Androgen-dependent hereditary mouse keratoconus: linkage to an MHC region.
OBJECTIVE
To better understand the pathogenesis of hereditary keratoconus, an inbred line of spontaneous mutant mice with keratoconus-affected corneas (SKC mice) was established and studied with a multidisciplinary approach.


METHODS
Using a mutant mouse with corneas having a keratoconical appearance as the progenitor, an inbred line of SKC mouse was established by repeated sibling mating. Morphology, cell growth, apoptosis and protein expression of SKC mouse corneas were examined. Castration of males and androgen treatment for females were conducted to determine any androgen dependency of the phenotype. Linkage analysis was conducted to reveal the responsible or predisposing gene of SKC mouse keratoconus.


RESULTS
Corneas of the SKC mouse resemble those of human eyes with keratoconus. Both are conical and show similar corneal changes, including apoptosis of keratocytes and increased expression of c-fos protein. The SKC mouse phenotype was transmitted in an autosomal recessive manner, although it was observed almost exclusively in males. Intriguingly, female mice showed the phenotype when injected with testosterone, whereas male incidence of the phenotype diminished drastically when mice were castrated. Linkage analysis localized a predisposition locus to an MHC region on mouse chromosome 17, which includes a locus for the gene for sex-limited protein (Slp).


CONCLUSIONS
SKC mouse keratoconus is a potential model for a subset of human keratoconus, which is a disease entity with heterogeneous pathogeneses. Alternatively, SKC mouse keratoconus could be a model for other human or mouse-specific keratopathies.
Tachibana
Masayoshi
M
Saitama Cancer Center, Research Institute, Ina, Saitama, Japan. mtachiba@cance-c.pref.saitama.jp
Adachi
Wakako
W
Kinoshita
Shigeru
S
Kobayashi
Yasuhito
Y
Honma
Yoshio
Y
Hiai
Hiroshi
H
Matsushima
Yoshibumi
Y
D000818:Animals; D017209:Apoptosis; D001798:Blood Proteins / Q000235:genetics; D003181:Complement C4; D003315:Cornea / Q000378:metabolism / Q000473:pathology*; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D008040:Genetic Linkage; D007124:Immunoenzyme Techniques; D007640:Keratoconus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008855:Microscopy, Electron, Scanning; D009919:Orchiectomy; D010641:Phenotype; D013739:Testosterone / Q000502:physiology*
D001798:Blood Proteins; C018386:C4a protein, mouse; D003181:Complement C4; D013739:Testosterone; D004247:DNA