Human photoreceptor outer segments shorten during light adaptation.

PURPOSE Best disease is a macular dystrophy caused by mutations in the BEST1 gene. Affected individuals exhibit a reduced electro-oculographic (EOG) response to changes in light exposure and have significantly longer outer segments (OS) than age-matched controls. The purpose of this study was to investigate the anatomical changes in the outer retina during dark and light adaptation in unaffected and Best disease subjects, and to compare these changes to the EOG. METHODS Unaffected (n = 11) and Best disease patients (n = 7) were imaged at approximately 4-minute intervals during an approximately 40-minute dark-light cycle using spectral domain optical coherence tomography (SD-OCT). EOGs of two subjects were obtained under the same conditions. Automated three-dimensional (3-D) segmentation allowed measurement of light-related changes in the distances between five retinal surfaces. RESULTS In normal subjects, there was a significant decrease in outer segment equivalent length (OSEL) of -2.14 μm (95% confidence interval [CI], -1.77 to -2.51 μm) 10 to 20 minutes after the start of light adaptation, while Best disease subjects exhibited a significant increase in OSEL of 2.07 μm (95% CI, 1.79-2.36 μm). The time course of the change in OS length corresponded to that of the EOG waveform. CONCLUSIONS Our results strongly suggest that the light peak phase of the EOG is temporally related to a decreased OSEL in normal subjects, and the lack of a light peak phase in Best disease subjects is associated with an increase in OSEL. One potential role of Bestrophin-1 is to trigger an increase in the standing potential that approximates the OS to the apical surface of the RPE to facilitate phagocytosis.

[1]  E. Stone,et al.  Late development of vitelliform lesions and flecks in a patient with best disease: clinicopathologic correlation. , 2005, Archives of ophthalmology.

[2]  Omer P. Kocaoglu,et al.  Phase-sensitive imaging of the outer retina using optical coherence tomography and adaptive optics , 2011, Biomedical optics express.

[3]  M. Metzker,et al.  Identification of the gene responsible for Best macular dystrophy , 1998, Nature Genetics.

[4]  Michael Bach,et al.  ISCEV standard for clinical electro-oculography (2010 update) , 2011, Documenta Ophthalmologica.

[5]  K. Palczewski,et al.  Phagocytosis of retinal rod and cone photoreceptors. , 2010, Physiology.

[6]  Edwin M Stone,et al.  Three-dimensional distribution of the vitelliform lesion, photoreceptors, and retinal pigment epithelium in the macula of patients with best vitelliform macular dystrophy. , 2012, Archives of ophthalmology.

[7]  G. Holder,et al.  Biallelic mutation of BEST1 causes a distinct retinopathy in humans. , 2008, American journal of human genetics.

[8]  H. C. Hartzell,et al.  Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. , 2008, Physiological reviews.

[9]  N. Peachey,et al.  The Light Peak of the Electroretinogram Is Dependent on Voltage-gated Calcium Channels and Antagonized by Bestrophin (Best-1) , 2006, The Journal of general physiology.

[10]  C. Wadelius,et al.  A model of best vitelliform macular dystrophy in rats. , 2004, Investigative ophthalmology & visual science.

[11]  E. Stone,et al.  Autosomal recessive best vitelliform macular dystrophy: report of a family and management of early-onset neovascular complications. , 2011, Archives of ophthalmology.

[12]  D. Mackey,et al.  AUTOSOMAL RECESSIVE VITELLIFORM MACULAR DYSTROPHY IN A LARGE COHORT OF VITELLIFORM MACULAR DYSTROPHY PATIENTS , 2011, Retina.

[13]  H. C. Hartzell,et al.  Suppression of Ca2+ signaling in a mouse model of Best disease. , 2010, Human molecular genetics.

[14]  M. Bach,et al.  ISCEV standard for clinical electro-oculography (2010 update) , 2017, Documenta ophthalmologica. Advances in ophthalmology.

[15]  F. Best.  II. Über eine hereditäre Maculaaffektion , 1905 .

[16]  R. W. Young.  THE RENEWAL OF PHOTORECEPTOR CELL OUTER SEGMENTS , 1967, The Journal of cell biology.

[17]  S. Jacobson,et al.  Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. , 2009, American journal of human genetics.

