TY  - JOUR
A1  - van Koolwijk, Leonieke M. E.
A1  - Ramdas, Wishal D.
A1  - Ikram, M. Kamran
A1  - Jansonius, Nomdo M.
A1  - Pasutto, Francesca
A1  - Hys, Pirro G.
A1  - Macgregor, Stuart
A1  - Janssen, Sarah F.
A1  - Hewitt, Alex W.
A1  - Viswanathan, Ananth C.
A1  - ten Brink, Jacoline B.
A1  - Hosseini, S. Mohsen
A1  - Amin, Najaf
A1  - Despriet, Dominiek D. G.
A1  - Willemse-Assink, Jacqueline J. M.
A1  - Kramer, Rogier
A1  - Rivadeneira, Fernando
A1  - Struchalin, Maksim
A1  - Aulchenko, Yurii S.
A1  - Weisschuh, Nicole
A1  - Zenkel, Matthias
A1  - Mardin, Christian Y.
A1  - Gramer, Eugen
A1  - Welge-Lüssen, Ulrich
A1  - Montgomery, Grant W.
A1  - Carbonaro, Francis
A1  - Young, Terri L.
A1  - Bellenguez, Céline
A1  - McGuffin, Peter
A1  - Foster, Paul J.
A1  - Topouzis, Fotis
A1  - Mitchell, Paul
A1  - Wang, Jie Jin
A1  - Wong, Tien Y.
A1  - Czudowska, Monika A.
A1  - Hofman, Albert
A1  - Uitterlinden, Andre G.
A1  - Wolfs, Roger C. W.
A1  - de Jong, Paulus T. V. M.
A1  - Oostra, Ben A.
A1  - Paterson, Andrew D.
A1  - Mackey, David A.
A1  - Bergen, Arthur A. B.
A1  - Reis, Andre
A1  - Hammond, Christopher J.
A1  - Vingerling, Johannes R.
A1  - Lemij, Hans G.
A1  - Klaver, Caroline C. W.
A1  - van Duijn, Cornelia M.
T1  - Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma
JF  - PLoS Genetics
N2  - Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4 x 10\(^{-8}\)), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6 x 10\(^{-8}\)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4 x 10\(^{-2}\) for rs11656696 and p = 9.1 x 10\(^{-4}\) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
KW  - expression
KW  - goldmann applanation tonometer
KW  - central corneal thickness
KW  - genome-wide scan
KW  - beaver-dam eye
KW  - to-disc ratio
KW  - onset
KW  - association
KW  - identification
KW  - population
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131378
VL  - 8
IS  - 5
ER  - 
TY  - JOUR
A1  - Kern, Selina
A1  - Agarwal, Shruti
A1  - Huber, Kilian
A1  - Gehring, Andre P.
A1  - Strödke, Benjamin
A1  - Wirth, Christine C.
A1  - Brügl, Thomas
A1  - Abodo, Liane Onambele
A1  - Dandekar, Thomas
A1  - Doerig, Christian
A1  - Fischer, Rainer
A1  - Tobin, Andrew B.
A1  - Alam, Mahmood M.
A1  - Bracher, Franz
A1  - Pradel, Gabriele
T1  - Inhibition of the SR Protein-Phosphorylating CLK Kinases of Plasmodium falciparum Impairs Blood Stage Replication and Malaria Transmission
JF  - PLOS ONE
N2  - Cyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified three plasmodial SR proteins, PfSRSF12, PfSFRS4 and PfSF-1, which are predominantly present in the nucleus of blood stage trophozoites, PfSRSF12 and PfSF-1 are further detectable in the nucleus of gametocytes. We found that recombinantly expressed SR proteins comprising the Arginine/Serine (RS)-rich domains were phosphorylated by the four PfCLKs in in vitro kinase assays, while a recombinant PfSF-1 peptide lacking the RS-rich domain was not phosphorylated. Since it was hitherto not possible to knock-out the pfclk genes by conventional gene disruption, we aimed at chemical knock-outs for phenotype analysis. We identified five human CLK inhibitors, belonging to the oxo-beta-carbolines and aminopyrimidines, as well as the antiseptic chlorhexidine as PfCLK-targeting compounds. The six inhibitors block P. falciparum blood stage replication in the low micromolar to nanomolar range by preventing the trophozoite-to-schizont transformation. In addition, the inhibitors impair gametocyte maturation and gametogenesis in in vitro assays. The combined data show that the four PfCLKs are involved in phosphorylation of SR proteins with essential functions for the blood and sexual stages of the malaria parasite, thus pointing to the kinases as promising targets for antimalarial and transmission blocking drugs.
KW  - parasite
KW  - expression
KW  - mosquito
KW  - splicing factors
KW  - lactate dehydrogenase
KW  - xanthurenic acid
KW  - in-vitro
KW  - RNA-SEQ
KW  - identification
KW  - culture
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115405
SN  - 1932-6203
VL  - 9
IS  - 9
ER  -