Functional roles of bestrophins in ocular epithelia.
There are four members of the bestrophin family of proteins in the human genome, of which two are known to be expressed in the eye. The gene BEST1 (formerly VMD2) which encodes the protein bestrophin-1 (Best1) was first identified in 1998. Mutations in this gene have now been associated with four clinically distinguishable human eye diseases, collectively referred to as "bestrophinopathies". Over the last decade, laboratories have sought to understand how Best1 mutations could result in eye diseases that range in presentation from macular degeneration to nanophthalmos. The majority of our knowledge comes from studies that have sought to understand how Best1 mutations or dysfunction could induce the classical symptoms of the most common of these diseases: Best vitelliform macular dystrophy (BVMD). BVMD is a dominant trait that is characterized electrophysiologically by a diminished electrooculogram light peak with a normal clinical electroretinogram. This together with the localization of Best1 to the retinal pigment epithelium (RPE) basolateral plasma membrane and data from heterologous expression studies, have led to the proposal that Best1 generates the light peak, and that bestrophins are a family of Ca(2+) activated Cl(-) channels (CaCCs). However, data from Best1 knock-out and knock-in mice, coupled with the recent discovery of a recessive bestrophinopathy suggest that Best1 does not generate the light peak. Recently Best2 was found to be expressed in non-pigmented epithelia in the ciliary body. However, aqueous dynamics in Best2 knock-out mice do not support a role for Best2 as a Cl(-) channel. Thus, the purported CaCC function of the bestrophins and how loss of this function relates to clinical disease needs to be reassessed. In this article, we examine data obtained from tissue-type and animal models and discuss the current state of bestrophin research, what roles Best1 and Best2 may play in ocular epithelia and ocular electrophysiology, and how perturbation of these functions may result in disease.
Marmorstein
Alan D
AD
Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ 85711, USA. amarmorstein@eyes.arizona.edu
Cross
Harold E
HE
Peachey
Neal S
NS
D000818:Animals; D000075002:Bestrophins; D018118:Chloride Channels / Q000502:physiology*; D055724:Electrophysiological Phenomena; D004848:Epithelium / Q000378:metabolism; D005123:Eye / Q000166:cytology / Q000378:metabolism*; D005128:Eye Diseases / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D023421:Models, Animal; D009154:Mutation
C113133:BEST1 protein, human; C465970:BEST2 protein, human; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins