Cataractogenesis in transgenic mice containing the HIV-1 protease linked to the lens alpha A-crystallin promoter.
Several lines of transgenic mice were generated with either active or inactive forms of the human immunodeficiency virus type 1 (HIV-1) protease gene under the control of the mouse lens alpha A-crystallin promoter. Mice bearing the inactive protease coding sequence displayed no gross abnormalities in the lens, while mice with the active protease developed time-dependent bilateral cataracts. One line, TG61, developed cataracts in utero while the second line, TG72, developed cataracts postnatally. TG61 mice, homozygous for the transgene, developed severe microphthalmia and were significantly smaller than the control mice at postnatal day 30. two-dimensional-polyacrylamide gel electrophoresis analysis of the protein profiles of TG72 and TG61 lenses revealed extensive modifications in the lens crystallins. Proteolysis in the homozygous TG72 mouse lenses began at postnatal day 20 with the disappearance or partial loss of beta B1-, beta B3-, and beta A3-crystallins and the appearance of crystallin fragments. Protein leakage and the gradual breakdown of cytoskeletal elements also occurred. In contrast, the opacification of the homozygous TG61 lenses appeared to have been influenced by differentiation and developmental processes. It appears that HIV-1 protease expression activates other proteases, and these enzymes, in concert with HIV-1 protease, are responsible for the protein modifications that eventually result in the opacification of the lens.
Laboratory of Mechanisms of Ocular Diseases, National Eye Institute, National Institues of Health, Bethesda, Maryland 20892, USA.
S J
SJ
Tumminia
G J
GJ
Jonak
R J
RJ
Focht
Y S
YS
Cheng
P
P
Russell
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002386:Cataract / Q000209:etiology / Q000235:genetics*; D003459:Crystallins / Q000235:genetics*; D015180:Electrophoresis, Gel, Two-Dimensional; D016333:HIV Protease / Q000235:genetics*; D006720:Homozygote; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
D003459:Crystallins; D012333:RNA, Messenger; D016333:HIV Protease