84 results on '"Weber BHF"'
Search Results
2. Die Augenstudie der Universität Regensburg (AugUR) – eine Plattform für populationsbasierte Analysen zur altersbedingten Makuladegeneration (AMD) in der älteren deutschen Bevölkerung
- Author
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Brandl, C, Stark, KJ, Olden, M, Schelter, SC, Zimmermann, ME, Weber, BHF, Helbig, H, and Heid, IM
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Populationsbasierte epidemiologische Daten zu häufigen ophthalmologischen Erkrankungen wie der altersbedingten Makuladegeneration (AMD) sind in Deutschland selten (DOG Weißbuch, 2012). Die Augenstudie der Universität Regensburg, AugUR, soll diese Lücken schließen und Daten über[zum vollständigen Text gelangen Sie über die oben angegebene URL], Jahrestagung der Vereinigung Bayerischer Augenärzte BayOG 2015
- Published
- 2015
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3. Das Translokatorprotein (18 kDa) (TSPO) wird von aktivierten Mikrogliazellen der Retina exprimiert und moduliert Entzündungsreaktionen und Phagozytose
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Scholz, R, Karlstetter, M, Nothdurfter, C, Aslanidis, A, Moeller, K, Horn, F, Neumann, H, Weber, BHF, Rupprecht, R, and Langmann, T
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Das Translokatorprotein (18kDa) (TSPO) ist ein mitochondriales Transmembranprotein, das von reaktiven Mikrogliazellen exprimiert wird und als Biomarker für Gliosen im Gehirn dient. In verschiedenen Modellen neurodegenerativer Erkrankungen zeigte die Behandlung mit TSPO-Liganden entzündungshemmende[for full text, please go to the a.m. URL], 27. Jahrestagung der Retinologischen Gesellschaft
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- 2014
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4. Multicenter cohort association study of SLC2A1 single nucleotide polymorphisms and age-related macular degeneration
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Baas, DC, Ho, Lintje, Tanck, MWT, Fritsche, LG, Merriam, JE, van 't Slot, R, Koeleman, BPC, Gorgels, TGMF (Theo), Duijn, Cornelia, Uitterlinden, André, de Jong, PTVM (Paulus), Hofman, Bert, Brink, JB, Vingerling, Hans, Klaver, Caroline, Dean, M, Weber, BHF, Allikmets, R, Hageman, GS, Bergen, Arthur, Epidemiology, Cell biology, Internal Medicine, Ophthalmology, and Pathology
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eye diseases - Abstract
Purpose: Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress-mediated AMD pathology. Methods: Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Wurzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed. Results: In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies. Conclusions: No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists.
- Published
- 2012
5. X-linked congenital retinoschisis: Loss of significance of the negative electroretinogram
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Renner, AB, Kellner, U, Cropp, E, Weber, BHF, and Foerster, MH
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ddc: 610 - Published
- 2006
6. Human complement factor H (CFH) is expressed in ARPE 19 cells
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Jung, C, Carstesen, D, Becker, J, Skerka, C, Zipfel, PF, Weber, BHF, Keilhauer, C, Walter, P, and Weinberger, AWA
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ddc: 610 - Published
- 2006
7. Intravitreal levels of human complement factor H (CFH)
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Weinberger, AWA, Skerka, C, Zipfel, PF, Weber, BHF, Becker, J, Carstesen, D, Jung, C, Keilhauer, C, and Walter, P
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ddc: 610 - Published
- 2006
8. Patterns of abnormal fundus autofluorescence in geographic atrophy - phenotype-genotype correlation
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Fleckenstein, M, Schmitz-Valckenberg, S, Bindewald-Wittich, A, Göbel, A, Keilhauer, C, Mansmann, U, Weber, BHF, Scholl, HPN, Holz, FG, and FAM Studiengruppe
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ddc: 610 - Published
- 2006
9. Complement factor H variant Tyr402His and basal laminar deposits in age-related macular degeneration
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Hermans, P, Lommatzsch, A, Rivera, A, Weber, BHF, and Pauleikhoff, D
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ddc: 610 - Published
- 2006
10. Klinische Befunde einer bayerischen Großfamilie mit autosomaldominanter zentraler areolärer choroidaler Dystrophie mit einer Arg195Leu-Mutation im Peripherin/RDS-Gen
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Keilhauer, CN, primary, Meigen, T, additional, and Weber, BHF, additional
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- 2005
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11. Limitations in next-generation sequencing-based genotyping of breast cancer polygenic risk score loci.
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Baumann A, Ruckert C, Meier C, Hutschenreiter T, Remy R, Schnur B, Döbel M, Fankep RCN, Skowronek D, Kutz O, Arnold N, Katzke AL, Forster M, Kobiela AL, Thiedig K, Zimmer A, Ritter J, Weber BHF, Honisch E, Hackmann K, Schmidt G, Sturm M, and Ernst C
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- Humans, Female, High-Throughput Nucleotide Sequencing methods, High-Throughput Nucleotide Sequencing standards, Genotyping Techniques methods, Genotyping Techniques standards, Genetic Predisposition to Disease, Genetic Testing methods, Genetic Testing standards, Gene Frequency, Algorithms, Genetic Risk Score, Breast Neoplasms genetics, Multifactorial Inheritance
- Abstract
Considering polygenic risk scores (PRSs) in individual risk prediction is increasingly implemented in genetic testing for hereditary breast cancer (BC) based on next-generation sequencing (NGS). To calculate individual BC risks, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) with the inclusion of the BCAC 313 or the BRIDGES 306 BC PRS is commonly used. The PRS calculation depends on accurately reproducing the variant allele frequencies (AFs) and, consequently, the distribution of PRS values anticipated by the algorithm. Here, the 324 loci of the BCAC 313 and the BRIDGES 306 BC PRS were examined in population-specific database gnomAD and in real-world data sets of five centers of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), to determine whether these expected AFs can be reproduced by NGS-based genotyping. Four PRS loci were non-existent in gnomAD v3.1.2 non-Finnish Europeans, further 24 loci showed noticeably deviating AFs. In real-world data, between 11 and 23 loci were reported with noticeably deviating AFs, and were shown to have effects on final risk prediction. Deviations depended on the sequencing approach, variant caller and calling mode (forced versus unforced) employed. Therefore, this study demonstrates the necessity to apply quality assurance not only in terms of sequencing coverage but also observed AFs in a sufficiently large cohort, when implementing PRSs in a routine diagnostic setting. Furthermore, future PRS design should be guided by the technical reproducibility of expected AFs across commonly used genotyping methods, especially NGS, in addition to the observed effect sizes., (© 2024. The Author(s).)
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- 2024
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12. Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.
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Hitti-Malin RJ, Panneman DM, Corradi Z, Boonen EGM, Astuti G, Dhaenens CM, Stöhr H, Weber BHF, Sharon D, Banin E, Karali M, Banfi S, Ben-Yosef T, Glavač D, Farrar GJ, Ayuso C, Liskova P, Dudakova L, Vajter M, Ołdak M, Szaflik JP, Matynia A, Gorin MB, Kämpjärvi K, Bauwens M, De Baere E, Hoyng CB, Li CHZ, Klaver CCW, Inglehearn CF, Fujinami K, Rivolta C, Allikmets R, Zernant J, Lee W, Podhajcer OL, Fakin A, Sajovic J, AlTalbishi A, Valeina S, Taurina G, Vincent AL, Roberts L, Ramesar R, Sartor G, Luppi E, Downes SM, van den Born LI, McLaren TL, De Roach JN, Lamey TM, Thompson JA, Chen FK, Tracewska AM, Kamakari S, Sallum JMF, Bolz HJ, Kayserili H, Roosing S, and Cremers FPM
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- Humans, Mutation, Penetrance, Pedigree, Retina, Phenotype, ATP-Binding Cassette Transporters genetics, Eye Proteins, Cadherin Related Proteins, Nerve Tissue Proteins genetics, Macular Degeneration genetics
- Abstract
Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1 :c.783G>A and CNGB3 :c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.
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- 2024
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13. QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration.
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Advani J, Mehta PA, Hamel AR, Mehrotra S, Kiel C, Strunz T, Corso-Díaz X, Kwicklis M, van Asten F, Ratnapriya R, Chew EY, Hernandez DG, Montezuma SR, Ferrington DA, Weber BHF, Segrè AV, and Swaroop A
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- Humans, Epigenesis, Genetic, Epigenome, Retina, DNA Methylation genetics, Macular Degeneration genetics
- Abstract
DNA methylation provides a crucial epigenetic mark linking genetic variations to environmental influence. We have analyzed array-based DNA methylation profiles of 160 human retinas with co-measured RNA-seq and >8 million genetic variants, uncovering sites of genetic regulation in cis (37,453 methylation quantitative trait loci and 12,505 expression quantitative trait loci) and 13,747 DNA methylation loci affecting gene expression, with over one-third specific to the retina. Methylation and expression quantitative trait loci show non-random distribution and enrichment of biological processes related to synapse, mitochondria, and catabolism. Summary data-based Mendelian randomization and colocalization analyses identify 87 target genes where methylation and gene-expression changes likely mediate the genotype effect on age-related macular degeneration. Integrated pathway analysis reveals epigenetic regulation of immune response and metabolism including the glutathione pathway and glycolysis. Our study thus defines key roles of genetic variations driving methylation changes, prioritizes epigenetic control of gene expression, and suggests frameworks for regulation of macular degeneration pathology by genotype-environment interaction in retina., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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14. The glucocorticoid receptor as a master regulator of the Müller cell response to diabetic conditions in mice.
