Macular Degeneration: Seeliger MW

Besch D, Jägle H, Scholl HP, Seeliger MW, Zrenner E. · University Eye Hospital, Schleichstr. 12-16, D-72076 Tübingen, Germany. · Vision Res. · Pubmed #14611947 No free full text.

Abstract: Alterations of retinoid cycle genes are known to cause retinal diseases characterized by focal white dot fundus lesions. Fundus appearances reveal circumscribed RPE-changes, although generalized metabolic defects and global functional abnormalities are present. As a possible explanation, topographic inhomogeneities of the human photoreceptor mosaic and the role of a cone specific visual cycle will be discussed. Due to particular characteristics of photoreceptor subtypes as well as different pathways for photopigment regeneration the metabolic demand of individual RPE cells might differ. In "flecked retina diseases" heterogeneity of metabolic demand in individual RPE cells could therefore be responsible for their multifocal appearance.

Seeliger MW, Jurklies B, Kellner U, Palmowski A, Bach M, Kretschmann U. · Universitäts-Augenklinik, Tübingen. · Ophthalmologe. · Pubmed #11729748 No free full text.

This publication has no abstract.

Bretillon L, Acar N, Seeliger MW, Santos M, Maire MA, Juanéda P, Martine L, Grégoire S, Joffre C, Bron AM, Creuzot-Garcher C. · INRA, UMR 1129 FLAVIC, Eye and Nutrition Research Group, F-21000 Dijon, France. · Invest Ophthalmol Vis Sci. · Pubmed #18385042 links to  free full text

Abstract: PURPOSE: To evaluate the retinal phenotype of 7- and 14-month-old apoB100,LDLR-/- mice, a relevant animal model of lipid metabolism dysfunction. METHODS: Single-flash electroretinograms were obtained from 7- and 14-month-old apoB100,LDLR-/- and control mice fed a standard diet under both scotopic and photopic conditions. Visual cycle retinoids were analyzed in eyes from dark-adapted mice. Retinal and choroidal vascularization was evaluated with scanning laser ophthalmoscopy. Fatty acids were analyzed in the retina. Esterified and free cholesterol was detected in eye cryosections. RESULTS: Scotopic and photopic b-wave amplitudes were significantly reduced in apoB100,LDLR-/- mice compared with control mice at 7 and 14 months of age (between -25% and -35% in 7-month-old animals and between -50% and -60% in 14-month-old animals at 25 cds/m2). Esterified cholesterol was found to accumulate at the basement of the retinal pigment epithelium in apoB100,LDLR-/- mouse eyes. On the contrary, no significant changes in the retinal profile of fatty acids and visual retinoids were observed in apoB100,LDLR-/- mice compared with control animals. CONCLUSIONS: The exclusive expression of apoB100 in LDL receptor-null mouse altered the ERG profile, without modifying the visual cycle of retinoids and led to cholesterol deposition in the retina. These findings clearly suggest the role of cholesterol metabolism in the functioning of the retina and possibly in the etiology of ocular diseases, including age-related macular degeneration.

Min SH, Molday LL, Seeliger MW, Dinculescu A, Timmers AM, Janssen A, Tonagel F, Tanimoto N, Weber BH, Molday RS, Hauswirth WW. · Department of Ophthalmology, University of Florida College of Medicine, Gainesville, 32610, USA. · Mol Ther. · Pubmed #16027044 No free full text.

Abstract: X-linked juvenile retinoschisis (RS) is a common cause of juvenile macular degeneration in males. RS is characterized by cystic spoke-wheel-like maculopathy, peripheral schisis, and a negative (b-wave more reduced than a-wave) electroretinogram (ERG). These symptoms are due to mutations in the RS1 gene in Xp22.2 leading to loss of functional protein. No medical treatment is currently available. We show here that in an Rs1h-deficient mouse model of human RS, delivery of the human RS1 cDNA with an AAV vector restored expression of retinoschisin to both photoreceptors and the inner retina essentially identical to that seen in wild-type mice. More importantly, unlike an earlier study with a different AAV vector and promoter, this work shows for the first time that therapeutic gene delivery using a highly specific AAV5-opsin promoter vector leads to progressive and significant improvement in both retinal function (ERG) and morphology, with preservation of photoreceptor cells that, without treatment, progressively degenerate.

Weber BH, Lin B, White K, Kohler K, Soboleva G, Herterich S, Seeliger MW, Jaissle GB, Grimm C, Reme C, Wenzel A, Asan E, Schrewe H. · Institute of Human Genetics, Biocenter, University of Wuerzburg, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #12147610 links to  free full text

Abstract: PURPOSE: Sorsby fundus dystrophy (SFD) is a rare, late-onset macular dystrophy caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene. The known mutations introduce potentially unpaired cysteine residues in the C terminus of the protein and result in the formation of higher-molecular-weight protein complexes of as yet unknown composition and functional consequences in the pathologic course of SFD. To facilitate in vivo investigation of mutant TIMP3, the authors generated a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine Timp3 gene. METHODS: Site-directed mutagenesis and homologous recombination in embryonic stem (ES) cells was used to generate mutant ES cells carrying the Timp3(S156C) allele. Chimeric animals were obtained, of which two displayed germline transmission of the mutated allele. Molecular genetic, biochemical, electron microscopic, and electrodiagnostic techniques were used for characterization. RESULTS: At 8 months of age, knock-in mice showed abnormalities in the inner aspect of Bruch's membrane and in the organization of the adjacent basal microvilli of the retinal pigment epithelium (RPE). Changes resembling those in the mutant animals were also present to some extent in normal littermates, but only at an advanced age of 30 months. Long-term electrodiagnostic recordings indicated normal retinal function throughout life. The biochemical characteristics of the mutant protein appear similar in humans and knock-in mice, suggesting common molecular pathways in the two species. The localization of the mutant protein in the eye is normal, although there is evidence of increased Timp3 levels in Bruch's membrane of mutant animals. CONCLUSIONS: The knock-in mice display early features of age-related changes in Bruch's membrane and the RPE that may represent the primary clinical manifestations of SFD. In addition, our immunolabeling studies and biochemical data support a model proposing that site-specific excess rather than absence or deficiency of functional Timp3 may be the primary consequence of the known Timp3 mutations.

Weber BH, Schrewe H, Molday LL, Gehrig A, White KL, Seeliger MW, Jaissle GB, Friedburg C, Tamm E, Molday RS. · Institute of Human Genetics, Biocenter, University of Würzburg, D-97074 Würzburg, Germany. · Proc Natl Acad Sci U S A. · Pubmed #11983912 links to  free full text

Abstract: Deleterious mutations in RS1 encoding retinoschisin are associated with X-linked juvenile retinoschisis (RS), a common form of macular degeneration in males. The disorder is characterized by a negative electroretinogram pattern and by a splitting of the inner retina. To gain further insight into the function of the retinoschisin protein and its role in the cellular pathology of RS, we have generated knockout mice deficient in Rs1h, the murine ortholog of the human RS1 gene. We show that pathologic changes in hemizygous Rs1h(-/Y) male mice are evenly distributed across the retina, apparently contrasting with the macula-dominated features in human. Similar functional anomalies in human and Rs1h(-/Y) mice, however, suggest that both conditions are a disease of the entire retina affecting the organization of the retinal cell layers as well as structural properties of the retinal synapse.