Best vitelliform macular dystrophy is a dominantly inherited, early onset, macular degenerative disease that exhibits some histopathologic similarities to age-related macular degeneration. Although the vitelliform lesion is common in the fundus of individuals with Best disease, diagnosis is based on a reduced ratio of the light peak to dark trough in the electrooculogram. Recently, the VMD2 gene on chromosome 11q13, encoding the protein bestrophin, was identified. The function of bestrophin is unknown. To facilitate studies of bestrophin, we produced both rabbit polyclonal and mouse monoclonal antibodies that proved useful for Western blotting, immunoprecipitation, and immunocytochemistry. To characterize bestrophin, we initially probed the retinal pigment epithelium (
Mutations in VMD2, encoding bestrophin (best-1), cause Best vitelliform macular dystrophy (BMD), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC). BMD is distinguished from AVMD by a diminished electrooculogram light peak (LP) in the absence of changes in the flash electroretinogram. Although the LP is thought to be generated by best-1, we find enhanced LP luminance responsiveness with normal amplitude in Vmd2 −/− mice and no differences in cellular Cl− currents in comparison to Vmd2 +/+ littermates. The putative Ca2+ sensitivity of best-1, and our recent observation that best-1 alters the kinetics of voltage-dependent Ca2+ channels (VDCC), led us to examine the role of VDCCs in the LP. Nimodipine diminished the LP, leading us to survey VDCC β-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the β4 subunit of VDCCs, exhibited a significant shift in LP luminance response, establishing a role for Ca2+ in LP generation. When stimulated with ATP, which increases [Ca++]I, retinal pigment epithelial cells derived from Vmd2 −/− mice exhibited a fivefold greater response than Vmd2 +/+ littermates, indicating that best-1 can suppress the rise in [Ca2+]I associated with the LP. We conclude that VDCCs regulated by a β4 subunit are required to generate the LP and that best-1 antagonizes the LP luminance response potentially via its ability to modulate VDCC function. Furthermore, we suggest that the loss of vision associated with BMD is not caused by the same pathologic process as the diminished LP, but rather is caused by as yet unidentified effects of best-1 on other cellular processes.
Malattia Leventinese (ML), an inherited macular degenerative disease, is closely reminiscent of age-related macular degeneration (AMD), the most common cause of incurable blindness. Both ML and AMD are characterized by extracellular deposits known as drusen between the retinal pigment epithelium (RPE) and Bruch's membrane. The mechanism underlying drusen formation is unknown. An Arg to Trp mutation in a gene of unknown function, EFEMP1, is responsible for ML, indicating EFEMP1 may be important in drusen formation. Here, we show that wild-type EFEMP1 is a secreted protein whereas mutant EFEMP1 is misfolded, secreted inefficiently, and retained within cells. In normal eyes, EFEMP1 is not present at the site of drusen formation. However, in ML eyes, EFEMP1 accumulates within the RPE cells and between the RPE and drusen, but does not appear to be a major component of drusen. Furthermore, in AMD eyes, EFEMP1 is found to accumulate beneath the RPE immediately overlaying drusen, but not in the region where there is no apparent retinal pathology observed. These data present evidence that misfolding and aberrant accumulation of EFEMP1 may cause drusen formation and cellular degeneration and play an important role in the etiology of both ML and AMD.T he macula, a central circular area of the retina 5 to 6 mm in diameter with the fovea at its center, facilitates central vision and high-resolution visual acuity. Various diseases causing macular degeneration result in severe and irreversible loss of vision. Malattia Leventinese (ML), also known as Doyne honeycomb retinal dystrophy, is a rare autosomal dominant macular degenerative disease with high penetrance (1-3). Onset of ML is generally in midlife but can vary from childhood until old age (4). An early characteristic feature of ML is the presence of amorphous sub-retinal pigment epithelium (RPE) deposits known as drusen between the RPE and Bruch's membrane (1, 5). At a later stage of the disease, ML exhibits a variety of clinical and histopathological features, including decreased visual acuity, geographic atrophy, pigmentary changes, and choroidal neovascularization (6). Drusen are also an early hallmark of age-related macular degeneration (AMD), a heterogeneous late onset macular degenerative condition (7). ML exhibits features more consistent with AMD than any other heritable macular disorder. Except for a late age of onset, AMD shares the typical clinical features of ML (8). AMD accounts for approximately 50% of registered blindness in the developed world (9, 10). More than 20% of the population over 65 years of age is affected with AMD. The molecular mechanism responsible for drusen formation and other retinal pathology observed in ML or AMD is currently unknown.A single mutation, Arg-345 to Trp (R345W) in the gene EFEMP1 (for epidermal growth factor-containing fibrillin-like extracellular matrix protein 1), was found to be responsible for ML (11). To date, no mutation in EFEMP1 has been found to be associated with AMD (11). Initially described as S1-5 (12), also kn...
Cutis laxa is a condition characterized by redundant, pendulous, and inelastic skin. We identified a patient with recessive inheritance of a missense mutation (169G-->A; E57K) in the Fibulin-4 gene. She had multiple bone fractures at birth and was diagnosed with cutis laxa, vascular tortuosity, ascending aortic aneurysm, developmental emphysema, inguinal and diaphragmatic hernia, joint laxity, and pectus excavatum by age 2 years. Her skin showed markedly underdeveloped elastic fibers, and the extracellular matrix laid down by her skin fibroblasts contained dramatically reduced amounts of fibulin-4. We conclude that fibulin-4 is necessary for elastic fiber formation and connective tissue development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.