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Pfaller AM, Kaplan L, Carido M, Grassmann F, Díaz-Lezama N, Ghaseminejad F, Wunderlich KA, Glänzer S, Bludau O, Pannicke T, Weber BHF, Koch SF, Bonev B, Hauck SM, and Grosche A
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- Animals, Mice, Ependymoglial Cells metabolism, Neuroglia metabolism, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Retina metabolism, Diabetes Mellitus metabolism, Diabetic Retinopathy genetics, Diabetic Retinopathy metabolism
- Abstract
Diabetic retinopathy (DR) is considered a primarily microvascular complication of diabetes. Müller glia cells are at the centre of the retinal neurovascular unit and play a critical role in DR. We therefore investigated Müller cell-specific signalling pathways that are altered in DR to identify novel targets for gene therapy. Using a multi-omics approach on purified Müller cells from diabetic db/db mice, we found the mRNA and protein expression of the glucocorticoid receptor (GR) to be significantly decreased, while its target gene cluster was down-regulated. Further, oPOSSUM TF analysis and ATAC- sequencing identified the GR as a master regulator of Müller cell response to diabetic conditions. Cortisol not only increased GR phosphorylation. It also induced changes in the expression of known GR target genes in retinal explants. Finally, retinal functionality was improved by AAV-mediated overexpression of GR in Müller cells. Our study demonstrates an important role of the glial GR in DR and implies that therapeutic approaches targeting this signalling pathway should be aimed at increasing GR expression rather than the addition of more ligand., (© 2024. The Author(s).)
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- 2024
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15. Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease.
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Cardon I, Grobecker S, Kücükoktay S, Bader S, Jahner T, Nothdurfter C, Koschitzki K, Berneburg M, Weber BHF, Stöhr H, Höring M, Liebisch G, Braun F, Rothammer-Hampl T, Riemenschneider MJ, Rupprecht R, Milenkovic VM, and Wetzel CH
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- Humans, Astrocytes, Depression, Mitochondria, Neurons, Fibroblasts, Mitomycin, Depressive Disorder, Major, Caricaceae
- Abstract
The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria's involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD's pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient ("Non-R") and another with an unexplained mitochondrial disorder ("Mito"). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient's data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient's data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.
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- 2024
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16. Targeted sequencing and in vitro splice assays shed light on ABCA4-associated retinopathies missing heritability.
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Corradi Z, Khan M, Hitti-Malin R, Mishra K, Whelan L, Cornelis SS, Hoyng CB, Kämpjärvi K, Klaver CCW, Liskova P, Stöhr H, Weber BHF, Banfi S, Farrar GJ, Sharon D, Zernant J, Allikmets R, Dhaenens CM, and Cremers FPM
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- Humans, HEK293 Cells, Mutation genetics, Sequence Analysis, ATP-Binding Cassette Transporters genetics, Macular Degeneration genetics, Retinal Dystrophies genetics
- Abstract
The ABCA4 gene is the most frequently mutated Mendelian retinopathy-associated gene. Biallelic variants lead to a variety of phenotypes, however, for thousands of cases the underlying variants remain unknown. Here, we aim to shed further light on the missing heritability of ABCA4-associated retinopathy by analyzing a large cohort of macular dystrophy probands. A total of 858 probands were collected from 26 centers, of whom 722 carried no or one pathogenic ABCA4 variant, while 136 cases carried two ABCA4 alleles, one of which was a frequent mild variant, suggesting that deep-intronic variants (DIVs) or other cis-modifiers might have been missed. After single molecule molecular inversion probes (smMIPs)-based sequencing of the complete 128-kb ABCA4 locus, the effect of putative splice variants was assessed in vitro by midigene splice assays in HEK293T cells. The breakpoints of copy number variants (CNVs) were determined by junction PCR and Sanger sequencing. ABCA4 sequence analysis solved 207 of 520 (39.8%) naive or unsolved cases and 70 of 202 (34.7%) monoallelic cases, while additional causal variants were identified in 54 of 136 (39.7%) probands carrying two variants. Seven novel DIVs and six novel non-canonical splice site variants were detected in a total of 35 alleles and characterized, including the c.6283-321C>G variant leading to a complex splicing defect. Additionally, four novel CNVs were identified and characterized in five alleles. These results confirm that smMIPs-based sequencing of the complete ABCA4 gene provides a cost-effective method to genetically solve retinopathy cases and that several rare structural and splice altering defects remain undiscovered in Stargardt disease cases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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17. Polarized Desmosome and Hemidesmosome Shedding via Small Extracellular Vesicles is an Early Indicator of Outer Blood-Retina Barrier Dysfunction.
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Hernandez BJ, Skiba NP, Plössl K, Strain M, Liu Y, Grigsby D, Kelly U, Cady MA, Manocha V, Maminishkis A, Watkins T, Miller SS, Ashley-Koch A, Stamer WD, Weber BHF, Bowes Rickman C, and Klingeborn M
- Abstract
The retinal pigmented epithelium (RPE) constitutes the outer blood-retinal barrier, enables photoreceptor function of the eye, and is constantly exposed to oxidative stress. As such, dysfunction of the RPE underlies pathology leading to development of age-related macular degeneration (AMD), the leading cause of vision loss among the elderly in industrialized nations. A major responsibility of the RPE is to process photoreceptor outer segments, which relies on the proper functioning of its endocytic pathways and endosomal trafficking. Exosomes and other extracellular vesicles (EVs) from RPE are an essential part of these pathways and may be early indicators of cellular stress. To test the role of small EVs (sEVs) including exosomes, that may underlie the early stages of AMD, we used a polarized primary RPE cell culture model under chronic subtoxic oxidative stress. Unbiased proteomic analyses of highly purified basolateral sEVs from oxidatively stressed RPE cultures revealed changes in proteins involved in epithelial barrier integrity. There were also significant changes in proteins accumulating in the basal-side sub-RPE extracellular matrix during oxidative stress, that could be prevented with an inhibitor of sEV release. Thus, chronic subtoxic oxidative stress in primary RPE cultures induces changes in sEV content, including basal-side specific desmosome and hemidesmosome shedding via sEVs. These findings provide novel biomarkers of early cellular dysfunction and opportunity for therapeutic intervention in age-related retinal diseases (e.g., AMD)., Competing Interests: Declaration of Interest Statement We confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
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- 2023
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18. Genetic Risk Score Analysis Supports a Joint View of Two Classification Systems for Age-Related Macular Degeneration.
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Herold JM, Zimmermann ME, Gorski M, Günther F, Weber BHF, Helbig H, Stark KJ, Heid IM, and Brandl C
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- Humans, Cross-Sectional Studies, Area Under Curve, Fundus Oculi, Risk Factors, Macular Degeneration diagnosis, Macular Degeneration genetics
- Abstract
Purpose: The purpose of this study was to evaluate the utility of combining the Clinical Classification (CC) and the Three Continent age-related macular degeneration (AMD) Consortium Severity Scale (3CACSS) for classification of AMD., Methods: In two independent cross-sectional datasets of our population-based AugUR study (Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg), we graded AMD via color fundus images applying two established classification systems (CC and 3CACSS). We calculated the genetic risk score (GRS) across 50 previously identified variants for late AMD, its association via logistic regression, and area under the curve (AUC) for each AMD stage., Results: We analyzed 2188 persons aged 70 to 95 years. When comparing the two classification systems, we found a distinct pattern: CC "age-related changes" and CC "early AMD" distinguished individuals with 3CACSS "no AMD"; 3CACSS "mild/moderate/severe early AMD" stages, and distinguished CC "intermediate AMD". This suggested a 7-step scale combining the 2 systems: (i) "no AMD", (ii) "age-related changes", (iii) "very early AMD", (i.e. CC "early"), (iv) "mild early AMD", (v) "moderate early AMD", (vi) "severe early AMD", and (vii) "late AMD". GRS association and diagnostic accuracy increased stepwise by increased AMD severity in the 7-step scale and by increased restriction of controls (e.g. for CC "no AMD without age-related changes": AUC = 55.1%, 95% confidence interval [CI] = 51.6, 58.6, AUC = 62.3%, 95% CI = 59.1, 65.6, AUC = 63.8%, 95% CI = 59.3, 68.3, AUC = 78.1%, 95% CI = 73.6, 82.5, AUC = 82.2%, 95% CI = 78.4, 86.0, and AUC = 79.2%, 95% CI = 75.4, 83.0). A stepwise increase was also observed by increased drusen size and area., Conclusions: The utility of a 7-step scale is supported by our clinical and GRS data. This harmonization and full data integration provides an immediate simplification over using either CC or 3CACSS and helps to sharpen the control group.
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- 2023
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19. Polarized Desmosome and Hemidesmosome Shedding via Exosomes is an Early Indicator of Outer Blood-Retina Barrier Dysfunction.
