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Biallelic Mutation of BEST1 Causes a Distinct Retinopathy in Humans
Burgess, R, Millar, I, Leroy, B, Urquhart, JE, Fearon, I, De Baere, E, Brown, P, Robson, A, Wright, G, Kestelyn, P, Holder, G, Webster, A, Manson, FDC, Black, GCM
American journal of human genetics. 2008;82(1):19-31.
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Abstract
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.
Keyword(s)
Adolescent; Adult; Amino Acid Sequence; Cell Line; Child; Child, Preschool; Codon, Nonsense; Female; Genes, Recessive; Humans; Male; Molecular Sequence Data; Mutation, Missense; Transfection; chemistry: Chloride Channels; chemistry: Eye Proteins; genetics: Retinal Diseases