COG5 variants lead to complex early onset retinal degeneration, upregulation of PERK and DNA damage Journal Articles uri icon

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abstract

  • AbstractLeber congenital amaurosis (LCA), a form of autosomal recessive severe early-onset retinal degeneration, is an important cause of childhood blindness. This may be associated with systemic features or not. Here we identified COG5 compound-heterozygous variants in patients affected with a complex LCA phenotype associated with microcephaly and skeletal dysplasia. COG5 is a component of the COG complex, which facilitates retrograde Golgi trafficking; if disrupted this can result in protein misfolding. To date, variants in COG5 have been associated with a distinct congenital disorder of glycosylation (type IIi) and with a variant of Friedreich’s ataxia. We show that COG5 variants can also result in fragmentation of the Golgi apparatus and upregulation of the UPR modulator, PKR-like endoplasmic reticulum kinase (PERK). In addition, upregulation of PERK induces DNA damage in cultured cells and in murine retina. This study identifies a novel role for COG5 in maintaining ER protein homeostasis and that disruption of that role results in activation of PERK and early-onset retinal degeneration, microcephaly and skeletal dysplasia. These results also highlight the importance of the UPR pathway in early-onset retinal dystrophy and as potential therapeutic targets for patients.

authors

  • DiScipio, Matteo
  • Tabbarah, Sami
  • Tavares, Erika
  • Charish, Jason
  • Vincent, Ajoy
  • Paterson, Andrew
  • Di Scipio, Matteo
  • Yin, Yue
  • Mendoza-Londono, Roberto
  • Maynes, Jason
  • Heon, Elise
  • Monnier, Philippe P

publication date

  • December 4, 2020