--- _id: '12364' abstract: - lang: eng text: "Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders character\x02ized 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." alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Christoph full_name: Dotter, Christoph id: 4C66542E-F248-11E8-B48F-1D18A9856A87 last_name: Dotter orcid: 0000-0002-9033-9096 citation: ama: Dotter C. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. 2022. doi:10.15479/at:ista:12094 apa: Dotter, C. (2022). Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:12094 chicago: Dotter, Christoph. “Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder.” Institute of Science and Technology Austria, 2022. https://doi.org/10.15479/at:ista:12094. 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. mla: Dotter, Christoph. Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder. Institute of Science and Technology Austria, 2022, doi:10.15479/at:ista:12094. short: C. Dotter, Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder, Institute of Science and Technology Austria, 2022. date_created: 2023-01-24T13:09:57Z date_published: 2022-09-19T00:00:00Z date_updated: 2023-11-16T13:10:22Z day: '19' ddc: - '570' degree_awarded: PhD department: - _id: GradSch - _id: GaNo doi: 10.15479/at:ista:12094 ec_funded: 1 file: - access_level: open_access checksum: 896f4cac9adb6d3f26a6605772f4e1a3 content_type: application/pdf creator: cchlebak date_created: 2023-01-24T13:15:45Z date_updated: 2023-09-20T22:30:03Z embargo: 2023-09-19 file_id: '12365' file_name: 220923_Thesis_CDotter_Final.pdf file_size: 20457465 relation: main_file - access_level: closed checksum: ad01bb20da163be6893b7af832e58419 content_type: application/x-zip-compressed creator: cchlebak date_created: 2023-02-02T09:15:35Z date_updated: 2023-09-20T22:30:03Z embargo_to: open_access file_id: '12482' file_name: latex_source_CDotter_Thesis_2022.zip file_size: 22433512 relation: source_file file_date_updated: 2023-09-20T22:30:03Z has_accepted_license: '1' language: - iso: eng month: '09' oa: 1 oa_version: Published Version page: '152' project: - _id: 254BA948-B435-11E9-9278-68D0E5697425 grant_number: '401299' name: Probing development and reversibility of autism spectrum disorders - _id: 9B91375C-BA93-11EA-9121-9846C619BF3A grant_number: '707964' name: Critical windows and reversibility of ASD associated with mutations in chromatin remodelers - _id: 25444568-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '715508' name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models - _id: 2690FEAC-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: I04205 name: Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '3' relation: part_of_dissertation status: public - id: '11160' relation: part_of_dissertation status: public status: public supervisor: - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 title: Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder type: dissertation user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9 year: '2022' ... --- _id: '3' 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. acknowledged_ssus: - _id: M-Shop - _id: PreCl 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. article_processing_charge: No article_type: original author: - first_name: Elena full_name: Deliu, Elena id: 37A40D7E-F248-11E8-B48F-1D18A9856A87 last_name: Deliu orcid: 0000-0002-7370-5293 - first_name: Niccoló full_name: Arecco, Niccoló last_name: Arecco - first_name: Jasmin full_name: Morandell, Jasmin id: 4739D480-F248-11E8-B48F-1D18A9856A87 last_name: Morandell - first_name: Christoph full_name: Dotter, Christoph id: 4C66542E-F248-11E8-B48F-1D18A9856A87 last_name: Dotter orcid: 0000-0002-9033-9096 - first_name: Ximena full_name: Contreras, Ximena id: 475990FE-F248-11E8-B48F-1D18A9856A87 last_name: Contreras - first_name: Charles full_name: Girardot, Charles last_name: Girardot - first_name: Eva full_name: Käsper, Eva last_name: Käsper - first_name: Alena full_name: Kozlova, Alena id: C50A9596-02D0-11E9-976E-E38CFE5CBC1D last_name: Kozlova - first_name: Kasumi full_name: Kishi, Kasumi id: 3065DFC4-F248-11E8-B48F-1D18A9856A87 last_name: Kishi - first_name: Ilaria full_name: Chiaradia, Ilaria id: B6467F20-02D0-11E9-BDA5-E960C241894A last_name: Chiaradia orcid: 0000-0002-9529-4464 - first_name: Kyung full_name: Noh, Kyung last_name: Noh - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 citation: ama: Deliu E, Arecco N, Morandell J, et al. Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. Nature Neuroscience. 2018;21(12):1717-1727. doi:10.1038/s41593-018-0266-2 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. Nature Neuroscience. Nature Publishing Group. https://doi.org/10.1038/s41593-018-0266-2 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.” Nature Neuroscience. Nature Publishing Group, 2018. https://doi.org/10.1038/s41593-018-0266-2. ieee: E. Deliu et al., “Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition,” Nature Neuroscience, vol. 21, no. 12. Nature Publishing Group, pp. 1717–1727, 2018. 