title: Involvement of TGF-{beta} receptor- and integrin-mediated signaling pathways in the pathogenesis of granular corneal dystrophy II.
abstract: Purpose. The purpose of this study was to elucidate the pathophysiological process in primary cultured corneal fibroblasts (PCFs) from normal subjects and granular corneal dystrophy (GCD) II patients, by using cDNA microarrays. Methods. PCFs were isolated from the corneas of normal subjects and GCD II patients who were heterozygous and homozygous for the TGFBI R124H mutation. RNA was isolated from each sample, and gene expression profiles were analyzed with a cDNA microarray consisting of approximately 29,000 genes. Cell adhesion assays were performed to confirm the functionality of the detected gene expression profiles. Results. Twofold differences were detected in the expression of 555 genes between wild-type and homozygous GCD II PCFs. Of these, 319 genes were upregulated, and 236 genes were downregulated in the homozygous GCD II PCFs. The most abundant and consistent changes were observed in gene families encoding signal transduction pathways involving the TGF-beta receptor- and integrin-mediated signaling, cell differentiation and proliferation, immune responses, cell adhesion, extracellular matrix (ECM) proteolytic enzymes, cell cycle, cytoskeletal organization, mitochondrial energy metabolism, collagen catabolism, response to wounding, response to oxidative stress, and the ubiquitin-mediated proteasomal degradation pathway. Cell adhesion assays demonstrated that heterozygous and homozygous GCD II PCFs strongly attached to collagen-I, collagen-IV, fibronectin, and laminin, compared with wild-type cells. Conclusions. Alterations in the TGF-beta receptor- and integrin-mediated signaling pathway may play a key role in GCD II pathophysiology. If the novel factors identified in this study are involved in GCD II pathogenesis, they could assist in designing further studies to elucidate specific mechanisms of this disease.
authors.affiliation: Corneal Dystrophy Research Institute, Department of Ophthalmology, College of Medicine, Yonsei University, Seoul, Korea.
authors.forename: Seung-Il
authors.initials: SI
authors.lastname: Choi
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Yoo
authors.forename: Bong-Yoon
authors.initials: BY
authors.lastname: Kim
authors.forename: Tae-Im
authors.initials: TI
authors.lastname: Kim
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Cho
authors.forename: So-Yoen
authors.initials: SY
authors.lastname: Ahn
authors.forename: Hyung Keun
authors.initials: HK
authors.lastname: Lee
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Eung Kweon
authors.initials: EK
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D003317:Corneal Dystrophies, Hereditary / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D055815:Young Adult; D000099222:betaIG-H3 Protein
chemical_list: D024042:Collagen Type I; D024141:Collagen Type IV; D016326:Extracellular Matrix Proteins; D016023:Integrins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein