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J. B. Stanton, J. Wu, Y. Zhang, L. Y. Marmorstein, N. S. Peachey, A. D. Marmorstein; Altered pH and Ca2+ Homeostasis in Mice Harboring the W93C Mutation in Bestrophin-1: Implications for the Pathogenesis of the Bestrophinopathies. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6005.
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© ARVO (1962-2015); The Authors (2016-present)
To understand the pathogenesis of Best vitelliform macular dystrophy (BVMD) and other diseases caused by mutations in the gene BEST1 encoding the protein bestrophin-1 (Best1).
Knock-in mice carrying the mutation W93C in Best1 were generated. Mice were examined using conventional electroretinography (ERG) to follow rod and cone function. RPE generated ERG responses were recorded by dc-ERG. Histopathology was examined in mice up to 2 years of age. Changes in Ca2+ and pH were determined using the fluorescent reporters fura-2 and SNARF-1 respectively.
No differences in scotopic or photopic ERG responses were observed in Best1 knock-in mice compared to wild type. However, dc-ERG recordings revealed significant differences primarily in the LP component that was enhanced at low stimulus intensities and reduced in the middle of the intensity range (-1.0 to +1.0 log cd/m2) in Best1+/ki and Best1ki/ki mice. As a result, there was no modulation of LP amplitude across a 2-log unit intensity range where the wild type response demonstrates a marked increase. Neither Best1+/ki mice nor Best1ki/ki mice exhibited a maximum LP amplitude that was significantly diminished with respect to their wild type littermates. Postmortem analysis identified an increase in lipofuscin accumulation in the RPE of Best1+/ki and Best1ki/ki mice by 2 years of age. Examination of RPE explants identified changes in pH homeostasis and inhibition of the ATP-stimulated release of intracellular Ca2+ stores.
We conclude from this data that Best1+/ki and Best1ki/ki mice reproduce two key features of BVMD: a diminished EOG LP and lipofuscin accumulation in the RPE. Importantly this phenotype is associated with functional deficits in pH homeostasis and Ca2+ signaling, implying that BVMD does not result from a loss of Best1 Cl- channel activity, but a more general dysfunction in ion transport and homeostasis.
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