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J. B. Stanton, J. Wu, P. J. McLaughlin, L. Y. Marmorstein, N. Peachey, A. D. Marmorstein; A Comparison of the Phenotypes of Bestrophin Knock-In and Knock-Out Mice: Implications for the Pathogenesis of Best Vitelliform Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5188.
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© ARVO (1962-2015); The Authors (2016-present)
To elucidate the physiological role of bestrophin-1 (Best1) in the retinal pigment epithelium (RPE) and its relationship to the light peak (LP) of the electrooculogram (EOG).
We have previously reported the generation and characteristics of Best1-/- mice (J. Gen. Physiol. 127(5):577-589, 2006). Knock-in mice carrying the mutation W93C were generated. Mice were examined using conventional electroretinography (ERG) to follow rod and cone function. RPE generated ERG responses were recorded by dc-ERG.
No differences in scotopic or photopic ERG responses were observed in Best1-/- or Best1 knock-in mice compared to Best1+/+ littermates. However, dc-ERG recordings revealed significant differences primarily in the LP component in comparison to wild type as well as between knockout and knock-in mice: LP responses of Best1+/ki and Best1ki/ki mice were enhanced at low stimulus intensities, and reduced in the middle of the intensity range. As a result, there was no modulation of LP amplitude across a 2-log unit intensity range (-1.0 to +1.0 log cd/m2) where the wild type response demonstrates a marked increase. In this intensity range, the Best1+/ki and Best1ki/ki mice also differ from Best1-/- mice, whose response is also modulated by stimulus intensity but is consistently greater than that of wild type mice. Analysis of the variance in LP luminance response functions amongst Knock-in, Knock-out, and wild type mice using ANOVA indicates significant differences between genotypes. Interestingly, neither Best1+/ki mice nor Best1ki/ki mice exhibited a maximum LP amplitude that was significantly diminished with respect to their wild type littermates.
We conclude from this data that Best1+/ki and Best1ki/ki mice reproduce the sole fully penetrant symptom of BVMD, a diminished EOG LP. This is not likely due to a loss of Best1 function as the Best1-/- mice exhibit exactly the opposite effect of the knock-in mice. Based on these data we hypothesize that the diminished LP in human BVMD patients is due to a shift in the luminance-response function, a feature of the EOG that is not routinely examined.
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