- Author
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Hernandez BJ, Skiba NP, Plößl K, Strain M, Grigsby D, Kelly U, Cady MA, Manocha V, Maminishkis A, Watkins T, Miller SS, Ashley-Koch A, Stamer WD, Weber BHF, Rickman CB, and Klingeborn M
- Abstract
The retinal pigmented epithelium (RPE) constitutes the outer blood-retinal barrier, enables photoreceptor function of the eye, and is constantly exposed to oxidative stress. As such, dysfunction of the RPE underlies pathology leading to development of age-related macular degeneration (AMD), the leading cause of vision loss among the elderly in industrialized nations. A major responsibility of the RPE is to process photoreceptor outer segments, which relies on the proper functioning of its endocytic pathways and endosomal trafficking. Exosomes and other extracellular vesicles from RPE are an essential part of these pathways and may be early indicators of cellular stress. To test the role of exosomes that may underlie the early stages of AMD, we used a polarized primary RPE cell culture model under chronic subtoxic oxidative stress. Unbiased proteomic analyses of highly purified basolateral exosomes from oxidatively stressed RPE cultures revealed changes in proteins involved in epithelial barrier integrity. There were also significant changes in proteins accumulating in the basal-side sub-RPE extracellular matrix during oxidative stress, that could be prevented with an inhibitor of exosome release. Thus, chronic subtoxic oxidative stress in primary RPE cultures induces changes in exosome content, including basal-side specific desmosome and hemidesmosome shedding via exosomes. These findings provide novel biomarkers of early cellular dysfunction and opportunity for therapeutic intervention in age-related retinal diseases, (e.g., AMD) and broadly from blood-CNS barriers in other neurodegenerative diseases.
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- 2023
- Full Text
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20. Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer.
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Rhiem K, Zachariae S, Waha A, Grill S, Hester A, Golatta M, van Mackelenbergh M, Fehm T, Schlaiß T, Ripperger T, Ledig S, Meisel C, Speiser D, Veselinovic K, Schröder C, Witzel I, Gallwas J, Weber BHF, Solbach C, Aktas B, Hahnen E, Engel C, and Schmutzler R
- Abstract
Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis., Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19-78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression., Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes ( BRCA1 : n = 170 [10.6%]; BRCA2 : n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years ( n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21-1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years., Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed., Competing Interests: Christopher Schröder reports an institutional grant from Illumina and research grants from BMS Stiftung Immunonkologie outside the submitted work. Julia Gallwas is a member of the academic advisory board of the Bundesaerztekammer and was paid for lectures for Merck Sharp & Dohme and Roche Diagnostics between 2017 and 2019. All other authors have no conflicts to declare., (Copyright © 2023 by The Author(s). Published by S. Karger AG, Basel.)
- Published
- 2023
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21. The extracellular microenvironment in immune dysregulation and inflammation in retinal disorders.
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Biasella F, Plössl K, Baird PN, and Weber BHF
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- Humans, Retina pathology, Inflammation pathology, Macular Degeneration genetics, Optic Disk Drusen pathology
- Abstract
Inherited retinal dystrophies (IRDs) as well as genetically complex retinal phenotypes represent a heterogenous group of ocular diseases, both on account of their phenotypic and genotypic characteristics. Therefore, overlaps in clinical features often complicate or even impede their correct clinical diagnosis. Deciphering the molecular basis of retinal diseases has not only aided in their disease classification but also helped in our understanding of how different molecular pathologies may share common pathomechanisms. In particular, these relate to dysregulation of two key processes that contribute to cellular integrity, namely extracellular matrix (ECM) homeostasis and inflammation. Pathological changes in the ECM of Bruch's membrane have been described in both monogenic IRDs, such as Sorsby fundus dystrophy (SFD) and Doyne honeycomb retinal dystrophy (DHRD), as well as in the genetically complex age-related macular degeneration (AMD) or diabetic retinopathy (DR). Additionally, complement system dysfunction and distorted immune regulation may also represent a common connection between some IRDs and complex retinal degenerations. Through highlighting such overlaps in molecular pathology, this review aims to illuminate how inflammatory processes and ECM homeostasis are linked in the healthy retina and how their interplay may be disturbed in aging as well as in disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Biasella, Plössl, Baird and Weber.)
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- 2023
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22. Systems genomics in age-related macular degeneration.
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den Hollander AI, Mullins RF, Orozco LD, Voigt AP, Chen HH, Strunz T, Grassmann F, Haines JL, Kuiper JJW, Tumminia SJ, Allikmets R, Hageman GS, Stambolian D, Klaver CCW, Boeke JD, Chen H, Honigberg L, Katti S, Frazer KA, Weber BHF, and Gorin MB
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- Humans, Retinal Pigment Epithelium metabolism, Complement System Proteins metabolism, Choroid metabolism, Proteins genetics, Genomics, Polymorphism, Single Nucleotide, Complement Factor H genetics, Complement Factor H metabolism, High-Temperature Requirement A Serine Peptidase 1 genetics, Macular Degeneration genetics, Macular Degeneration metabolism
- Abstract
Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD., Competing Interests: Declaration of competing interest AIdH is currently an employee of AbbVie; LDO, HHC, HC and LH are employees of Genentech; SK is an employee of Gemini Therapeutics. GSH is a shareholder, consultant, and co-founder of Perceive Biotherapeutics, Inc. and an inventor on patents and patent applications owned by the University of Iowa and the University of Utah. RFM, APV, TS, FG, JLH, JJW, SJT, RA, DS, CCWK, JDB, KAF, BHFW and MBG have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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23. Transient Retention of Photoreceptor Outer Segments in Matrigel-Embedded Retinal Organoids.
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Berber P, Bondarenko S, Michaelis L, and Weber BHF
- Subjects
- Organoids, Retina physiology, Cell Differentiation, Photoreceptor Cells, Retinal Pigment Epithelium metabolism, Induced Pluripotent Stem Cells
- Abstract
Retinal organoids (ROs) are three-dimensional retinal tissues, which are differentiated in vitro from induced pluripotent stem cells (iPSC), ultimately forming all main retinal cell types under defined culture conditions. ROs show several highly specialized retinal features, including the outgrowth of photoreceptor outer segments (OSs). In vivo, the photoreceptor OSs are enveloped and maintained by protrusions of retinal pigment epithelium (RPE) cells, the so-called apical microvilli, while ROs fail to recapitulate this critical interaction in culture development. Here, we define specific co-culture conditions aiming to compensate for the missing physical proximity of RPE and OSs in RO development. Accordingly, functional RPE cells and ROs were differentiated simultaneously from the same iPSC clone, the former resulting in byproduct RPE or bRPE cells. While some co-culture approaches indicated a temporary functional interaction between bRPE and RO photoreceptors, they did not improve the photoreceptor histoarchitecture. In contrast, embedding ROs in a basement membrane extract without bRPE cells showed a robust improvement in the rate of photoreceptor OS retention. RO embedding is a quick and easy method that greatly enhances the preservation of photoreceptor OSs, an important structure for modelling retinal diseases with the involvement of photoreceptors.
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- 2022
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24. Retinoschisin and novel Na/K-ATPase interaction partners Kv2.1 and Kv8.2 define a growing protein complex at the inner segments of mammalian photoreceptors.
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Schmid V, Wurzel A, Wetzel CH, Plössl K, Bruckmann A, Luckner P, Weber BHF, and Friedrich U
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- Animals, Male, Mammals metabolism, Mice, Photoreceptor Cells metabolism, Potassium metabolism, Sodium-Potassium-Exchanging ATPase genetics, Sodium-Potassium-Exchanging ATPase metabolism, Swine, Eye Proteins genetics, Retinoschisis genetics, Retinoschisis metabolism, Retinoschisis pathology
- Abstract
The RS1 gene on Xp 22.13 encodes retinoschisin which is known to directly interact with the retinal Na/K-ATPase at the photoreceptor inner segments. Pathologic mutations in RS1 cause X-linked juvenile retinoschisis (XLRS), a hereditary retinal dystrophy in young males. To further delineate the retinoschisin-Na/K-ATPase complex, co-immunoprecipitation was performed with porcine and murine retinal lysates targeting the ATP1A3 subunit. This identified the voltage-gated potassium (Kv) channel subunits Kv2.1 and Kv8.2 as direct interaction partners of the retinal Na/K-ATPase. Colocalization of the individual components of the complex was demonstrated at the membrane of photoreceptor inner segments. We further show that retinoschisin-deficiency, a frequent consequence of molecular pathology in XLRS, causes mislocalization of the macromolecular complex during postnatal retinal development with a simultaneous reduction of Kv2.1 and Kv8.2 protein expression, while the level of retinal Na/K-ATPase expression remains unaffected. Patch-clamp analysis revealed no effect of retinoschisin-deficiency on Kv channel mediated potassium ion currents in vitro. Together, our data suggest that Kv2.1 and Kv8.2 together with retinoschisin and the retinal Na/K-ATPase are integral parts of a macromolecular complex at the photoreceptor inner segments. Defective compartmentalization of this complex due to retinoschisin-deficiency may be a crucial step in initial XLRS pathogenesis., (© 2022. The Author(s).)
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- 2022
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25. Uncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry.
