Person: Marneros, Alexander
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Marneros
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Alexander
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Marneros, Alexander
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Publication BMS1 Is Mutated in Aplasia Cutis Congenita(Public Library of Science, 2013) Marneros, AlexanderAplasia cutis congenita (ACC) manifests with localized skin defects at birth of unknown cause, mostly affecting the scalp vertex. Here, genome-wide linkage analysis and exome sequencing was used to identify the causative mutation in autosomal dominant ACC. A heterozygous Arg-to-His missense mutation (p.R930H) in the ribosomal GTPase BMS1 is identified in ACC that is associated with a delay in 18S rRNA maturation, consistent with a role of BMS1 in processing of pre-rRNAs of the small ribosomal subunit. Mutations that affect ribosomal function can result in a cell cycle defect and ACC skin fibroblasts with the BMS1 p.R930H mutation show a reduced cell proliferation rate due to a p21-mediated G1/S phase transition delay. Unbiased comparative global transcript and proteomic analyses of ACC fibroblasts with this mutation confirm a central role of increased p21 levels for the ACC phenotype, which are associated with downregulation of heterogenous nuclear ribonucleoproteins (hnRNPs) and serine/arginine-rich splicing factors (SRSFs). Functional enrichment analysis of the proteomic data confirmed a defect in RNA post-transcriptional modification as the top-ranked cellular process altered in ACC fibroblasts. The data provide a novel link between BMS1, the cell cycle, and skin morphogenesis.Publication Increased VEGF‐A promotes multiple distinct aging diseases of the eye through shared pathomechanisms(John Wiley and Sons Inc., 2016) Marneros, AlexanderAbstract While increased VEGF‐A has been associated with neovascular age‐related macular degeneration (AMD), it is not known whether VEGF‐A may also promote other age‐related eye diseases. Here, we show that an increase in VEGF‐A is sufficient to cause multiple distinct common aging diseases of the eye, including cataracts and both neovascular and non‐exudative AMD‐like pathologies. In the lens, increased VEGF‐A induces age‐related opacifications that are associated with ERK hyperactivation, increased oxidative damage, and higher expression of the NLRP3 inflammasome effector cytokine IL‐1β. Similarly, increased VEGF‐A induces oxidative stress and IL‐1β expression also in the retinal pigment epithelium (RPE). Targeting NLRP3 inflammasome components or Il1r1 strongly inhibited not only VEGF‐A‐induced cataract formation, but also both neovascular and non‐exudative AMD‐like pathologies. Moreover, increased VEGF‐A expression specifically in the RPE was sufficient to cause choroidal neovascularization (CNV) as in neovascular AMD, which could be inhibited by RPE‐specific inactivation of Flk1, while Tlr2 inactivation strongly reduced CNV. These findings suggest a shared pathogenic role of VEGF‐A‐induced and NLRP3 inflammasome‐mediated IL‐1β activation for multiple distinct ocular aging diseases.Publication Age-Dependent Iris Abnormalities in Collagen XVIII/Endostatin Deficient Mice with Similarities to Human Pigment Dispersion Syndrome(Association for Research in Vision and Ophthalmology (ARVO), 2003-06-01) Marneros, Alexander; Olsen, BjornPurpose: Collagen XVIII is expressed in ocular basement membranes (BMs) and inactivating mutations cause Knobloch syndrome, with several ocular abnormalities. In this study we investigated ocular structures in collagen XVIII/endostatin (Col18a1(-/-))-deficient mice to elucidate the role of this extracellular matrix component in the eye. Methods: Eyes of Col18a1(-/-) and control mice were examined by light and transmission electron microscopy, laser scanning ophthalmoscopy, and fluorescence angiography. Immunohistochemical analysis of neuronal, epithelial, and immune cells in the eye was performed with antibodies against established cell markers. Results: Col18a1(-/-) mice showed a disruption of the posterior iris pigment epithelial (IPE) cell layer with release of melanin granules. The BM of the posterior IPE was attached to the lens and the nonpigmented epithelium of the ciliary body, which was flattened in mutant mice. In aged mutant mice a severe thickening of the stromal iris BM zone was found, and pigmented cells migrated out of the iris and covered the retina along the inner limiting membrane (ILM), sometimes penetrating into the retina. These cells resembled iris clump cells, and immunohistochemistry demonstrated that they were macrophage-like cells. Furthermore, morphologically abnormal retinal vasculature was seen by fluorescence angiography. Conclusions: The abnormalities in the iris and ciliary body of Col18a1(-/-) mice demonstrate an important role of collagen XVIII for the function of ocular BMs. The absence of this collagen alters the properties of BMs and leads to severe defects in the iris, showing striking similarities to human pigment dispersion syndrome. In addition, loss of collagen XVIII creates changes that allow clump cells to migrate out of the iris. These cells have not been well characterized previously. In the current study we showed that they are macrophage-like cells and are able to penetrate the ILM in mutant mice. The disease mechanism of human pigment dispersion syndrome is not well understood, but Col18a1(-/-) mice may serve as a model and demonstrate the potential importance of alterations in extracellular matrix components in this disease.