Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa
Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa
Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST1 gene cause the retinal dystrophies vitelliform macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP). The physiological function of bestrophin-1 remains poorly understood although its heterologous expression induces a Cl--specific current. We tested the effect of RP-causing variants on Cl- channel activity and cellular localization of bestrophin-1. Two (p.L140V and p.I205T) produced significantly decreased chloride-selective whole-cell currents in comparison to those of wild-type protein. In a model system of a polarized epithelium, two of three mutations (p.L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy.
581-592
Davidson, Alice E.
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Millar, Ian D.
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Urquhart, Jill E.
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Burgess-Mullan, Rosemary
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Shweikh, Yusrah
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Parry, Neil
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O'Sullivan, James
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Maher, Geoffrey J.
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McKibbin, Martin
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Downes, Susan M.
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Lotery, Andrew J.
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Jacobson, Samuel G.
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Brown, Peter D.
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Black, Graeme C.M.
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Manson, Forbes D.C.
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13 November 2009
Davidson, Alice E.
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Millar, Ian D.
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Urquhart, Jill E.
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Burgess-Mullan, Rosemary
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Shweikh, Yusrah
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Parry, Neil
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O'Sullivan, James
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Maher, Geoffrey J.
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McKibbin, Martin
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Downes, Susan M.
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Lotery, Andrew J.
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Jacobson, Samuel G.
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Brown, Peter D.
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Black, Graeme C.M.
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Manson, Forbes D.C.
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Davidson, Alice E., Millar, Ian D., Urquhart, Jill E., Burgess-Mullan, Rosemary, Shweikh, Yusrah, Parry, Neil, O'Sullivan, James, Maher, Geoffrey J., McKibbin, Martin, Downes, Susan M., Lotery, Andrew J., Jacobson, Samuel G., Brown, Peter D., Black, Graeme C.M. and Manson, Forbes D.C.
(2009)
Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.
American Journal of Human Genetics, 85 (5), .
(doi:10.1016/j.ajhg.2009.09.015.).
Abstract
Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST1 gene cause the retinal dystrophies vitelliform macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP). The physiological function of bestrophin-1 remains poorly understood although its heterologous expression induces a Cl--specific current. We tested the effect of RP-causing variants on Cl- channel activity and cellular localization of bestrophin-1. Two (p.L140V and p.I205T) produced significantly decreased chloride-selective whole-cell currents in comparison to those of wild-type protein. In a model system of a polarized epithelium, two of three mutations (p.L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy.
Text
Missense_Mutations_in_a_Retinal_Pigment_Epithelium_Protein,_Bestrophin-1,_Cause_Retinitis_Pigmentosa.pdf
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Published date: 13 November 2009
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Local EPrints ID: 73565
URI: http://eprints.soton.ac.uk/id/eprint/73565
ISSN: 0002-9297
PURE UUID: 6ff50a6d-9f49-4b8f-b56a-eca8351bbc0f
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Date deposited: 09 Mar 2010
Last modified: 14 Mar 2024 02:48
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Author:
Alice E. Davidson
Author:
Ian D. Millar
Author:
Jill E. Urquhart
Author:
Rosemary Burgess-Mullan
Author:
Yusrah Shweikh
Author:
Neil Parry
Author:
James O'Sullivan
Author:
Geoffrey J. Maher
Author:
Martin McKibbin
Author:
Susan M. Downes
Author:
Samuel G. Jacobson
Author:
Peter D. Brown
Author:
Graeme C.M. Black
Author:
Forbes D.C. Manson
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