Biallelic mutation of BEST1 causes a distinct retinopathy in humans

Am J Hum Genet. 2008 Jan;82(1):19-31. doi: 10.1016/j.ajhg.2007.08.004.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Bestrophins
  • Cell Line
  • Child
  • Child, Preschool
  • Chloride Channels / chemistry
  • Chloride Channels / genetics*
  • Codon, Nonsense
  • Eye Proteins / chemistry
  • Eye Proteins / genetics*
  • Female
  • Genes, Recessive
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • Retinal Diseases / genetics*
  • Transfection


  • BEST1 protein, human
  • Bestrophins
  • Chloride Channels
  • Codon, Nonsense
  • Eye Proteins