Bestrophin 1 and retinal disease.
Mutations in the gene BEST1 are causally associated with as many as five clinically distinct retinal degenerative diseases, which are collectively referred to as the "bestrophinopathies". These five associated diseases are: Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, adult-onset vitelliform macular dystrophy, autosomal dominant vitreoretinochoroidopathy, and retinitis pigmentosa. The most common of these is Best vitelliform macular dystrophy. Bestrophin 1 (Best1), the protein encoded by the gene BEST1, has been the subject of a great deal of research since it was first identified nearly two decades ago. Today we know that Best1 functions as both a pentameric anion channel and a regulator of intracellular Ca2+signaling. Best1 is an integral membrane protein which, within the eye, is uniquely expressed in the retinal pigment epithelium where it predominantly localizes to the basolateral plasma membrane. Within the brain, Best1 expression has been documented in both glial cells and astrocytes where it functions in both tonic GABA release and glutamate transport. The crystal structure of Best1 has revealed critical information about how Best1 functions as an ion channel and how Ca2+regulates that function. Studies using animal models have led to critical insights into the physiological roles of Best1 and advances in stem cell technology have allowed for the development of patient-derived, "disease in a dish" models. In this article we review our knowledge of Best1 and discuss prospects for near-term clinical trials to test therapies for the bestrophinopathies, a currently incurable and untreatable set of diseases.
Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA; Nikon Instruments, Melville, NY, USA.
Adiv A
AA
Johnson
Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Karina E
KE
Guziewicz
Center for Neuroscience and Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
C Justin
CJ
Lee
New York Structural Biology Center, New York Consortium on Membrane Protein Structure, New York, NY, USA.
Ravi C
RC
Kalathur
Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA.
Jose S
JS
Pulido
Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA.
Lihua Y
LY
Marmorstein
Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA. Electronic address: Marmorstein.alan@mayo.edu.
Alan D
AD
Marmorstein
D000818:Animals; D000075002:Bestrophins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009154:Mutation; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism
C113133:BEST1 protein, human; C491856:Best1 protein, mouse; D000075002:Bestrophins; D004247:DNA
Anion channel; Best1; Bestrophin; Maculopathy; Retinal disease; Retinal pigment epithelium