Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 1, 19-31, 10 January 2008
doi:10.1016/j.ajhg.2007.08.004
Article
Biallelic Mutation of BEST1 Causes a Distinct Retinopathy in Humans
Rosemary Burgess1, 8, Ian D. Millar2, Bart P. Leroy3, 4, Jill E. Urquhart1, 8, Ian M. Fearon2, Elfrida De Baere4, Peter D. Brown2, Anthony G. Robson5, 6, Genevieve A. Wright5, Philippe Kestelyn3, Graham E. Holder5, 6, Andrew R. Webster5, 6, Forbes D.C. Manson1, 7, 8 and Graeme C.M. Black1, 7, 8, 
, 
1 Academic Unit of Medical Genetics and Regional Genetics Service, St. Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK
2 Faculty of Life Sciences, Core Technology Facility, University of Manchester, Manchester M13 9NT, UK
3 Department of Ophthalmology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
4 Centre for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
5 Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, UK
6 UCL Institute of Ophthalmology, University College of London, 11-43 Bath Street, London EC1V 9EL, UK
7 Academic Department of Ophthalmology, Manchester Royal Eye Hospital, Oxford Road, Manchester, M13 9WH, UK
8 Centre for Molecular Medicine, Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
Corresponding authorAbstract
We describe a distinct retinal disorder, autosomal-recessive bestrophinopathy (ARB), that is consequent upon biallelic mutation in BEST1 and is associated with central visual loss, a characteristic retinopathy, an absent electro-oculogram light rise, and a reduced electroretinogram. Heterozygous mutations in BEST1 have previously been found to cause the two dominantly inherited disorders, Best macular dystrophy and autosomal-dominant vitreoretinochoroidopathy. The transmembrane protein bestrophin-1, encoded by BEST1, is located at the basolateral membrane of the retinal pigment epithelium in which it probably functions as a Cl− channel. We sequenced BEST1 in five families, identifying DNA variants in each of ten alleles. These encoded six different missense variants and one nonsense variant. The alleles segregated appropriately for a recessive disorder in each family. No clinical or electrophysiological abnormalities were identified in any heterozygotes. We conducted whole-cell patch-clamping of HEK293 cells transfected with bestrophin-1 to measure the Cl− current. Two ARB missense isoforms severely reduced channel activity. However, unlike two other alleles previously associated with Best disease, cotransfection with wild-type bestrophin-1 did not impair the formation of active wild-type bestrophin-1 channels, consistent with the recessive nature of the condition. We propose that ARB is the null phenotype of bestrophin-1 in humans.
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