title: Corneal dystrophy-associated R124H mutation disrupts TGFBI interaction with Periostin and causes mislocalization to the lysosome.
abstract: The 5q31-linked corneal dystrophies are heterogeneous autosomal-dominant eye disorders pathologically characterized by the progressive accumulation of aggregated proteinaceous deposits in the cornea, which manifests clinically as severe vision impairment. The 5q31-linked corneal dystrophies are commonly caused by mutations in the TGFBI (transforming growth factor-beta-induced) gene. However, despite the identification of the culprit gene, the cellular roles of TGFBI and the molecular mechanisms underlying the pathogenesis of corneal dystrophy remain poorly understood. Here we report the identification of periostin, a molecule that is highly related to TGFBI, as a specific TGFBI-binding partner. The association of TGFBI and periostin is mediated by the amino-terminal cysteine-rich EMI domains of TGFBI and periostin. Our results indicate that the endogenous TGFBI and periostin colocalize within the trans-Golgi network and associate prior to secretion. The corneal dystrophy-associated R124H mutation in TGFBI severely impairs interaction with periostin in vivo. In addition, the R124H mutation causes aberrant redistribution of the mutant TGFBI into lysosomes. We also find that the periostin-TGFBI interaction is disrupted in corneal fibroblasts cultured from granular corneal dystrophy type II patients and that periostin accumulates in TGFBI-positive corneal deposits in granular corneal dystrophy type II (also known as Avellino corneal dystrophy). Together, our findings suggest that TGFBI and periostin may play cooperative cellular roles and that periostin may be involved in the pathogenesis of 5q31-linked corneal dystrophies.
authors.affiliation: Corneal Dystrophy Research Institute and Department of Ophthalmology, South Korea.
authors.forename: Bong-Yoon
authors.initials: BY
authors.lastname: Kim
authors.forename: James A
authors.initials: JA
authors.lastname: Olzmann
authors.forename: Seung-Il
authors.initials: SI
authors.lastname: Choi
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Ahn
authors.forename: Tae-Im
authors.initials: TI
authors.lastname: Kim
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Hwal
authors.initials: H
authors.lastname: Suh
authors.forename: Eung Kweon
authors.initials: EK
authors.lastname: Kim
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003315:Cornea / Q000166:cytology / Q000378:metabolism; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics / Q000473:pathology; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; C512835:POSTN protein, human; D011993:Recombinant Fusion Proteins; D053773:Transforming Growth Factor beta1; D049452:Green Fluorescent Proteins