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.
Davidson
Alice E
AE
Genetic Medicine, The University of Manchester, Manchester Academic Heath Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Millar
Ian D
ID
Urquhart
Jill E
JE
Burgess-Mullan
Rosemary
R
Shweikh
Yusrah
Y
Parry
Neil
N
O'Sullivan
James
J
Maher
Geoffrey J
GJ
McKibbin
Martin
M
Downes
Susan M
SM
Lotery
Andrew J
AJ
Jacobson
Samuel G
SG
Brown
Peter D
PD
Black
Graeme C M
GC
Manson
Forbes D C
FD
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