrying the severe, MECD-associated, K12-Leu132Pro mutation.Although no overt changes in corneal opacity were detected by slit-lamp examination, the corneas of homozygous mutant mice exhibited histological and ultrastructural epithelial cell fragility phenotypes. An altered keratin expression profile was observed in the cornea of mutant mice, confirmed by Western blot, RNA-seq and qRT-PCR. Mass spectrometry and immunohistochemistry demonstrated a similarly altered keratin profile in corneal tissue from a K12-Leu132Pro MECD patient.The K12-Leu132Pro mutation results in cytoplasmic keratin aggregates. RNA-seq analysis revealed increased chaperone gene expression, while apoptotic unfolded protein response (UPR) markers, CHOP and Caspase 12, were also increased in the MECD mice. Corneal epithelial cell apoptosis was increased 17-fold in the mutant cornea, compared to the wild-type (p<0.001). This elevation of UPR marker expression was also observed in the human MECD cornea.This is the first reporting of a mouse model for MECD that recapitulates the human disease, and is a valuable resource in understanding the pathomechanism of the disease. While the most severe phenotype is observed in the homozygous mice, this model will still provide a test-bed for therapies not only for corneal dystrophies but also for other keratinopathies caused by similar mutations.

Original languageEnglish
JournalHuman Molecular Genetics
Volume25
Issue6
Pages (from-to)1176-1191
Number of pages16
ISSN0964-6906
DOIs
Publication statusPublished - 11 Jan 2016

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