Purchase this article with an account.
Scott H. Greenwald, James A. Kuchenbecker, Maureen Neitz, Jay Neitz; A Mouse Model of Cone Dystrophy Caused by a Toxic Opsin Variant. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4643.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Unequal meiotic recombination between the long (OPN1LW) and middle (OPN1MW) wavelength opsin genes have produced opsin variants that underlie vision disorders. One such variant, which we have designated LVAVA to denote the amino acids encoded at positions 153, 171, 174, 178, and 180, is associated with two distinct vision disorders. Males with LVAVA in one of the first two genes in the opsin array have a syndromic pathological high myopia (i.e. Bornholm eye disease), while those with only a single opsin gene with that one gene having LVAVA exhibit a cone dystrophy mediated by a specific opsin type. Results from humans with cone dystrophy associated with LVAVA opsin suggest that in younger eyes, cones with an LVAVA variant serve normal visual acuity; however, they progressively lose function and ultimately die. The purpose of the experiments reported is to create a mouse model in which to investigate the effects of the LVAVA variant on cone structure and function.
Two mouse lines were created in which the endogenous mouse Opn1mw gene was replaced with a human OPN1LW gene encoding either the LVAVA variant or a normal control variant designated LIAIS. Each of these lines was bred to UV opsin knockout (Opn1sw-/-) mice to create mice that have cones exclusively expressing either the LVAVA mutant or the LIAIS control opsin. A longitudinal study (over ~1 year) of cone function was conducted by recording intensity response functions for full field, photopic 1 Hz ON-OFF, electroretinograms from LVAVA Opn1sw-/- (n=15) and age-matched LIAIS Opn1sw-/- mice (n=10).
The progression of cone dysfunction is slow in the LVAVA mouse model as in human subjects with LVAVA associated cone-type specific mediated dystrophy. The LVAVA Opn1sw-/- mice show a ~40% reduction in the b-wave amplitude by 9 months of age, compared to the control mice (p<0.01).
We have created a mouse line that appears to be a good model of the physiological progression of cone-type specific mediated dystrophy observed in people expressing an LVAVA opsin. Results obtained so far indicate that the cone dystrophy is slow, suggesting that this condition in humans may be amendable to gene therapy. Continued evaluation of photoreceptor structure and function in this mouse model will further elucidate the mechanism of pathology in humans with the LVAVA variant.
This PDF is available to Subscribers Only