Abstract
Leber 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.
Highlights
Severe retinal degeneration (RD) with early-onset and nystagmus is often referred to as Leber’s congenital amaurosis (LCA), which is a genetically heterogeneous form of inherited retinal disease (IRD)[1] for which gene-specific treatments have been initiated[2]
COG5 variants are associated with severe retinal degeneration, microcephaly and skeletal dysplasia
We identified two COG5 variants that when compounded act as a novel cause of complex LCA, for which we propose a potential mechanism whereby these variants promote photoreceptor dysfunction
Summary
Severe retinal degeneration (RD) with early-onset and nystagmus is often referred to as Leber’s congenital amaurosis (LCA), which is a genetically heterogeneous form of inherited retinal disease (IRD)[1] for which gene-specific treatments have been initiated[2]. At least 25 genes are associated with LCA, which accounts for ~ 80% of cases Given this genetic heterogeneity, there are numerous mechanisms underlying the resulting retinal degeneration, these disease mechanisms typically do not involve glycosylation a bnormalities[3]. There are no currently available treatments for any of the COG-CDGs. Disruption in glycosylation or Golgi trafficking due to dysfunctional COG subunits could lead to an aggregation of misfolded proteins causing ER stress and activation of the unfolded protein response (UPR). We demonstrate in vitro that expression of both COG5 variants resulted in the activation of the PERK branch of the UPR with an increase in Golgi fragmentation, and induction of DNA damage
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