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. mla: Deliu, Elena, et al. “Haploinsufficiency of the Intellectual Disability Gene SETD5 Disturbs Developmental Gene Expression and Cognition.” Nature Neuroscience, vol. 21, no. 12, Nature Publishing Group, 2018, pp. 1717–27, doi:10.1038/s41593-018-0266-2. 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. date_created: 2018-12-11T11:44:05Z date_published: 2018-11-19T00:00:00Z date_updated: 2024-03-25T23:30:25Z day: '19' ddc: - '570' department: - _id: GaNo - _id: EdHa doi: 10.1038/s41593-018-0266-2 external_id: isi: - '000451324700010' file: - access_level: open_access checksum: 60abd0f05b7cdc08a6b0ec460884084f content_type: application/pdf creator: dernst date_created: 2019-04-09T07:41:57Z date_updated: 2020-07-14T12:45:58Z file_id: '6255' file_name: 2017_NatureNeuroscience_Deliu.pdf file_size: 8167169 relation: main_file file_date_updated: 2020-07-14T12:45:58Z has_accepted_license: '1' intvolume: ' 21' isi: 1 issue: '12' language: - iso: eng month: '11' oa: 1 oa_version: Submitted Version page: 1717 - 1727 project: - _id: 254BA948-B435-11E9-9278-68D0E5697425 grant_number: '401299' name: Probing development and reversibility of autism spectrum disorders publication: Nature Neuroscience publication_status: published publisher: Nature Publishing Group publist_id: '8054' pubrep_id: '1071' quality_controlled: '1' related_material: 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/ record: - id: '6074' relation: popular_science status: public - id: '12364' relation: dissertation_contains status: public scopus_import: '1' status: public title: Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 21 year: '2018' ... --- _id: '691' 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 article_type: original author: - first_name: Isaac full_name: Marin Valencia, Isaac last_name: Marin Valencia - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 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 - first_name: Mahmoud full_name: Issa, Mahmoud last_name: Issa - first_name: Damir full_name: Musaev, Damir last_name: Musaev - first_name: Gifty full_name: Bhat, Gifty last_name: Bhat - first_name: Eric full_name: Scott, Eric last_name: Scott - first_name: Jennifer full_name: Silhavy, Jennifer last_name: Silhavy - first_name: Valentina full_name: Stanley, Valentina last_name: Stanley - first_name: Rasim full_name: Rosti, Rasim last_name: Rosti - first_name: Jeremy full_name: Gleeson, Jeremy last_name: Gleeson - first_name: Farhad full_name: Imam, Farhad last_name: Imam - first_name: Maha full_name: Zaki, Maha last_name: Zaki - first_name: Joseph full_name: Gleeson, Joseph last_name: Gleeson citation: 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. Journal of Medical Genetics. 2018;55(1):48-54. doi:10.1136/jmedgenet-2017-104627 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. Journal of Medical Genetics. BMJ Publishing Group. https://doi.org/10.1136/jmedgenet-2017-104627 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.” Journal of Medical Genetics. BMJ Publishing Group, 2018. https://doi.org/10.1136/jmedgenet-2017-104627. ieee: I. Marin Valencia et al., “A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features,” Journal of Medical Genetics, vol. 55, no. 1. BMJ Publishing Group, pp. 48–54, 2018. 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. mla: Marin Valencia, Isaac, et al. “A Homozygous Founder Mutation in TRAPPC6B Associates with a Neurodevelopmental Disorder Characterised by Microcephaly Epilepsy and Autistic Features.” Journal of Medical Genetics, vol. 55, no. 1, BMJ Publishing Group, 2018, pp. 48–54, doi:10.1136/jmedgenet-2017-104627. 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. date_created: 2018-12-11T11:47:57Z date_published: 2018-01-01T00:00:00Z date_updated: 2023-10-16T09:55:43Z day: '01' department: - _id: GaNo doi: 10.1136/jmedgenet-2017-104627 external_id: isi: - '000418199800007' pmid: - '28626029' intvolume: ' 55' isi: 1 issue: '1' language: - iso: eng main_file_link: - open_access: '1' url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056005/ month: '01' oa: 1 oa_version: Submitted Version page: 48 - 54 pmid: 1 project: - _id: 254BA948-B435-11E9-9278-68D0E5697425 grant_number: '401299' name: Probing development and reversibility of autism spectrum disorders publication: Journal of Medical Genetics publication_identifier: issn: - 0022-2593 publication_status: published publisher: BMJ Publishing Group publist_id: '7016' quality_controlled: '1' scopus_import: '1' status: public title: A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 55 year: '2018' ...