Suppression of Ca2+ signaling in a mouse model of Best disease

Youwen Zhang, J. Brett Stanton, Jiang Wu, Kuai Yu, H. Criss Hartzell, Neal S. Peachey, Lihua Y Marmorstein, Alan D Marmorstein

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Mutations in BEST1, encoding bestrophin-1 (Best1), cause Best vitelliform macular dystrophy (BVMD), a dominantly inherited macular degeneration characterized by a diminished electrooculogram light peak (LP), lipofuscin in retinal pigment epithelial cells (RPE), and fluid-and debris-filled retinal detachments. To understand the pathogenesis of BVMD we generated knock-in mice carrying the BVMD-causing mutation W93C in Best1. Both Best1+/W93Cand Best1W93C/W93C mice had normal ERG a- and b-waves, but exhibited an altered LP luminance response reminiscent of that observed in BVMD patients. Morphological analysis identified fluid-and debris-filled retinal detachments in mice as young as 6 months of age. By 18-24 months of age Best1+/W93Cand Best1W93C/W93C mice exhibited enhanced accumulation of lipofuscin in the RPE, and a significant deposition of debris composed of unphagocytosed photoreceptor outer segments and lipofuscin granules in the subretinal space. Although Best1 is thought to function as a Ca2+-activated Cl- channel, RPE cells from Best1W93C mice exhibited normal Cl- conductances. We have previously shown that Best1-/- mice exhibit increased [Ca2+]i in response to ATP stimulation. However, ATP-stimulated changes in [Ca2+]i in RPE cells from Best1+/W93C and Best1W93C/W93C mice were suppressed relative to Best1+/+ littermates. Based on these data we conclude that mice carrying the Best1W93C mutation are a valid model for BVMD. Furthermore, these data suggest that BVMD is not because of Best1 deficiency, as the phenotypes of Best1+/W93C and Best1W93C/W93C mice are distinct from that of Best1-/- mice with regard to lipofuscin accumulation, and changes in the LP and ATP Ca2+ responses. Published by Oxford University Press 2010.

Original languageEnglish (US)
Article numberddp583
Pages (from-to)1108-1118
Number of pages11
JournalHuman Molecular Genetics
Volume19
Issue number6
DOIs
StatePublished - Mar 2010
Externally publishedYes

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Vitelliform Macular Dystrophy
Lipofuscin
Retinal Pigments
Epithelial Cells
Adenosine Triphosphate
Retinal Detachment
Light
Mutation
Electrooculography
Macular Degeneration

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Zhang, Y., Stanton, J. B., Wu, J., Yu, K., Hartzell, H. C., Peachey, N. S., ... Marmorstein, A. D. (2010). Suppression of Ca2+ signaling in a mouse model of Best disease. Human Molecular Genetics, 19(6), 1108-1118. [ddp583]. https://doi.org/10.1093/hmg/ddp583

Suppression of Ca2+ signaling in a mouse model of Best disease. / Zhang, Youwen; Stanton, J. Brett; Wu, Jiang; Yu, Kuai; Hartzell, H. Criss; Peachey, Neal S.; Marmorstein, Lihua Y; Marmorstein, Alan D.

In: Human Molecular Genetics, Vol. 19, No. 6, ddp583, 03.2010, p. 1108-1118.

Research output: Contribution to journalArticle

Zhang, Y, Stanton, JB, Wu, J, Yu, K, Hartzell, HC, Peachey, NS, Marmorstein, LY & Marmorstein, AD 2010, 'Suppression of Ca2+ signaling in a mouse model of Best disease', Human Molecular Genetics, vol. 19, no. 6, ddp583, pp. 1108-1118. https://doi.org/10.1093/hmg/ddp583
Zhang Y, Stanton JB, Wu J, Yu K, Hartzell HC, Peachey NS et al. Suppression of Ca2+ signaling in a mouse model of Best disease. Human Molecular Genetics. 2010 Mar;19(6):1108-1118. ddp583. https://doi.org/10.1093/hmg/ddp583
Zhang, Youwen ; Stanton, J. Brett ; Wu, Jiang ; Yu, Kuai ; Hartzell, H. Criss ; Peachey, Neal S. ; Marmorstein, Lihua Y ; Marmorstein, Alan D. / Suppression of Ca2+ signaling in a mouse model of Best disease. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 6. pp. 1108-1118.
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abstract = "Mutations in BEST1, encoding bestrophin-1 (Best1), cause Best vitelliform macular dystrophy (BVMD), a dominantly inherited macular degeneration characterized by a diminished electrooculogram light peak (LP), lipofuscin in retinal pigment epithelial cells (RPE), and fluid-and debris-filled retinal detachments. To understand the pathogenesis of BVMD we generated knock-in mice carrying the BVMD-causing mutation W93C in Best1. Both Best1+/W93Cand Best1W93C/W93C mice had normal ERG a- and b-waves, but exhibited an altered LP luminance response reminiscent of that observed in BVMD patients. Morphological analysis identified fluid-and debris-filled retinal detachments in mice as young as 6 months of age. By 18-24 months of age Best1+/W93Cand Best1W93C/W93C mice exhibited enhanced accumulation of lipofuscin in the RPE, and a significant deposition of debris composed of unphagocytosed photoreceptor outer segments and lipofuscin granules in the subretinal space. Although Best1 is thought to function as a Ca2+-activated Cl- channel, RPE cells from Best1W93C mice exhibited normal Cl- conductances. We have previously shown that Best1-/- mice exhibit increased [Ca2+]i in response to ATP stimulation. However, ATP-stimulated changes in [Ca2+]i in RPE cells from Best1+/W93C and Best1W93C/W93C mice were suppressed relative to Best1+/+ littermates. Based on these data we conclude that mice carrying the Best1W93C mutation are a valid model for BVMD. Furthermore, these data suggest that BVMD is not because of Best1 deficiency, as the phenotypes of Best1+/W93C and Best1W93C/W93C mice are distinct from that of Best1-/- mice with regard to lipofuscin accumulation, and changes in the LP and ATP Ca2+ responses. Published by Oxford University Press 2010.",
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