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Dumont M, Weber-Lassalle N, Joly-Beauparlant C, Ernst C, Droit A, Feng BJ, Dubois S, Collin-Deschesnes AC, Soucy P, Vallée M, Fournier F, Lemaçon A, Adank MA, Allen J, Altmüller J, Arnold N, Ausems MGEM, Berutti R, Bolla MK, Bull S, Carvalho S, Cornelissen S, Dufault MR, Dunning AM, Engel C, Gehrig A, Geurts-Giele WRR, Gieger C, Green J, Hackmann K, Helmy M, Hentschel J, Hogervorst FBL, Hollestelle A, Hooning MJ, Horváth J, Ikram MA, Kaulfuß S, Keeman R, Kuang D, Luccarini C, Maier W, Martens JWM, Niederacher D, Nürnberg P, Ott CE, Peters A, Pharoah PDP, Ramirez A, Ramser J, Riedel-Heller S, Schmidt G, Shah M, Scherer M, Stäbler A, Strom TM, Sutter C, Thiele H, van Asperen CJ, van der Kolk L, van der Luijt RB, Volk AE, Wagner M, Waisfisz Q, Wang Q, Wang-Gohrke S, Weber BHF, Genome Of The Netherlands Project, Ghs Study Group, Devilee P, Tavtigian S, Bader GD, Meindl A, Goldgar DE, Andrulis IL, Schmutzler RK, Easton DF, Schmidt MK, Hahnen E, and Simard J
- Abstract
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
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- 2022
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26. Genetic Association Analysis of Anti-VEGF Treatment Response in Neovascular Age-Related Macular Degeneration.
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Strunz T, Pöllmann M, Gamulescu MA, Tamm S, and Weber BHF
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- Angiogenesis Inhibitors therapeutic use, Antibodies, Monoclonal therapeutic use, Humans, Intravitreal Injections, Ranibizumab therapeutic use, Treatment Outcome, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A therapeutic use, Vascular Endothelial Growth Factors, Genome-Wide Association Study, Macular Degeneration drug therapy, Macular Degeneration genetics
- Abstract
Anti-VEGF treatment for neovascular age-related macular degeneration (nAMD) has been FDA-approved in 2004, and since then has helped tens of thousands of patients worldwide to preserve vision. Still, treatment responses vary widely, emphasizing the need for genetic biomarkers to robustly separate responders from non-responders. Here, we report the findings of an observational study compromising 179 treatment-naïve nAMD patients and their reaction to treatment after three monthly doses of anti-VEGF antibodies. We show that established criteria of treatment response such as visual acuity and central retinal thickness successfully divides our cohort into 128 responders and 51 non-responders. Nevertheless, retinal thickness around the fovea revealed significant reaction to treatment even in the formally categorized non-responders. To elucidate genetic effects underlying our criteria, we conducted an undirected genome-wide association study followed by a directed replication study of 30 previously reported genetic variants. Remarkably, both approaches failed to result in significant findings, suggesting study-specific effects were confounding the present and previous discovery studies. Of note, all studies so far are greatly underpowered, hampering interpretation of genetic findings. In consequence, we highlight the need for an extensive phenotyping study with sample sizes exceeding at least 15,000 to reliably assess anti-VEGF treatment responses in nAMD.
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- 2022
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27. Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology.
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Biasella F, Strunz T, Kiel C, On Behalf Of The International Amd Genomics Consortium Iamdgc, Weber BHF, and Friedrich U
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- Aged, Angiogenesis Inhibitors, Endothelial Cells, Genome-Wide Association Study, Humans, Middle Aged, Vascular Endothelial Growth Factor A, Visual Acuity, Macular Degeneration genetics, Macular Degeneration pathology, Plasminogen Activator Inhibitor 1 genetics, Vitronectin genetics
- Abstract
The pathogenesis of age-related macular degeneration (AMD), a frequent disorder of the central retina, is incompletely understood. Genome-wide association studies (GWAS) suggest a strong contribution of genomic variation in AMD susceptibility. Nevertheless, little is known about biological mechanisms of the disease. We reported previously that the AMD-associated polymorphism rs704C > T in the vitronectin (VTN) gene influences protein expression and functional aspects of encoded vitronectin, a human blood and extracellular matrix (ECM) protein. Here, we refined the association of rs704 with AMD in 16,144 cases and 17,832 controls and noted that rs704 is carried exclusively by the neovascular AMD subtype. Interaction studies demonstrate that rs704 affects the ability of vitronectin to bind the angiogenic regulator plasminogen activator inhibitor 1 (PAI-1) but has no influence on stabilizing its active state. Western blot analysis and confocal imaging reveal a strong enrichment of PAI-1 in the ECM of cultured endothelial cells and RPE cell line ARPE-19 exposed to vitronectin. Large-scale gene expression of VTN and PAI-1 showed positive correlations and a statistically significant increase in human retinal and blood tissues aged 60 years and older. Our results suggest a mechanism by which the AMD-associated rs704 variant in combination with ageing may contribute to the vascular complications in AMD.
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- 2022
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28. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants.
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Li S, Silvestri V, Leslie G, Rebbeck TR, Neuhausen SL, Hopper JL, Nielsen HR, Lee A, Yang X, McGuffog L, Parsons MT, Andrulis IL, Arnold N, Belotti M, Borg Å, Buecher B, Buys SS, Caputo SM, Chung WK, Colas C, Colonna SV, Cook J, Daly MB, de la Hoya M, de Pauw A, Delhomelle H, Eason J, Engel C, Evans DG, Faust U, Fehm TN, Fostira F, Fountzilas G, Frone M, Garcia-Barberan V, Garre P, Gauthier-Villars M, Gehrig A, Glendon G, Goldgar DE, Golmard L, Greene MH, Hahnen E, Hamann U, Hanson H, Hassan T, Hentschel J, Horvath J, Izatt L, Janavicius R, Jiao Y, John EM, Karlan BY, Kim SW, Konstantopoulou I, Kwong A, Laugé A, Lee JW, Lesueur F, Mebirouk N, Meindl A, Mouret-Fourme E, Musgrave H, Ngeow Yuen Yie J, Niederacher D, Park SK, Pedersen IS, Ramser J, Ramus SJ, Rantala J, Rashid MU, Reichl F, Ritter J, Rump A, Santamariña M, Saule C, Schmidt G, Schmutzler RK, Senter L, Shariff S, Singer CF, Southey MC, Stoppa-Lyonnet D, Sutter C, Tan Y, Teo SH, Terry MB, Thomassen M, Tischkowitz M, Toland AE, Torres D, Vega A, Wagner SA, Wang-Gohrke S, Wappenschmidt B, Weber BHF, Yannoukakos D, Spurdle AB, Easton DF, Chenevix-Trench G, Ottini L, and Antoniou AC
- Subjects
- BRCA1 Protein genetics, BRCA2 Protein genetics, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Newborn, Male, Mutation, Risk, Breast Neoplasms, Breast Neoplasms, Male, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms genetics
- Abstract
Purpose: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management., Methods: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment., Results: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers., Conclusion: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs., Competing Interests: Timothy R. RebbeckHonoraria: AstraZeneca (I)Consulting or Advisory Role: AstraZeneca (I) Andrew LeeEmployment: IlluminaPatents, Royalties, Other Intellectual Property: I am an inventor of the BOADICEA model that is licensed to Cambridge Enterprise (part of the University of Cambridge) for commercialization. I have received royalties from Cambridge Enterprise. Norbert ArnoldHonoraria: AstraZeneca Åke BorgHonoraria: Roche, AstraZenecaTravel, Accommodations, Expenses: Roche, AstraZeneca Sandrine CaputoResearch Funding: AstraZeneca/France (Inst) Wendy K. ChungConsulting or Advisory Role: RegeneronResearch Funding: Biogen Chrystelle ColasConsulting or Advisory Role: AstraZeneca/Merck, Pfizer Miguel de la HoyaConsulting or Advisory Role: AstraZenecaResearch Funding: AstraZeneca D. Gareth EvansHonoraria: AstraZeneca Tanja N. FehmConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD OncologyTravel, Accommodations, Expenses: Roche George FountzilasStock and Other Ownership Interests: GENPREX Inc (I), ARIAD (I), Deciphera Pharmaceuticals Inc (I), Daiichi Sankyo, RFL Holdings, FORMYCONHonoraria: AstraZenecaConsulting or Advisory Role: Pfizer, Roche, NovartisSpeakers' Bureau: Roche (I), LEO Pharma (I), Pfizer (I)Travel, Accommodations, Expenses: Merck (I), Pfizer (I), K.A.M Oncology/Hematology (I) Megan FronePatents, Royalties, Other Intellectual Property: Receive royalties for being a codeveloper of CancerGene Connect Eric HahnenConsulting or Advisory Role: AstraZeneca Helen HansonHonoraria: Pfizer Beth Y. KarlanConsulting or Advisory Role: Roche Pharma AG, Merck, Mercy Bioanalytics, GRAILResearch Funding: GOG Foundation (Inst), NCI-NRG Oncology (Inst), Genentech/Roche (Inst)Patents, Royalties, Other Intellectual Property: US and EU patent on gene signatureOther Relationship: Elsevier Irene KonstantopoulouSpeakers' Bureau: AstraZenecaResearch Funding: AstraZeneca Ava KwongHonoraria: Stryker, AstraZeneca Taiwan Limited, Roche Singapore, Pfizer, AstraZeneca Hong Kong Ltd Joanne Ngeow Yuen YieResearch Funding: AstraZeneca Rita K. SchmutzlerHonoraria: AstraZeneca, Clovis, MSD/AstraZenecaConsulting or Advisory Role: AstraZeneca, MSD/AstraZenecaResearch Funding: Amgen Leigha SenterConsulting or Advisory Role: AstraZeneca/MerckSpeakers' Bureau: AstraZeneca/Merck Christian F. SingerHonoraria: Novartis, AstraZeneca/MedImmune, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: AstraZeneca/MedImmune, Daiichi-Sankyo, Gilead Sciences, Sanofi/Aventis, NovartisSpeakers' Bureau: Novartis, AstraZeneca/MedImmuneResearch Funding: Novartis, Sanofi, Myriad Genetics, Roche, AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Novartis Dominique Stoppa-LyonnetHonoraria: AstraZeneca/Merck (Inst) Soo Hwang TeoSpeakers' Bureau: AstraZeneca, Pfizer, Roche Sebastian A. WagnerConsulting or Advisory Role: Bayer Antonis C. AntoniouPatents, Royalties, Other Intellectual Property: Inventor of the BOADICEA model, which has been licensed to Cambridge Enterprise for commercialization. May receive royalties if commercialization is realized.No other potential conflicts of interest were reported.
