title: Biallelic mutation of BEST1 causes a distinct retinopathy in humans.
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.
authors.affiliation: Academic Unit of Medical Genetics and Regional Genetics Service, St. Mary's Hospital, Hathersage Road, Manchester M13 0JH, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burgess
authors.forename: Ian D
authors.initials: ID
authors.lastname: Millar
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.forename: Ian M
authors.initials: IM
authors.lastname: Fearon
authors.forename: Elfrida
authors.initials: E
authors.lastname: De Baere
authors.forename: Peter D
authors.initials: PD
authors.lastname: Brown
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Wright
authors.forename: Philippe
authors.initials: P
authors.lastname: Kestelyn
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.forename: Forbes D C
authors.initials: FD
authors.lastname: Manson
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Black
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000075002:Bestrophins; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics*; D018389:Codon, Nonsense; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012164:Retinal Diseases / Q000235:genetics*; D014162:Transfection
chemical_list: C113133:BEST1 protein, human; D000075002:Bestrophins; D018118:Chloride Channels; D018389:Codon, Nonsense; D005136:Eye Proteins