[{"page":"152","file_date_updated":"2023-09-20T22:30:03Z","day":"19","type":"dissertation","supervisor":[{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178","first_name":"Gaia"}],"status":"public","degree_awarded":"PhD","has_accepted_license":"1","department":[{"_id":"GradSch"},{"_id":"GaNo"}],"file":[{"relation":"main_file","content_type":"application/pdf","creator":"cchlebak","file_id":"12365","access_level":"open_access","date_updated":"2023-09-20T22:30:03Z","file_size":20457465,"embargo":"2023-09-19","file_name":"220923_Thesis_CDotter_Final.pdf","checksum":"896f4cac9adb6d3f26a6605772f4e1a3","date_created":"2023-01-24T13:15:45Z"},{"file_size":22433512,"file_name":"latex_source_CDotter_Thesis_2022.zip","checksum":"ad01bb20da163be6893b7af832e58419","date_created":"2023-02-02T09:15:35Z","embargo_to":"open_access","access_level":"closed","date_updated":"2023-09-20T22:30:03Z","relation":"source_file","content_type":"application/x-zip-compressed","file_id":"12482","creator":"cchlebak"}],"date_created":"2023-01-24T13:09:57Z","month":"09","date_published":"2022-09-19T00:00:00Z","publisher":"Institute of Science and Technology Austria","language":[{"iso":"eng"}],"oa":1,"date_updated":"2023-11-16T13:10:22Z","article_processing_charge":"No","_id":"12364","publication_identifier":{"issn":["2663-337X"]},"user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","project":[{"grant_number":"401299","_id":"254BA948-B435-11E9-9278-68D0E5697425","name":"Probing development and reversibility of autism spectrum disorders"},{"_id":"9B91375C-BA93-11EA-9121-9846C619BF3A","name":"Critical windows and reversibility of ASD associated with mutations in chromatin remodelers","grant_number":"707964"},{"call_identifier":"H2020","_id":"25444568-B435-11E9-9278-68D0E5697425","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508"},{"grant_number":"I04205","_id":"2690FEAC-B435-11E9-9278-68D0E5697425","name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy","call_identifier":"FWF"}],"oa_version":"Published Version","publication_status":"published","citation":{"chicago":"Dotter, Christoph. “Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder.” Institute of Science and Technology Austria, 2022. <a href=\"https://doi.org/10.15479/at:ista:12094\">https://doi.org/10.15479/at:ista:12094</a>.","apa":"Dotter, C. (2022). <i>Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder</i>. Institute of Science and Technology Austria. <a href=\"https://doi.org/10.15479/at:ista:12094\">https://doi.org/10.15479/at:ista:12094</a>","ieee":"C. Dotter, “Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder,” Institute of Science and Technology Austria, 2022.","ista":"Dotter C. 2022. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. Institute of Science and Technology Austria.","short":"C. Dotter, Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder, Institute of Science and Technology Austria, 2022.","mla":"Dotter, Christoph. <i>Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder</i>. Institute of Science and Technology Austria, 2022, doi:<a href=\"https://doi.org/10.15479/at:ista:12094\">10.15479/at:ista:12094</a>.","ama":"Dotter C. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. 2022. doi:<a href=\"https://doi.org/10.15479/at:ista:12094\">10.15479/at:ista:12094</a>"},"abstract":[{"lang":"eng","text":"Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders character\u0002ized by behavioral symptoms such as problems in social communication and interaction, as\r\nwell as repetitive, restricted behaviors and interests. These disorders show a high degree\r\nof heritability and hundreds of risk genes have been identifed using high throughput\r\nsequencing technologies. This genetic heterogeneity has hampered eforts in understanding\r\nthe pathogenesis of ASD but at the same time given rise to the concept of convergent\r\nmechanisms. Previous studies have identifed that risk genes for ASD broadly converge\r\nonto specifc functional categories with transcriptional regulation being one of the biggest\r\ngroups. In this thesis, I focus on this subgroup of genes and investigate the gene regulatory\r\nconsequences of some of them in the context of neurodevelopment.