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- 2022
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29. Seed sequence polymorphism rs2168518 and allele-specific target gene regulation of hsa-miR-4513.
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Kiel C, Strunz T, Hasler D, Meister G, Grassmann F, and Weber BHF
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- Alleles, Animals, Gene Expression Regulation genetics, Humans, Mice, Endothelial Cells metabolism, MicroRNAs metabolism
- Abstract
MicroRNAs (miRNAs) are small post-transcriptional regulators that offer promising targets for treating complex diseases. To this end, hsa-miR-4513 is an excellent candidate as this gene harbors within its conserved heptametrical seed sequence a frequent polymorphism (rs2168518), which has previously been associated with several complex phenotypes. So far, little is known about the biological mechanism(s) underlying these associations. In an initial step, we now aimed to identify allele-specific target genes of hsa-miR-4513. We performed RNA sequencing in a miRNA overexpression model in human umbilical vein endothelial cells transfected with separated hsa-miR-4513 alleles at rs2168518, namely hsa-miR-4513-G and hsa-miR-4513-A. Genes specifically regulated by the rs2168518 alleles were independently verified by quantitative reverse transcription PCR (qRT-PCR), western blot analysis and allele-specific miRNA binding via a luciferase reporter assay. By a text-based search publicly available databases such as Online Mendelian Inheritance in Man and Mouse Genome Informatics were utilized to link target genes of hsa-miR-4513 to previously described phenotypes. Overall, we identified 23 allele-specific hsa-miR-4513 target genes and replicated 19 of those independently via qRT-PCR. Western blot analysis and luciferase reporter assays conducted for an exemplary subsample further confirmed the allele-specific regulation of these genes by hsa-miR-4513. Remarkably, multiple allele-specific target genes identified are linked via text retrieval to several phenotypes previously reported to be associated with hsa-miR-4513. These genes offer promising candidates for ongoing research on the functional pathobiological impact of hsa-miR-4513 and its seed polymorphism rs2168518. This could give rise to therapeutic applications targeting this miRNA., (© The Author(s) 2021. Published by Oxford University Press.)
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- 2022
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30. Incidence, progression and risk factors of age-related macular degeneration in 35-95-year-old individuals from three jointly designed German cohort studies.
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Brandl C, Günther F, Zimmermann ME, Hartmann KI, Eberlein G, Barth T, Winkler TW, Linkohr B, Heier M, Peters A, Li JQ, Finger RP, Helbig H, Weber BHF, Küchenhoff H, Mueller A, Stark KJ, and Heid IM
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Fundus Oculi, Humans, Incidence, Middle Aged, Risk Factors, Macular Degeneration diagnosis
- Abstract
Objective: To estimate age-related macular degeneration (AMD) incidence/progression across a wide age range., Methods and Analysis: AMD at baseline and follow-up (colour fundus imaging, Three Continent AMD Consortium Severity Scale, 3CACSS, clinical classification, CC) was assessed for 1513 individuals aged 35-95 years at baseline from three jointly designed population-based cohorts in Germany: Kooperative Gesundheitsforschung in der Region Augsburg (KORA-Fit, KORA-FF4) and Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg (AugUR) with 18-year, 14-year or 3-year follow-up, respectively. Baseline assessment included lifestyle, metabolic and genetic markers. We derived cumulative estimates, rates and risk factor association for: (1) incident early AMD, (2) incident late AMD among no AMD at baseline (definition 1), (3) incident late AMD among no/early AMD at baseline (definition 2), (4) progression from early to late AMD., Results: Incidence/progression increased by age, except progression in 70+-year old. We observed 35-55-year-old with 3CACSS-based early AMD who progressed to late AMD. Predominant risk factor for incident late AMD definition 2 was early AMD followed by genetics and smoking. When separating incident late AMD definition 1 from progression (instead of combined as incident late AMD definition 2), estimates help judge an individual's risk based on age and (3CACSS) early AMD status: for example, for a 65-year old, 3-year late AMD risk with no or early AMD is 0.5% or 7%, 3-year early AMD risk is 3%; for an 85-year old, these numbers are 0.5%, 21%, 12%, respectively. For CC-based 'early/intermediate' AMD, incidence was higher, but progression was lower., Conclusion: We provide a practical guide for AMD risk for ophthalmology practice and healthcare management and document a late AMD risk for individuals aged <55 years., Competing Interests: Competing interests: TB is a member of the advisory board of Novartis; this is unrelated to the work presented here. RPF is a consultant for Novartis, Bayer, Roche/Genentech, Allergan, Alimera, Böhringer-Ingelheim, Chiesi, ProQR, Opthea and Inositec, and receives research support from Novartis, Biogen, Zeiss Meditec, Heidelberg Engineering and Centrevue; none of this has any relation to the presented work. HH received honoraria for lectures and advisory boards unrelated to this work from Alcon, Allergan, Apellis, Bayer, Novartis and Theapharm. BHFW has cooperation agreements for projects unrelated to this work with Alcon, Allergan, Apellis, Gensight Biologics, Novartis, Shire, F. Hoffmann-La Roche and ModernaTX, and is a member of the clinical advisory board of Gyroscope Therapeutics. IMH has received support from Roche Diagnostics for a project related to age-related macular degeneration, but unrelated to this work presented here. No conflicting relationship exists for the other authors., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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31. Challenges and opportunities for modeling monogenic and complex disorders of the human retina via induced pluripotent stem cell technology.
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Plössl K, Milenkovic A, and Weber BHF
- Abstract
The human retina is a highly structured and complex neurosensory tissue central to perceiving and processing visual signals. In a healthy individual, the close interplay between the neuronal retina, the adjacent retinal pigment epithelium and the underlying blood supply, the choriocapillaris, is critical for maintaining eyesight over a lifetime. An impairment of this delicate and metabolically highly active system, caused by genetic alteration, environmental impact or both, results in a multitude of pathological phenotypes of the retina. Understanding and treating these disease processes are motivated by a marked medical need in young as well as in older patients. While naturally occurring or gene-manipulated animal models have been used successfully in ophthalmological research for many years, recent advances in induced pluripotent stem cell technology have opened up new avenues to generate patient-derived retinal model systems. Here, we explore to what extent these cellular models can be useful to mirror human pathologies in vitro ultimately allowing to analyze disease mechanisms and testing treatment options in the cell type of interest on an individual patient-specific genetic background., Competing Interests: Conflict of interest: The authors state no conflict of interest., (© 2021 Plössl et al., published by De Gruyter.)
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- 2021
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32. Assigning Co-Regulated Human Genes and Regulatory Gene Clusters.
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Strunz T, Kellner M, Kiel C, and Weber BHF
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- Gene Expression Profiling, Genome-Wide Association Study, Humans, Computational Biology methods, Genes, Regulator, Genetic Predisposition to Disease, Multigene Family, Polymorphism, Single Nucleotide, Quantitative Trait Loci
- Abstract
Elucidating the role of genetic variation in the regulation of gene expression is key to understanding the pathobiology of complex diseases which, in consequence, is crucial in devising targeted treatment options. Expression quantitative trait locus (eQTL) analysis correlates a genetic variant with the strength of gene expression, thus defining thousands of regulated genes in a multitude of human cell types and tissues. Some eQTL may not act independently of each other but instead may be regulated in a coordinated fashion by seemingly independent genetic variants. To address this issue, we combined the approaches of eQTL analysis and colocalization studies. Gene expression was determined in datasets comprising 49 tissues from the Genotype-Tissue Expression (GTEx) project. From about 33,000 regulated genes, over 14,000 were found to be co-regulated in pairs and were assembled across all tissues to almost 15,000 unique clusters containing up to nine regulated genes affected by the same eQTL signal. The distance of co-regulated eGenes was, on average, 112 kilobase pairs. Of 713 genes known to express clinical symptoms upon haploinsufficiency, 231 (32.4%) are part of at least one of the identified clusters. This calls for caution should treatment approaches aim at an upregulation of a haploinsufficient gene. In conclusion, we present an unbiased approach to identifying co-regulated genes in and across multiple tissues. Knowledge of such common effects is crucial to appreciate implications on biological pathways involved, specifically when a treatment option targets a co-regulated disease gene.
