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.
Genetic Medicine, The University of Manchester, Manchester Academic Heath Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Alice E
AE
Davidson
Ian D
ID
Millar
Jill E
JE
Urquhart
Rosemary
R
Burgess-Mullan
Yusrah
Y
Shweikh
Neil
N
Parry
James
J
O'Sullivan
Geoffrey J
GJ
Maher
Martin
M
McKibbin
Susan M
SM
Downes
Andrew J
AJ
Lotery
Samuel G
SG
Jacobson
Peter D
PD
Brown
Graeme C M
GC
Black
Forbes D C
FD
Manson
D000595:Amino Acid Sequence; D000075002:Bestrophins; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D017124:Conserved Sequence; D005091:Exons; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000166:cytology; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009679:Nuclear Family; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000209:etiology* / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
C113133:BEST1 protein, human; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins; D020033:Protein Isoforms