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Structural Abnormalities of the Cornea and Lid Resulting from Collagen V Mutations

¹From the Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada; the ²Department of Ophthalmology, Toronto Western Hospital, Toronto, Ontario, Canada; ³The Genetics and Genomic Biology Program, The Hospital for Sick Children Research Institute, ⁴Division of Orthopedic Surgery, Department of Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; the ⁵Division of Human Genetics, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio; the ⁶Departments of Pathology, Anatomy, and Cell Biology, and ⁷Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.

PURPOSE. Type V collagen forms heterotypic fibrils with type I collagen and accounts for 10% to 20% of corneal collagen. The purpose of this study was to define the ocular phenotype resulting from mutations in the type V collagen genes COL5A1 and COL5A2 and to study the pathogenesis of anomalies in a Col5a1-deficient mouse.

METHODS. Seven patients with classic Ehlers-Danlos syndrome (EDS) due to COL5A1 haploinsufficiency and one with an exon-skipping mutation in COL5A2 underwent an ocular examination, corneal topography, pachymetry, and specular microscopy. A Col5a1-haploinsufficient mouse model of classic EDS was used for biochemical and immunochemical analyses of corneas. Light and electron microscopy were used to quantify stromal thickness, fibril density, fibril structure, and diameter.

RESULTS. Five males and three females (mean age, 26 ± 13.57 years; range, 11–52) were studied. All patients had "floppy eyelids." The corneas of all eyes were thinner (mean corneal thickness: 435.75 ± 12.51 µm) when compared with control corneas (568.89 ± 28.46 µm; P < 0.0001). In the Col5a1^+/– mouse cornea, type V collagen content was reduced by 49%, and stromal thickness was reduced by 26%. Total collagen deposition in Col5a1^+/– corneas also was reduced. Collagen fibril diameters were increased, but fibril density was decreased throughout the stroma at all developmental stages.

CONCLUSIONS. In the eye, COL5A1 and COL5A2 mutations manifest as abnormally thin and steep corneas with floppy eyelids. Mechanisms involved in producing the latter anomalies probably involve altered regulation of collagen fibrillogenesis due to abnormalities in heterotypic type I/V collagen interactions similar to those observed in the Col5a1^+/– mouse cornea.

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