[18]  C. Wadelius,et al.  Expression and localization of bestrophin during normal mouse development. , 2003, Investigative ophthalmology & visual science.

[19]  C. Karwoski,et al.  Light-evoked expansion of subretinal space volume in the retina of the frog , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[20]  G. Aguirre,et al.  Assessment of canine BEST1 variations identifies new mutations and establishes an independent bestrophinopathy model (cmr3) , 2010, Molecular vision.

[21]  E. Stone,et al.  Differential macular and peripheral expression of bestrophin in human eyes and its implication for best disease. , 2007, Investigative ophthalmology & visual science.

[22]  Xiaodong Wu,et al.  Automated 3-D Intraretinal Layer Segmentation of Macular Spectral-Domain Optical Coherence Tomography Images , 2009, IEEE Transactions on Medical Imaging.

[23]  M. Larsen,et al.  Evaluation of macular structure and function by OCT and electrophysiology in patients with vitelliform macular dystrophy due to mutations in BEST1. , 2010, Investigative ophthalmology & visual science.

[24]  K. Kawasaki,et al.  International society for clinical electrophysiology of vision (ISCEV) , 2006, Graefe's Archive for Clinical and Experimental Ophthalmology.

[25]  J. Hollyfield,et al.  Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Nathans,et al.  The vitelliform macular dystrophy protein defines a new family of chloride channels , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  E. Stone,et al.  VISUAL OUTCOME FOLLOWING SUBRETINAL HEMORRHAGE IN BEST DISEASE , 2001, Retina.

[28]  Milan Sonka,et al.  Segmentation of the Surfaces of the Retinal Layer from OCT Images , 2006, MICCAI.

[29]  Paul A. Constable,et al.  The electro-oculogram , 2006, Progress in Retinal and Eye Research.

[30]  V. Sheffield,et al.  Genetic linkage of vitelliform macular degeneration (Best's disease) to chromosome 11q13 , 1992, Nature Genetics.

[31]  S S Miller,et al.  K+ and Cl‐ transport mechanisms in bovine pigment epithelium that could modulate subretinal space volume and composition. , 1994, The Journal of physiology.

[32]  G. L. Walls,et al.  The Vertebrate Eye and Its Adaptive Radiation. , 2013 .

[33]  R. Weleber.  Fast and slow oscillations of the electro-oculogram in Best's macular dystrophy and retinitis pigmentosa. , 1989, Archives of ophthalmology.

[34]  M. P. White,et al.  Effects of continuous darkness on ERG correlates of disc shedding in rabbit retina. , 1992, Experimental eye research.

[35]  Eberhart Zrenner,et al.  Standard for clinical electro-oculography , 1993 .

[36]  Yuan-yuan Cui,et al.  Looking chloride channels straight in the eye: bestrophins, lipofuscinosis, and retinal degeneration. , 2005, Physiology.

[37]  G. Acland,et al.  Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease. , 2007, Investigative ophthalmology & visual science.

[38]  M. Sonka,et al.  Retinal Imaging and Image Analysis. , 2010, IEEE transactions on medical imaging.

[39]  R. Steinberg,et al.  Evidence in support of a photoreceptoral origin for the "light-peak substance". , 1988, Investigative ophthalmology & visual science.

[40]  B. J. Klevering,et al.  The spectrum of ocular phenotypes caused by mutations in the BEST1 gene , 2009, Progress in Retinal and Eye Research.

[41]  Donald T. Miller,et al.  Imaging outer segment renewal in living human cone photoreceptors. , 2010, Optics express.

[42]  T. Hirose,et al.  Correlating visual acuity and electrooculogram recordings in Best's disease. , 1993, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde.

[43]  M. Lavail,et al.  Rod outer segment disc shedding in relation to cyclic lighting. , 1976, Experimental eye research.

[44]  D. Baralle,et al.  Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). , 2004, Investigative ophthalmology & visual science.

[45]  C. Wadelius,et al.  Expression of bestrophin‐1, the product of the VMD2 gene, modulates voltage‐dependent Ca2+ channels in retinal pigment epithelial cells , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[46]  C. Curcio,et al.  ANATOMICAL CORRELATES TO THE BANDS SEEN IN THE OUTER RETINA BY OPTICAL COHERENCE TOMOGRAPHY: Literature Review and Model , 2011, Retina.