title: Intracellularly-retained decorin lacking the C-terminal ear repeat causes ER stress: a cell-based etiological mechanism for congenital stromal corneal dystrophy.
abstract: Decorin, a small leucine-rich proteoglycan (SLRP), is involved in the pathophysiology of human congenital stromal corneal dystrophy (CSCD). This disease is characterized by corneal opacities and vision impairment. In reported cases, the human gene encoding decorin contains point mutations in exon 10, generating a truncated form of decorin lacking the C-terminal 33 amino acid residues. We have previously described a transgenic mouse model carrying a similar mutation in the decorin gene that leads to an ocular phenotype characterized by corneal opacities identical to CSCD in humans. We have also identified abnormal synthesis and secretion of various SLRPs in mutant mouse corneas. In the present study, we found that mutant C-terminal truncated decorin was retained in the cytoplasm of mouse keratocytes in vivo and of transfected human embryonic kidney cells. This resulted in endoplasmic reticulum stress and an unfolded protein response. Thus, we propose a novel cell-based mechanism underlying CSCD in which a truncated SLRP protein core is retained intracellularly, its accumulation triggering endoplasmic reticulum stress that results in abnormal SLRP synthesis and secretion, which ultimately affects stromal structure and corneal transparency.
authors.affiliation: Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612-4799, USA.
authors.forename: Shoujun
authors.initials: S
authors.lastname: Chen
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
mesh_terms: D000818:Animals; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000378:metabolism; D058575:Decorin / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005819:Genetic Markers; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D021381:Protein Transport; D013312:Stress, Physiological; D020079:Terminal Repeat Sequences
chemical_list: C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D005819:Genetic Markers