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- 2021
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33. Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers.
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Borde J, Ernst C, Wappenschmidt B, Niederacher D, Weber-Lassalle K, Schmidt G, Hauke J, Quante AS, Weber-Lassalle N, Horváth J, Pohl-Rescigno E, Arnold N, Rump A, Gehrig A, Hentschel J, Faust U, Dutrannoy V, Meindl A, Kuzyakova M, Wang-Gohrke S, Weber BHF, Sutter C, Volk AE, Giannakopoulou O, Lee A, Engel C, Schmidt MK, Antoniou AC, Schmutzler RK, Kuchenbaecker K, and Hahnen E
- Subjects
- Checkpoint Kinase 2 genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Mutation, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics
- Abstract
Background: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2., Methods: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided., Results: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26)., Conclusions: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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34. Epistatic interactions of genetic loci associated with age-related macular degeneration.
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Kiel C, Nebauer CA, Strunz T, Stelzl S, and Weber BHF
- Subjects
- BRCA1 Protein genetics, BRCA1 Protein metabolism, Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor genetics, Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor metabolism, Complement Pathway, Classical genetics, Extracellular Matrix genetics, Extracellular Matrix metabolism, Gene Expression Regulation, Genetic Variation genetics, Humans, Lipid Metabolism genetics, Liver metabolism, Epistasis, Genetic genetics, Genetic Loci genetics, Macular Degeneration genetics
- Abstract
The currently largest genome-wide association study (GWAS) for age-related macular degeneration (AMD) defines disease association with genome-wide significance for 52 independent common and rare genetic variants across 34 chromosomal loci. Overall, these loci contain over 7200 variants and are enriched for genes with functions indicating several shared cellular processes. Still, the precise mechanisms leading to AMD pathology are largely unknown. Here, we exploit the phenomenon of epistatic interaction to identify seemingly independent AMD-associated variants that reveal joint effects on gene expression. We focus on genetic variants associated with lipid metabolism, organization of extracellular structures, and innate immunity, specifically the complement cascade. Multiple combinations of independent variants were used to generate genetic risk scores allowing gene expression in liver to be compared between low and high-risk AMD. We identified genetic variant combinations correlating significantly with expression of 26 genes, of which 19 have not been associated with AMD before. This study defines novel targets and allows prioritizing further functional work into AMD pathobiology.
- Published
- 2021
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35. Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene.
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Hufendiek K, Hufendiek K, Jägle H, Stöhr H, Book M, Spital G, Rustambayova G, Framme C, Weber BHF, Renner AB, and Kellner U
- Subjects
- Adult, Alleles, Child, Child, Preschool, Eye Diseases, Hereditary diagnostic imaging, Eye Diseases, Hereditary pathology, Female, Humans, Male, Middle Aged, Mutation, Pedigree, Retinal Diseases diagnostic imaging, Retinal Diseases pathology, Bestrophins genetics, Eye Diseases, Hereditary genetics, Phenotype, Retinal Diseases genetics
- Abstract
Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02-1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1 -associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.
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- 2020
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36. Altered Protein Function Caused by AMD-associated Variant rs704 Links Vitronectin to Disease Pathology.
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Biasella F, Plössl K, Karl C, Weber BHF, and Friedrich U
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- Blotting, Western, Cell Encapsulation, Cloning, Molecular, Electrophoresis, Polyacrylamide Gel, Extracellular Matrix metabolism, Fluorescent Antibody Technique, Genetic Variation genetics, Human Umbilical Vein Endothelial Cells, Humans, Macular Degeneration pathology, Protein Isoforms, Recombinant Proteins, Retina cytology, Retina metabolism, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium pathology, Vitronectin metabolism, Macular Degeneration genetics, Vitronectin genetics
- Abstract
Purpose: Vitronectin, a cell adhesion and spreading factor, is suspected to play a role in the pathogenesis of age-related macular degeneration (AMD), as it is a major component of AMD-specific extracellular deposits (e.g., soft drusen, subretinal drusenoid deposits). The present study addressed the impact of AMD-associated non-synonymous variant rs704 in the vitronectin-encoding gene VTN on vitronectin functionality., Methods: Effects of rs704 on vitronectin expression and processing were analyzed by semi-quantitative sequencing of VTN transcripts from retinal pigment epithelium (RPE) cells generated from human induced pluripotent stem cells (hiPSCs) and from human neural retina, as well as by western blot analyses on heterologously expressed vitronectin isoforms. Binding of vitronectin isoforms to retinal and endothelial cells was analyzed by western blot. Immunofluorescence staining followed extracellular matrix (ECM) deposition in cultured RPE cells heterologously expressing the vitronectin isoforms. Adhesion of fluorescently labeled RPE or endothelial cells in dependence of recombinant vitronectin or vitronectin-containing ECM was investigated fluorometrically or microscopically. Tube formation and migration assays addressed effects of vitronectin on angiogenesis-related processes., Results: Variant rs704 affected expression, secretion, and processing but not oligomerization of vitronectin. Cell binding and influence on RPE-mediated ECM deposition differed between AMD-risk-associated and non-AMD-risk-associated protein isoforms. Finally, vitronectin affected adhesion and endothelial tube formation., Conclusions: The AMD-risk-associated vitronectin isoform exhibits increased expression and altered functionality in cellular processes related to the sub-RPE aspects of AMD pathology. Although further research is required to address the subretinal disease aspects, this initial study supports an involvement of vitronectin in AMD pathogenesis.
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- 2020
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37. Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration.
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Strunz T, Kiel C, Sauerbeck BL, and Weber BHF
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- Databases, Genetic, Gene Expression genetics, Gene Expression Regulation genetics, Genetic Predisposition to Disease genetics, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Transcriptome genetics, Genome-Wide Association Study trends, Macular Degeneration genetics
- Abstract
Over the last 15 years, genome-wide association studies (GWAS) have greatly advanced our understanding of the genetic landscape of complex phenotypes. Nevertheless, causal interpretations of GWAS data are challenging but crucial to understand underlying mechanisms and pathologies. In this review, we explore to what extend the research community follows up on GWAS data. We have traced the scientific activities responding to the two largest GWAS conducted on age-related macular degeneration (AMD) so far. Altogether 703 articles were manually categorized according to their study type. This demonstrates that follow-up studies mainly involve "Review articles" (33%) or "Genetic association studies" (33%), while 19% of publications report on findings from experimental work. It is striking to note that only three of 16 AMD-associated loci described de novo in 2016 were examined in the four-year follow-up period after publication. A comparative analysis of five studies on gene expression regulation in AMD-associated loci revealed consistent gene candidates for 15 of these loci. Our random survey highlights the fact that functional follow-up studies on GWAS results are still in its early stages hampering a significant refinement of the vast association data and thus a more accurate insight into mechanisms and pathways.
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- 2020
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38. Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD).
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Kiel C, Strunz T, International Amd Genomics Consortium Project Manager Susan Blanton Iamdgc, Grassmann F, and Weber BHF
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- Choroidal Neovascularization genetics, Choroidal Neovascularization metabolism, Chromosomes, Human, Pair 15 genetics, Databases, Genetic, Female, Genetic Loci genetics, Genetic Pleiotropy genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Humans, Male, MicroRNAs metabolism, Polymorphism, Single Nucleotide genetics, Sex Factors, Macular Degeneration genetics, MicroRNAs genetics
- Abstract
Genome-wide association studies (GWAS) have identified an abundance of genetic loci associated with complex traits and diseases. In contrast, in-depth characterization of an individual genetic signal is rarely available. Here, we focus on the genetic variant rs2168518 in 15q24.1 previously associated with age-related macular degeneration (AMD), but only with suggestive evidence. In a two-step procedure, we initially conducted a series of association analyses to further delineate the association of rs2168518 with AMD but also with other complex phenotypes by using large independent datasets from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank. We then performed a functional annotation with reference to gene expression regulation based on data from the Genotype-Tissue Expression (GTEx) project and RegulomeDB. Association analysis revealed a gender-specific association with male AMD patients and an association predominantly with choroidal neovascularization. Further, the AMD association colocalizes with an association signal of several blood pressure-related phenotypes and with the gene expression regulation of CYP1A1 , a member of the cytochrome P450 superfamily of monooxygenases. Functional annotation revealed altered transcription factor (TF) binding sites for gender-specific TFs, including SOX9 and SRY. In conclusion, the pleiotropic 15q24.1 association signal suggests a shared mechanism between blood pressure regulation and choroidal neovascularization with a potential involvement of CYP1A1.
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- 2020
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39. A mega-analysis of expression quantitative trait loci in retinal tissue.