\r\nFirst, we showed that mutations in the ASD and intellectual disability risk gene Setd5 lead\r\nto perturbations of gene regulatory programs in early cell fate specifcation. In addition,\r\nadult animals display abnormal learning behavior which is mirrored at the transcriptional\r\nlevel by altered activity dependent regulation of postsynaptic gene expression. Lastly,\r\nwe link the regulatory function of Setd5 to its interaction with the Paf1 and the NCoR\r\ncomplex.\r\nSecond, by modeling the heterozygous loss of the top ASD gene CHD8 in human cerebral\r\norganoids we demonstrate profound changes in the developmental trajectories of both\r\ninhibitory and excitatory neurons using single cell RNA-sequencing. While the former\r\nwere generated earlier in CHD8+/- organoids, the generation of the latter was shifted to\r\nlater times in favor of a prolonged progenitor expansion phase and ultimately increased\r\norganoid size.\r\nFinally, by modeling heterozygous mutations for four ASD associated chromatin modifers,\r\nASH1L, KDM6B, KMT5B, and SETD5 in human cortical spheroids we show evidence of\r\nregulatory convergence across three of those genes. We observe a shift from dorsal cortical\r\nexcitatory neuron fates towards partially ventralized cell types resembling cells from the\r\nlateral ganglionic eminence. As this project is still ongoing at the time of writing, future\r\nexperiments will aim at elucidating the regulatory mechanisms underlying this shift with\r\nthe aim of linking these three ASD risk genes through biological convergence."}],"author":[{"id":"4C66542E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-9033-9096","last_name":"Dotter","full_name":"Dotter, Christoph","first_name":"Christoph"}],"alternative_title":["ISTA Thesis"],"related_material":{"record":[{"status":"public","id":"3","relation":"part_of_dissertation"},{"status":"public","id":"11160","relation":"part_of_dissertation"}]},"ddc":["570"],"doi":"10.15479/at:ista:12094","year":"2022","ec_funded":1,"title":"Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder"},{"abstract":[{"lang":"eng","text":"SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder."}],"author":[{"id":"37A40D7E-F248-11E8-B48F-1D18A9856A87","first_name":"Elena","orcid":"0000-0002-7370-5293","last_name":"Deliu","full_name":"Deliu, Elena"},{"last_name":"Arecco","full_name":"Arecco, Niccoló","first_name":"Niccoló"},{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"id":"4C66542E-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph","last_name":"Dotter","full_name":"Dotter, Christoph","orcid":"0000-0002-9033-9096"},{"id":"475990FE-F248-11E8-B48F-1D18A9856A87","first_name":"Ximena","full_name":"Contreras, Ximena","last_name":"Contreras"},{"last_name":"Girardot","full_name":"Girardot, Charles","first_name":"Charles"},{"last_name":"Käsper","full_name":"Käsper, Eva","first_name":"Eva"},{"id":"C50A9596-02D0-11E9-976E-E38CFE5CBC1D","first_name":"Alena","last_name":"Kozlova","full_name":"Kozlova, Alena"},{"id":"3065DFC4-F248-11E8-B48F-1D18A9856A87","first_name":"Kasumi","last_name":"Kishi","full_name":"Kishi, Kasumi"},{"first_name":"Ilaria","orcid":"0000-0002-9529-4464","last_name":"Chiaradia","full_name":"Chiaradia, Ilaria","id":"B6467F20-02D0-11E9-BDA5-E960C241894A"},{"full_name":"Noh, Kyung","last_name":"Noh","first_name":"Kyung"},{"first_name":"Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino","full_name":"Novarino, Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"citation":{"apa":"Deliu, E., Arecco, N., Morandell, J., Dotter, C., Contreras, X., Girardot, C., … Novarino, G. (2018). Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. <i>Nature Neuroscience</i>. Nature Publishing Group. <a href=\"https://doi.org/10.1038/s41593-018-0266-2\">https://doi.org/10.1038/s41593-018-0266-2</a>","ieee":"E. Deliu <i>et al.