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155 results on '"Schmidt-Kastner, Rainald"'

23. F215. Gene- and Pathway-Based Analysis of the Ischemia-Hypoxia Response to Developmental Adversities: Testing the Developmental Origins of Health and Disease (DOHaD) Model in Mental Health

Author

Guloksuz, Sinan, primary, Schmidt-Kastner, Rainald, additional, Richards, Alexander, additional, Drukker, Marjan, additional, Kenis, Gunter, additional, Viechtbauer, Wolfgang, additional, Pishva, Ehsan, additional, Wichers, Marieke, additional, Jacobs, Nele, additional, Thiery, Evert, additional, Derom, Catherine, additional, van Winkel, Ruud, additional, Holmans, Peter, additional, O’Donovan, Michael, additional, van Os, Jim, additional, and Rutten, Bart, additional

Published
2018
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25. Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: possible role in autosomal dominant retinitis pigmentosa

Author

Schmidt-Kastner, Rainald, Yamamoto, Hideo, Hamasaki, Duco, Yamamoto, Hiroko, Parel, Jean-Marie, Schmitz, Christoph, Dorey, C. Kathy, Blanks, Janet C., and Preising, Markus N.

Subjects
Male, Ribonucleoprotein, U4-U6 Small Nuclear, Pancreatitis-Associated Proteins, Ribonucleoproteins, Small Nuclear, Immunohistochemistry, Brain Ischemia, Alternative Splicing, Macaca fascicularis, Mice, Oxidative Stress, Dogs, Antigens, Neoplasm, Databases, Genetic, Animals, Humans, Hypoxia, Brain, Retinitis Pigmentosa, Ribonucleoprotein, U5 Small Nuclear, Research Article, Genes, Dominant
Abstract

Purpose High oxygen consumption and cyclical changes related to dark-adaptation are characteristic of the outer retina. Oxygenation changes may contribute to the selective vulnerability of the retina in retinitis pigmentosa (RP) patients, especially for those forms involving genes with global cellular functions. Genes coding for components of the U4/U6.U5 tri small nuclear ribonucleoprotein (tri-snRNP) complex of the spliceosome stand out, because mutations in four genes cause RP, i.e., RP9 (PAP1), RP11 (PRPF31), RP13 (PRPF8), and RP18 (PRPF3), while there is no degeneration outside the retina despite global expression of these genes. With the assumption that variable oxygenation plays a role in RP forms related to pre-mRNA splicing and the retina and brain are similar, we searched a data collection of ischemia-hypoxia regulated genes of the brain for oxygen regulated genes of the U4/U6.U5 tri-snRNP complex. Methods A database of ischemia-hypoxia response (IHR) genes in the brain was generated from gene expression profiling studies [n=24]. Public databases (NCBI) were searched for RP genes with global function that are expressed in the brain. From the IHR gene list, we extracted genes that were directly related to retinal degeneration through a listed mutation (OMIM, Retnet, RISN). The database was then examined for indirect links to RP forms affecting the U4/U6.U5 tri-snRNP complex by searching for IHR genes contributing to this complex. Potential expression of matched genes in the retina was ascertained using NEIBank. Immunohistochemistry was used to localize a selected protein of the U4/U6.U5 tri-snRNP complex in cynomolgus monkey and human retina specimens. Results The approach identified genes that cause retinal degeneration (CNGB1, SEMA4A, RRG4) or developmental changes (SOX2) when mutated. One IHR gene, Pim1, is the immediate binding partner for PAP1 (RP9). Three IHR genes linked the U4/U6.U5 tri-snRNP complex to regulation by oxygenation: PRPF4; SART1, also known as 110 kDa SR-related protein of the U4/U6.U5 tri-snRNP or as hypoxia associated factor (HAF); and LSM8, U6 snRNA-associated Sm-like protein. The 110 kDa SR-related protein was localized in all retinal cells including photoreceptors. Conclusions Regulation by changes in oxygenation within the U4/U6.U5 tri-snRP complex could be particularly important for photoreceptors where oxygen consumption follows a circadian rhythm. If the U4/U6.U5 tri-snRP complex is already impaired by mutations in any of the four genes causing RP, it may be unable to follow properly the physiological demands of oxygenation which are mediated by the four hypoxia-regulated proteins emerging in this study. Selective vulnerability may involve complex combinations of widely expressed genes, specific cellular functions and local energy availability.

Published
2008

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