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Strunz T, Kiel C, Grassmann F, Ratnapriya R, Kwicklis M, Karlstetter M, Fauser S, Arend N, Swaroop A, Langmann T, Wolf A, and Weber BHF
- Subjects
- Autopsy, Gene Expression genetics, Gene Expression Profiling methods, Gene Expression Regulation genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Genome-Wide Association Study methods, Genomics methods, Genotype, Healthy Volunteers, Humans, Phenotype, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Retina metabolism, Retina physiology, Retinal Diseases genetics
- Abstract
Significant association signals from genome-wide association studies (GWAS) point to genomic regions of interest. However, for most loci the causative genetic variant remains undefined. Determining expression quantitative trait loci (eQTL) in a disease relevant tissue is an excellent approach to zoom in on disease- or trait-associated association signals and hitherto on relevant disease mechanisms. To this end, we explored regulation of gene expression in healthy retina (n = 311) and generated the largest cis-eQTL data set available to date. Genotype- and RNA-Seq data underwent rigorous quality control protocols before FastQTL was applied to assess the influence of genetic markers on local (cis) gene expression. Our analysis identified 403,151 significant eQTL variants (eVariants) that regulate 3,007 genes (eGenes) (Q-Value < 0.05). A conditional analysis revealed 744 independent secondary eQTL signals for 598 of the 3,007 eGenes. Interestingly, 99,165 (24.71%) of all unique eVariants regulate the expression of more than one eGene. Filtering the dataset for eVariants regulating three or more eGenes revealed 96 potential regulatory clusters. Of these, 31 harbour 130 genes which are partially regulated by the same genetic signal. To correlate eQTL and association signals, GWAS data from twelve complex eye diseases or traits were included and resulted in identification of 80 eGenes with potential association. Remarkably, expression of 10 genes is regulated by eVariants associated with multiple eye diseases or traits. In conclusion, we generated a unique catalogue of gene expression regulation in healthy retinal tissue and applied this resource to identify potentially pleiotropic effects in highly prevalent human eye diseases. Our study provides an excellent basis to further explore mechanisms of various retinal disease etiologies., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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40. Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease.
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Winkler TW, Grassmann F, Brandl C, Kiel C, Günther F, Strunz T, Weidner L, Zimmermann ME, Korb CA, Poplawski A, Schuster AK, Müller-Nurasyid M, Peters A, Rauscher FG, Elze T, Horn K, Scholz M, Cañadas-Garre M, McKnight AJ, Quinn N, Hogg RE, Küchenhoff H, Heid IM, Stark KJ, and Weber BHF
- Subjects
- Case-Control Studies, Humans, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Macular Degeneration genetics, Macular Degeneration pathology, Polymorphism, Single Nucleotide
- Abstract
Background: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD., Methods: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants., Results: Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10
- 8 ), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism)., Conclusions: Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.- Published
- 2020
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41. Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.
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Khan M, Cornelis SS, Pozo-Valero MD, Whelan L, Runhart EH, Mishra K, Bults F, AlSwaiti Y, AlTalbishi A, De Baere E, Banfi S, Banin E, Bauwens M, Ben-Yosef T, Boon CJF, van den Born LI, Defoort S, Devos A, Dockery A, Dudakova L, Fakin A, Farrar GJ, Sallum JMF, Fujinami K, Gilissen C, Glavač D, Gorin MB, Greenberg J, Hayashi T, Hettinga YM, Hoischen A, Hoyng CB, Hufendiek K, Jägle H, Kamakari S, Karali M, Kellner U, Klaver CCW, Kousal B, Lamey TM, MacDonald IM, Matynia A, McLaren TL, Mena MD, Meunier I, Miller R, Newman H, Ntozini B, Oldak M, Pieterse M, Podhajcer OL, Puech B, Ramesar R, Rüther K, Salameh M, Salles MV, Sharon D, Simonelli F, Spital G, Steehouwer M, Szaflik JP, Thompson JA, Thuillier C, Tracewska AM, van Zweeden M, Vincent AL, Zanlonghi X, Liskova P, Stöhr H, Roach JN, Ayuso C, Roberts L, Weber BHF, Dhaenens CM, and Cremers FPM
- Subjects
- ATP-Binding Cassette Transporters genetics, Genomics, Humans, Introns, Mutation, Pedigree, Stargardt Disease, Macular Degeneration genetics, Transcriptome
- Abstract
Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands., Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays., Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband., Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
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- 2020
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42. Retinoschisin and Cardiac Glycoside Crosstalk at the Retinal Na/K-ATPase.
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Schmid V, Plössl K, Schmid C, Bernklau S, Weber BHF, and Friedrich U
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Humans, Immunohistochemistry, Mice, Inbred C57BL, Protein Binding, Signal Transduction, Digoxin metabolism, Eye Proteins metabolism, Ouabain metabolism, Retinoschisis metabolism, Sodium-Potassium-Exchanging ATPase metabolism
- Abstract
Purpose: Mutations in the RS1 gene, which encodes retinoschisin, cause X-linked juvenile retinoschisis, a retinal dystrophy in males. Retinoschisin specifically interacts with the retinal sodium-potassium adenosine triphosphatase (Na/K-ATPase), a transmembrane ion pump. Na/K-ATPases also bind cardiac glycosides, which control the activity of the pump and have been linked to disturbances in retinal homeostasis. In this study, we investigated the crosstalk between retinoschisin and cardiac glycosides at the retinal Na/K-ATPase and the consequences of this interplay on retinal integrity., Methods: The effect of cardiac glycosides (ouabain and digoxin) on the binding of retinoschisin to the retinal Na/K-ATPase was investigated via western blot and immunocytochemistry. Also, the influence of retinoschisin on the binding of cardiac glycosides was analyzed via enzymatic assays, which quantified cardiac glycoside-sensitive Na/K-ATPase pump activity. Moreover, retinoschisin-dependent binding of tritium-labeled ouabain to the Na/K-ATPase was determined. Finally, a reciprocal effect of retinoschisin and cardiac glycosides on Na/K-ATPase localization and photoreceptor degeneration was addressed using immunohistochemistry in retinoschisin-deficient murine retinal explants., Results: Cardiac glycosides displaced retinoschisin from the retinal Na/K-ATPase; however, retinoschisin did not affect cardiac glycoside binding. Notably, cardiac glycosides reduced the capacity of retinoschisin to regulate Na/K-ATPase localization and to protect against photoreceptor degeneration., Conclusions: Our findings reveal opposing effects of retinoschisin and cardiac glycosides on retinal Na/K-ATPase binding and on retinal integrity, suggesting that a fine-tuned interplay between both components is required to maintain retinal homeostasis. This observation provides new insight into the mechanisms underlying the pathological effects of cardiac glycoside treatment on retinal integrity.
- Published
- 2020
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43. A Circulating MicroRNA Profile in a Laser-Induced Mouse Model of Choroidal Neovascularization.
- Author
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Kiel C, Berber P, Karlstetter M, Aslanidis A, Strunz T, Langmann T, Grassmann F, and Weber BHF
- Subjects
- Animals, Cells, Cultured, Choroidal Neovascularization metabolism, Choroidal Neovascularization pathology, Disease Models, Animal, Disease Susceptibility, Endothelial Cells metabolism, Female, Gene Expression Profiling, Gene Expression Regulation, High-Throughput Nucleotide Sequencing, Mice, MicroRNAs genetics, Microglia metabolism, Retina metabolism, Retinal Pigment Epithelium metabolism, Transcriptome, Choroidal Neovascularization blood, Choroidal Neovascularization etiology, Circulating MicroRNA genetics, Lasers adverse effects
- Abstract
Choroidal neovascularization (CNV) is a pathological process in which aberrant blood vessels invade the subretinal space of the mammalian eye. It is a characteristic feature of the prevalent neovascular age-related macular degeneration (nAMD). Circulating microRNAs (cmiRNAs) are regarded as potentially valuable biomarkers for various age-related diseases, including nAMD. Here, we investigated cmiRNA expression in an established laser-induced CNV mouse model. Upon CNV induction in C57Bl/6 mice, blood-derived cmiRNAs were initially determined globally by RNA next generation sequencing, and the most strongly dysregulated cmiRNAs were independently replicated by quantitative reverse transcription PCR (RT-qPCR) in blood, retinal, and retinal pigment epithelium (RPE)/choroidal tissue. Our findings suggest that two miRNAs, mmu-mir-486a-5p and mmur-mir-92a-3p, are consistently dysregulated during CNV formation. Furthermore, in functional in vitro assays, a significant impact of mmu-mir-486a-5p and mmu-mir-92a-3p on murine microglial cell viability was observed, while mmu-mir-92a-3p also showed an impact on microglial mobility. Taken together, we report a robust dysregulation of two miRNAs in blood and RPE/choroid after laser-induced initiation of CNV lesions in mice, highlighting their potential role in pathology and eventual therapy of CNV-associated complications.
- Published
- 2020
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44. [Mutation-Dependent Mechanisms and Their Impact on Targeted Therapeutic Strategies with Reference to Bestrophin 1 and the Bestrophinopathies].
- Author
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Milenkovic A, Brandl C, Nachtigal AL, Kellner U, and Weber BHF
- Subjects
- Bestrophins, Child, Child, Preschool, Chloride Channels genetics, Eye Proteins genetics, Humans, Mutation, Eye Diseases, Hereditary, Retinal Diseases
- Abstract
Bestrophin 1 ( BEST1 ) encodes an integral membrane protein localized in the basolateral aspect of the retinal pigment epithelium. Mutations in BEST1 are associated with distinct retinal dystrophies, the so-called "bestrophinopathies", often causing visual impairment, even in early childhood. The clinical entities of the bestrophinopathies can be distinguished by phenotypic characteristics and mode of inheritance of the respective gene defect. While the autosomal dominant inheritance pattern with one altered copy of BEST1 is common, heterozygous carriers of the autosomal recessive bestrophinopathy are generally but not consistently symptom-free. This review highlights the significance of understanding the underlying molecular mechanisms that contribute to disease pathogenesis of autosomal dominant and autosomal recessive bestrophinopathies. This knowledge is deemed crucial and needs to be considered in future planning of treatment strategies., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)
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- 2020
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45. Insights into the loss of the Y chromosome with age in control individuals and in patients with age-related macular degeneration using genotyping microarray data.