</i>, “Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition,” <i>Nature Neuroscience</i>, vol. 21, no. 12. Nature Publishing Group, pp. 1717–1727, 2018.","chicago":"Deliu, Elena, Niccoló Arecco, Jasmin Morandell, Christoph Dotter, Ximena Contreras, Charles Girardot, Eva Käsper, et al. “Haploinsufficiency of the Intellectual Disability Gene SETD5 Disturbs Developmental Gene Expression and Cognition.” <i>Nature Neuroscience</i>. Nature Publishing Group, 2018. <a href=\"https://doi.org/10.1038/s41593-018-0266-2\">https://doi.org/10.1038/s41593-018-0266-2</a>.","mla":"Deliu, Elena, et al. “Haploinsufficiency of the Intellectual Disability Gene SETD5 Disturbs Developmental Gene Expression and Cognition.” <i>Nature Neuroscience</i>, vol. 21, no. 12, Nature Publishing Group, 2018, pp. 1717–27, doi:<a href=\"https://doi.org/10.1038/s41593-018-0266-2\">10.1038/s41593-018-0266-2</a>.","ama":"Deliu E, Arecco N, Morandell J, et al. Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. <i>Nature Neuroscience</i>. 2018;21(12):1717-1727. doi:<a href=\"https://doi.org/10.1038/s41593-018-0266-2\">10.1038/s41593-018-0266-2</a>","short":"E. Deliu, N. Arecco, J. Morandell, C. Dotter, X. Contreras, C. Girardot, E. Käsper, A. Kozlova, K. Kishi, I. Chiaradia, K. Noh, G. Novarino, Nature Neuroscience 21 (2018) 1717–1727.","ista":"Deliu E, Arecco N, Morandell J, Dotter C, Contreras X, Girardot C, Käsper E, Kozlova A, Kishi K, Chiaradia I, Noh K, Novarino G. 2018. Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. Nature Neuroscience. 21(12), 1717–1727."},"publication_status":"published","_id":"3","oa_version":"Submitted Version","quality_controlled":"1","project":[{"_id":"254BA948-B435-11E9-9278-68D0E5697425","name":"Probing development and reversibility of autism spectrum disorders","grant_number":"401299"}],"acknowledgement":"This work was supported by the Simons Foundation Autism Research Initiative (grant 401299) to G.N. and the DFG (SPP1738 grant NO 1249) to K.-M.N.","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","article_processing_charge":"No","date_updated":"2024-03-25T23:30:25Z","publist_id":"8054","oa":1,"volume":21,"external_id":{"isi":["000451324700010"]},"title":"Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition","pubrep_id":"1071","year":"2018","doi":"10.1038/s41593-018-0266-2","acknowledged_ssus":[{"_id":"M-Shop"},{"_id":"PreCl"}],"related_material":{"record":[{"relation":"popular_science","id":"6074","status":"public"},{"id":"12364","relation":"dissertation_contains","status":"public"}],"link":[{"description":"News on IST Homepage","relation":"press_release","url":"https://ist.ac.at/en/news/mutation-that-causes-autism-and-intellectual-disability-makes-brain-less-flexible/"}]},"ddc":["570"],"isi":1,"intvolume":"        21","status":"public","day":"19","type":"journal_article","publication":"Nature Neuroscience","issue":"12","file_date_updated":"2020-07-14T12:45:58Z","page":"1717 - 1727","scopus_import":"1","publisher":"Nature Publishing Group","language":[{"iso":"eng"}],"month":"11","article_type":"original","date_published":"2018-11-19T00:00:00Z","date_created":"2018-12-11T11:44:05Z","file":[{"date_updated":"2020-07-14T12:45:58Z","access_level":"open_access","file_name":"2017_NatureNeuroscience_Deliu.pdf","file_size":8167169,"date_created":"2019-04-09T07:41:57Z","checksum":"60abd0f05b7cdc08a6b0ec460884084f","content_type":"application/pdf","relation":"main_file","creator":"dernst","file_id":"6255"}],"has_accepted_license":"1","department":[{"_id":"GaNo"},{"_id":"EdHa"}]},{"citation":{"ista":"Marin Valencia I, Novarino G, Johansen A, Rosti B, Issa M, Musaev D, Bhat G, Scott E, Silhavy J, Stanley V, Rosti R, Gleeson J, Imam F, Zaki M, Gleeson J. 2018. A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features. Journal of Medical Genetics. 55(1), 48–54.","short":"I. Marin Valencia, G. Novarino, A. Johansen, B. Rosti, M. Issa, D. Musaev, G. Bhat, E. Scott, J. Silhavy, V. Stanley, R. Rosti, J. Gleeson, F. Imam, M. Zaki, J. Gleeson, Journal of Medical Genetics 55 (2018) 48–54.","ama":"Marin Valencia I, Novarino G, Johansen A, et al. A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features. <i>Journal of Medical Genetics</i>. 