Bestrophinopathy: An RPE-photoreceptor interface disease

Abstract

Bestrophinopathies, one of the most common forms of inherited macular degenerations, are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine BEST1-linked maculopathies are characterized by abnormal accumulation of autofluorescent material within RPE cells and bilateral macular or multifocal lesions; however, the specific mechanism leading to the formation of these lesions remains unclear. We now provide an overview of the current state of knowledge on the molecular pathology of bestrophinopathies, and explore factors promoting formation of RPE-neuroretinal separations, using the first spontaneous animal model of BEST1-associated retinopathies, canine Best (cBest). Here, we characterize the nature of the autofluorescent RPE cell inclusions and report matching spectral signatures of RPE-associated fluorophores between human and canine retinae, indicating an analogous composition of endogenous RPE deposits in Best Vitelliform Macular Dystrophy (BVMD) patients and its canine disease model. This study also exposes a range of biochemical and structural abnormalities at the RPE-photoreceptor interface related to the impaired cone-associated microvillar ensheathment and compromised insoluble interphotoreceptor matrix (IPM), the major pathological culprits responsible for weakening of the RPE-neuroretina interactions, and consequently, formation of vitelliform lesions. These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies.

Novel BEST1 gene mutations associated with two different forms of macular dystrophy in Tunisian families

“…Clinical exploration indicates also detachments of the neurosensory retina due to the accumulation of fluid in the macula for all patients. An abnormal accumulation of yellowish deposits (lipofucsin) is a major risk factor implicated in different forms of macular degeneration . ARB and BVMD are characterized by an excessive accumulation of lipofuscin material within RPE cells, formation of multifocal vitelliform subretinal lesions with subretinal fluid or macular oedema accompanied generally by an abnormal EOG …”

“…An abnormal accumulation of yellowish deposits (lipofucsin) is a major risk factor implicated in different forms of macular degeneration. 3 ARB and BVMD are characterized by an excessive accumulation of lipofuscin material within RPE cells, formation of multifocal vitelliform subretinal lesions with subretinal fluid or macular oedema accompanied generally by an abnormal EOG. 3 Although our patients' phenotypes are similar with those reported previously with ARB or BVMD, some clinical differences have been noticed.…”

“…BEST1 (VMD2) is a gene located on chromosome 11 (11q12.3) that encodes for a 585 amino acid transmembrane channel protein called bestrophin 1 (or Best1), 1,2 located in the retinal pigment epithelium (RPE). 1,3 Although the exact function of BEST1 is still not clear, it is generally believed to act as a chloride ion channel and possibly to have dual functions as a chloride channel and a regulator of Ca2 + channels in RPE cells. 4,5 These functions can be affected by a large spectrum of mutations.…”

Inhibition of Ca 2+ channel surface expression by mutant bestrophin‐1 in RPE cells

“…This can also result from a reduced activity of the volume‐activated Cl channel function because the phagocytosis process requires an efficient volume regulation . Furthermore, also the recently reported changes in the RPE apical surface in canine bestrophinopathy support a phagocytosis defect as a loss of RPE function leading to retinal degeneration …”

“…[4][5][6] Since the RPE is a close interaction partner of photoreceptors and responsible for maintaining photoreceptor structure and function, 7 it is hypothesized that mutations in BEST1 lead to impairment of RPE function and subsequently to photoreceptor loss. 5,8 Hallmarks of the disease are a reduced light-peak in the patient's electrooculogram (EOG) [3][4][5]8,9 and characteristic alterations in the central retina, vitelliform lesions, accompanied by accumulation of lipofuscin in the RPE. 3,10 Bestrophin-1 has been described as Ca 2+ -dependent and volume-activated Cl − channel.…”