- Author
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Grassmann F, Weber BHF, and Veitia RA
- Subjects
- Aneuploidy, Chromosome Deletion, Genotype, Humans, Leukocytes physiology, Male, Aging genetics, Chromosomes, Human, Y genetics, Macular Degeneration genetics
- Abstract
The extent of aneuploidy of the sex chromosomes increases with age in human leukocytes. Here, we re-explore the dynamics of normal loss of the Y chromosome (LOY) with age based on microarray data using two exponential models and two different ways to estimate the fraction of LOY. This analysis shows the existence of a significant correlation between the fraction of LOY estimated from molecular cytogenetics and genotyping microarray data. Although the specific estimates of the parameters for the two exponential models are different from those derived from cytogenetics data, the present analysis in an independent dataset of normal individuals confirms that X0 cells have a selective advantage over XY cells. Moreover, patients with age-related macular degeneration display higher fraction of LOY values and seem to have a predisposition to lose their Y chromosome even at young ages compared to control individuals. As there are no data available for the same individuals at different time points, the parameters reported here are average values drawn from population analyses.
- Published
- 2020
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46. Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies.
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Nachtigal AL, Milenkovic A, Brandl C, Schulz HL, Duerr LMJ, Lang GE, Reiff C, Herrmann P, Kellner U, and Weber BHF
- Subjects
- Cell Line, Choroid Diseases genetics, Choroid Diseases metabolism, Choroid Diseases pathology, Eye Diseases, Hereditary metabolism, Eye Diseases, Hereditary pathology, Genes, Recessive, Genetic Predisposition to Disease genetics, Homeostasis, Humans, Hydrogen-Ion Concentration, Induced Pluripotent Stem Cells, Retina metabolism, Retina pathology, Retinal Degeneration genetics, Retinal Degeneration metabolism, Retinal Degeneration pathology, Retinal Diseases metabolism, Retinal Diseases pathology, Retinal Pigment Epithelium metabolism, Vitelliform Macular Dystrophy, Bestrophins genetics, Bestrophins metabolism, Eye Diseases, Hereditary genetics, Mutation, Phenotype, Retinal Diseases genetics
- Abstract
Best vitelliform macular dystrophy (BD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and the autosomal recessive bestrophinopathy (ARB), together known as the bestrophinopathies, are caused by mutations in the bestrophin-1 ( BEST1 ) gene affecting anion transport through the plasma membrane of the retinal pigment epithelium (RPE). To date, while no treatment exists a better understanding of BEST1-related pathogenesis may help to define therapeutic targets. Here, we systematically characterize functional consequences of mutant BEST1 in thirteen RPE patient cell lines differentiated from human induced pluripotent stem cells (hiPSCs). Both BD and ARB hiPSC-RPEs display a strong reduction of BEST1-mediated anion transport function compared to control, while ADVIRC mutations trigger an increased anion permeability suggesting a stabilized open state condition of channel gating. Furthermore, BD and ARB hiPSC-RPEs differ by the degree of mutant protein turnover and by the site of subcellular protein quality control with adverse effects on lysosomal pH only in the BD-related cell lines. The latter finding is consistent with an altered processing of catalytic enzymes in the lysosomes. The present study provides a deeper insight into distinct molecular mechanisms of the three bestrophinopathies facilitating functional categorization of the more than 300 known BEST1 mutations that result into the distinct retinal phenotypes.
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- 2020
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47. Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial.
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Liao DS, Grossi FV, El Mehdi D, Gerber MR, Brown DM, Heier JS, Wykoff CC, Singerman LJ, Abraham P, Grassmann F, Nuernberg P, Weber BHF, Deschatelets P, Kim RY, Chung CY, Ribeiro RM, Hamdani M, Rosenfeld PJ, Boyer DS, Slakter JS, and Francois CG
- Subjects
- Aged, Aged, 80 and over, Female, Fluorescein Angiography, Geographic Atrophy diagnosis, Geographic Atrophy etiology, Humans, Intravitreal Injections, Male, Middle Aged, Prospective Studies, Tomography, Optical Coherence, Visual Acuity physiology, Complement C3 antagonists & inhibitors, Complement Inactivating Agents therapeutic use, Geographic Atrophy drug therapy, Macular Degeneration complications
- Abstract
Purpose: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA., Design: Prospective, multicenter, randomized, sham-controlled phase 2 study., Participants: Two hundred forty-six patients with GA., Methods: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging., Main Outcome Measures: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events., Results: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%])., Conclusions: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
48. A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration.
- Author
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Strunz T, Lauwen S, Kiel C, Hollander AD, and Weber BHF
- Subjects
- Gene Expression Profiling, Gene Regulatory Networks genetics, Genes genetics, Genome-Wide Association Study, Humans, Genetic Predisposition to Disease genetics, Macular Degeneration genetics, Transcriptome genetics
- Abstract
Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value < 0.001). Gene enrichment analysis highlighted rather systemic than tissue- or cell-specific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature.
- Published
- 2020
- Full Text
- View/download PDF
49. Correlating Adaptive Optics Images to Clinical Findings in Juvenile Macular Dystrophy with Hypotrichosis in Siblings with Homozygous CDH3 Pathogenic Variation.
- Author
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Nasser F, Kempf M, Kurtenbach A, Stöhr H, Weber BHF, Neuhaus C, Rating P, and Zrenner E
- Subjects
- Adolescent, Adult, Cadherins metabolism, DNA Mutational Analysis, Electroretinography, Female, Humans, Hypotrichosis congenital, Hypotrichosis metabolism, Macular Degeneration genetics, Macular Degeneration physiopathology, Male, Siblings, Tomography, Optical Coherence, Cadherins genetics, DNA genetics, Hypotrichosis diagnosis, Macular Degeneration diagnosis, Mutation, Retinal Cone Photoreceptor Cells pathology, Visual Acuity
- Abstract
Objective: We report on two German siblings diagnosed with congenital hypotrichosis and juvenile macular dystrophy, an extremely rare syndrome affecting both hair growth and visual functions., Methods: A detailed ophthalmological examination was carried out including fundus examination, visual acuity assessment, visual field determination, color vision testing, and electrophysiology (electroretinography [ERG]). Additionally, fundus photography and autofluorescence imaging (FAF) was performed, along with optical coherence tomography (OCT) and adaptive optics (AO) fundus imaging. Targeted Sanger sequencing and next-generation gene panel sequencing were carried out., Results: Macular dystrophy was evident in the fundus of both patients, as was a central scotoma in the static visual field. The kinetic visual field was normal. The ERG recordings were also normal, but the amplitudes of the multifocal ERG were reduced in the central 4-5° of the retina. The FAF images revealed a large central hypofluorescent area surrounded by a hyperfluorescent ring. The OCT images showed atrophy in the outer layers and tubulations. The AO images depicted a loss of central photoreceptors, as well as severe central atrophy in patient 1. A cone mosaic was observable in the peripheral AO fundus images of both patients. The disrupted cone mosaic on the AO images correlated with the hypofluorescent areas on autofluorescence. DNA testing identified the homozygous, likely pathogenic variant c.1508G>A/p.(Arg503His) (chr16:68719191) in the CDH3 gene., Conclusions: The two siblings revealed hypotrichosis and macular dystrophy in both eyes. The identification of a homozygous CDH3 mutation in each patient confirms the syndromic entity of hypotrichosis with juvenile macular degeneration., (© 2020 S. Karger AG, Basel.)
- Published
- 2020
- Full Text
- View/download PDF
50. Cell-Type-Specific Complement Expression in the Healthy and Diseased Retina.
- Author
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Pauly D, Agarwal D, Dana N, Schäfer N, Biber J, Wunderlich KA, Jabri Y, Straub T, Zhang NR, Gautam AK, Weber BHF, Hauck SM, Kim M, Curcio CA, Stambolian D, Li M, and Grosche A
- Subjects
- Animals, Humans, Mice, Complement System Proteins metabolism, Retina physiopathology
- Abstract
Complement dysregulation is a feature of many retinal diseases, yet mechanistic understanding at the cellular level is limited. Given this knowledge gap about which retinal cells express complement, we performed single-cell RNA sequencing on ∼92,000 mouse retinal cells and validated our results in five major purified retinal cell types. We found evidence for a distributed cell-type-specific complement expression across 11 cell types. Notably, Müller cells are the major contributor of complement activators c1s, c3, c4, and cfb. Retinal pigment epithelium (RPE) mainly expresses cfh and the terminal complement components, whereas cfi and cfp transcripts are most abundant in neurons. Aging enhances c1s, cfb, cfp, and cfi expression, while cfh expression decreases. Transient retinal ischemia increases complement expression in microglia, Müller cells, and RPE. In summary, we report a unique complement expression signature for murine retinal cell types suggesting a well-orchestrated regulation of local complement expression in the retinal microenvironment., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
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