2018;55(1):48-54. doi:<a href=\"https://doi.org/10.1136/jmedgenet-2017-104627\">10.1136/jmedgenet-2017-104627</a>","mla":"Marin Valencia, Isaac, et al. “A Homozygous Founder Mutation in TRAPPC6B Associates with a Neurodevelopmental Disorder Characterised by Microcephaly Epilepsy and Autistic Features.” <i>Journal of Medical Genetics</i>, vol. 55, no. 1, BMJ Publishing Group, 2018, pp. 48–54, doi:<a href=\"https://doi.org/10.1136/jmedgenet-2017-104627\">10.1136/jmedgenet-2017-104627</a>.","chicago":"Marin Valencia, Isaac, Gaia Novarino, Anide Johansen, Başak Rosti, Mahmoud Issa, Damir Musaev, Gifty Bhat, et al. “A Homozygous Founder Mutation in TRAPPC6B Associates with a Neurodevelopmental Disorder Characterised by Microcephaly Epilepsy and Autistic Features.” <i>Journal of Medical Genetics</i>. BMJ Publishing Group, 2018. <a href=\"https://doi.org/10.1136/jmedgenet-2017-104627\">https://doi.org/10.1136/jmedgenet-2017-104627</a>.","apa":"Marin Valencia, I., Novarino, G., Johansen, A., Rosti, B., Issa, M., Musaev, D., … Gleeson, J. (2018). A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features. <i>Journal of Medical Genetics</i>. BMJ Publishing Group. <a href=\"https://doi.org/10.1136/jmedgenet-2017-104627\">https://doi.org/10.1136/jmedgenet-2017-104627</a>","ieee":"I. Marin Valencia <i>et al.</i>, “A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features,” <i>Journal of Medical Genetics</i>, vol. 55, no. 1. BMJ Publishing Group, pp. 48–54, 2018."},"publication_status":"published","author":[{"first_name":"Isaac","last_name":"Marin Valencia","full_name":"Marin Valencia, Isaac"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia","full_name":"Novarino, Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178"},{"first_name":"Anide","full_name":"Johansen, Anide","last_name":"Johansen"},{"first_name":"Başak","full_name":"Rosti, Başak","last_name":"Rosti"},{"full_name":"Issa, Mahmoud","last_name":"Issa","first_name":"Mahmoud"},{"last_name":"Musaev","full_name":"Musaev, Damir","first_name":"Damir"},{"first_name":"Gifty","last_name":"Bhat","full_name":"Bhat, Gifty"},{"last_name":"Scott","full_name":"Scott, Eric","first_name":"Eric"},{"full_name":"Silhavy, Jennifer","last_name":"Silhavy","first_name":"Jennifer"},{"last_name":"Stanley","full_name":"Stanley, Valentina","first_name":"Valentina"},{"last_name":"Rosti","full_name":"Rosti, Rasim","first_name":"Rasim"},{"first_name":"Jeremy","last_name":"Gleeson","full_name":"Gleeson, Jeremy"},{"first_name":"Farhad","last_name":"Imam","full_name":"Imam, Farhad"},{"first_name":"Maha","full_name":"Zaki, Maha","last_name":"Zaki"},{"first_name":"Joseph","last_name":"Gleeson","full_name":"Gleeson, Joseph"}],"abstract":[{"lang":"eng","text":"Background: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain.\r\n\r\nObjective: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.\r\n\r\nMethods: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease.\r\n\r\nResults: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.\r\n\r\nConclusion: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function."}],"article_processing_charge":"No","publist_id":"7016","volume":55,"oa":1,"date_updated":"2023-10-16T09:55:43Z","oa_version":"Submitted Version","project":[{"grant_number":"401299","_id":"254BA948-B435-11E9-9278-68D0E5697425","name":"Probing development and reversibility of autism spectrum disorders"}],"quality_controlled":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publication_identifier":{"issn":["0022-2593"]},"pmid":1,"_id":"691","year":"2018","doi":"10.1136/jmedgenet-2017-104627","title":"A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features","external_id":{"pmid":["28626029"],"isi":["000418199800007"]},"main_file_link":[{"open_access":"1","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056005/"}],"isi":1,"type":"journal_article","day":"01","status":"public","intvolume":"        55","page":"48 - 54","publication":"Journal of Medical Genetics","issue":"1","article_type":"original","date_published":"2018-01-01T00:00:00Z","month":"01","language":[{"iso":"eng"}],"scopus_import":"1","publisher":"BMJ Publishing Group","department":[{"_id":"GaNo"}],"date_created":"2018-12-11T11:47:57Z"}]