Differential Macular and Peripheral Expression of Bestrophin in Human Eyes and Its Implication for Best Disease

Mullins, Robert F.; Kuehn, Markus H.; Faidley, Elizabeth A.; Syed, Nasreen A.; Stone, Edwin M.

doi:10.1167/iovs.06-0868

Cited by 101 publications

(104 citation statements)

References 39 publications

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“…Of interest, the protein product of another disease-causing RPE gene, VMD2, showed a different topography of expression, with a relative deficiency state in the central versus the peripheral retina. RPE65, used as a control in that study, had properties consistent with our observations (31). Taken together, these observations suggest a potential role of both RPE65-based and RPE65-independent pigment regeneration pathways in maintaining cone function and survival in primate maculas.…”

Section: Discussionsupporting

confidence: 86%

Human cone photoreceptor dependence on RPE65 isomerase

Jacobson

Alemán

Cideciyan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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138

144

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The visual (retinoid) cycle, the enzymatic pathway that regenerates chromophore after light absorption, is located primarily in the retinal pigment epithelium (RPE) and is essential for rod photoreceptor survival. Whether this pathway also is essential for cone photoreceptor survival is unknown, and there are no data from man or monkey to address this question. The visual cycle is naturally disrupted in humans with Leber congenital amaurosis (LCA), which is caused by mutations in RPE65, the gene that encodes the retinoid isomerase. We investigated such patients over a wide age range (3-52 years) for effects on the cone-rich human fovea. In vivo microscopy of the fovea showed that, even at the youngest ages, patients with RPE65-LCA exhibited cone photoreceptor loss. This loss was incomplete, however, and residual cone photoreceptor structure and function persisted for decades. Basic questions about localization of RPE65 and isomerase activity in the primate eye were addressed by examining normal macaque. RPE65 was definitively localized by immunocytochemistry to the central RPE and, by immunoblotting, appeared to concentrate in the central retina. The central retinal RPE layer also showed a 4-fold higher retinoid isomerase activity than more peripheral RPE. Early cone photoreceptor losses in RPE65-LCA suggest that robust RPE65-based visual chromophore production is important for cones; the residual retained cone structure and function support the speculation that alternative pathways are critical for cone photoreceptor survival.optical coherence tomography ͉ retinal degeneration ͉ retinoid cycle ͉ Leber congenital amaurosis ͉ gene therapy V ertebrate retinas have two types of photoreceptors: rods for the perception of dim light and cones for the perception of bright light. Light absorbed by visual pigments of photoreceptors triggers a series of enzymatic reactions known as phototransduction (1). The light-capturing part of the visual pigment, the chromophore, must then be regenerated. The pathway for regeneration of rhodopsin (the rod visual pigment) is known as the visual (retinoid) cycle (2, 3) and involves both rod cells and the adjacent retinal pigment epithelium (RPE). All-trans-retinal is reisomerized to 11-cis-retinal by a reaction in the RPE that requires the retinal isomerase, retinal pigment epithelium-specific 65-kDa protein (RPE65), and lecithinretinol acyltransferase (LRAT) activities. Functional visual pigment is then reformed by combining the 11-cis-chromophore with the photoreceptor opsin apoprotein (4). Molecular knowledge of the visual cycle has increased as the genes encoding the enzymes of this pathway have been elucidated (2, 5, 6).Decades ago, cone pigment regeneration was proposed to be RPE cell-independent (7, 8). More recently, cone-dominant ground squirrel and chicken retinas have been shown to exhibit retinoid isomerase activity that is distinct from RPE65 (5, 9, 10). Murine double knockout experiments, however, provide evidence that RPE65 and the RPE are essential for cone function (11...

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Section: Discussionsupporting

confidence: 86%

Human cone photoreceptor dependence on RPE65 isomerase

Jacobson

Alemán

Cideciyan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

138

144

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“…Bestrophin-1 is strongly expressed in the retinal pigment epithelium (RPE), where it mainly localizes to the basolateral membrane (Gouras et al, 2009;Guziewicz et al, 2007;Marmorstein et al, 2000;Mullins et al, 2007;Mullins et al, 2005;Neussert et al, 2010). The RPE fulfills a multitude of functions that are essential for excitability and the structural integrity of the photoreceptors (Strauss, 2005).…”

Section: Introductionmentioning

confidence: 99%

Disease-associated missense mutations in bestrophin-1 affect cellular trafficking and anion conductance

Milenkovic

Röhrl

Weber

et al. 2011

Journal of Cell Science

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SummaryBestrophin-1, an integral membrane protein encoded by the BEST1 gene, is localized predominantly to the basolateral membrane of the retinal pigment epithelium. Mutations in the BEST1 gene have been associated with Best vitelliforme macular dystrophy (BMD), a central retinopathy with autosomal dominant inheritance and variable penetrance. Over 120 disease-causing mutations are known, the majority of which result in amino acid substitutions within four mutational hot-spot regions in the highly conserved N-terminal half of the protein. Although initially thought to impair Cl -channel function, the molecular pathology of BEST1 mutations is still controversial. We have analyzed the subcellular localization of 13 disease-associated BEST1 mutant proteins in polarized MDCK II cells, an established model of apical to basolateral protein sorting. Immunostaining demonstrated that nine of the 13 mutant proteins failed to integrate into the cell membrane. The defective proteins were predominantly retained in the cytoplasm, whereas wild-type bestrophin-1 revealed cell membrane localization. Functional analysis of I -fluxes in HEK-293 cells showed that all mutants exhibited a significant reduction in anion conductance. Our data indicate that defective intracellular trafficking could be a common cause of BMD accompanied by impaired anion conductance, representing a loss of anion channel function that is probably due to mistargeting of mutant protein.

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“…Also, the possibility of bestrophins forming heteromeric complexes in native tissues is limited due to their restricted distribution. The hBest1 mainly expresses in retina and RPE cells (1,11,44), whereas hBest2 and hBest4 express mostly in different cell types in colon (goblet cells and small intestine, respectively) (45,46).…”

Section: Discussionmentioning

confidence: 99%

Stoichiometry and specific assembly of Best ion channels

Bharill

Palty

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Human Bestrophin 1 (hBest1) is a calcium-activated chloride channel that regulates neuronal excitability, synaptic activity, and retinal homeostasis. Mutations in hBest1 cause the autosomal-dominant Best macular dystrophy (BMD). Because hBest1 mutations cause BMD, but a knockout does not, we wondered if hBest1 mutants exert a dominant negative effect through interaction with other calciumactivated chloride channels, such as hBest2, 3, or 4, or transmembrane member 16A (TMEM16A), a member of another channel family. The subunit architecture of Best channels is debated, and their ability to form heteromeric channel assemblies is unclear. Using single-molecule subunit analysis, we find that each of hBest1, 2, 3, and 4 forms a homotetrameric channel. Despite considerable conservation among hBests, hBest1 has little or no interaction with other hBests or mTMEM16A. We identify the domain responsible for assembly specificity. This domain also plays a role in channel function. Our results indicate that Best channels preferentially self-assemble into homotetramers.

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Differential Macular and Peripheral Expression of Bestrophin in Human Eyes and Its Implication for Best Disease

Abstract: Topographic differences in the levels of bestrophin protein may in part explain the propensity for the macula to develop lesions in Best disease.

Cited by 101 publications

References 39 publications

Human cone photoreceptor dependence on RPE65 isomerase

Human cone photoreceptor dependence on RPE65 isomerase

Disease-associated missense mutations in bestrophin-1 affect cellular trafficking and anion conductance

Stoichiometry and specific assembly of Best ion channels

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