International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)


I22. The First Mouse Model of Hereditary Keratoconus: Androgen Dependency and Mapping to a Locus in MHC

Masayoshi Tachibana1, Wakako Adachi2, Shigeru Kinoshita2, Yasuhito Kobayashi3, Yoshio Honma1, Hiroshi Hiai4, Yoshibumi Matsushima1
1Research Institute and 3Laboratory of Clinical Pathology, Saitama Cancer Center, 818 Komuro, Ina, Saitama 362-0806, Japan
2Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Sakyo-ku, Kyoto 606, Japan
4Department of Pathology and Biolgies of Diseases, Kyoto University Graduate School of Medicine, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606, Japan

Keratoconus is a vision-threatening corneal disease with an incidence of ~50 persons per 100,000. Although hereditary family and genetic predisposition have been reported, no responsible gene has been identified. This is partly due to the lack of animal models, so we established the first animal model of hereditary keratoconus, termed spontaneous keratoconus (SKC) mice, which develop keratoconus spontaneously in adolescence. The corneal phenotype of SKC mice resembles human keratoconus: SKC corneas are conical in shape and showed pathological changes similar to human keratoconus, e.g., apoptosis of keratocytes and their expression of matrix metalloproteinase 2 (MMP2) and c-fos protein. Although keratoconus of SKC mice is observed almost exclusively in males, breeding analyses revealed that the phenotype is transmitted in an autosomal recessive manner. Intriguingly, female SKC mice show keratoconus when injected with testosterone, and males do not show it when castrated. Because corneal cells of SKC mice express androgen receptor (AR), interaction of testosterone and AR may take place in these cells to exacerbate keratoconus. Linkage analysis mapped a locus to a Class II-III region of MHC on chromosome 17: homozygotes at this allelic site are associated with higher and earlier incidence of keratoconus (P<10-6). These data indicate keratoconus of SKC mice resembles of human keratoconus, is androgen dependent, and is genetically predisposed by a locus in MHC.


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