[{"article_number":"110615","project":[{"_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"},{"call_identifier":"FWF","_id":"2690FEAC-B435-11E9-9278-68D0E5697425","name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy","grant_number":"I04205"}],"citation":{"chicago":"Villa, Carlo Emanuele, Cristina Cheroni, Christoph Dotter, Alejandro López-Tóbon, Bárbara Oliveira, Roberto Sacco, Aysan Çerağ Yahya, et al. “CHD8 Haploinsufficiency Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.” Cell Reports. Elsevier, 2022. https://doi.org/10.1016/j.celrep.2022.110615.","ista":"Villa CE, Cheroni C, Dotter C, López-Tóbon A, Oliveira B, Sacco R, Yahya AÇ, Morandell J, Gabriele M, Tavakoli M, Lyudchik J, Sommer CM, Gabitto M, Danzl JG, Testa G, Novarino G. 2022. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. 39(1), 110615.","mla":"Villa, Carlo Emanuele, et al. “CHD8 Haploinsufficiency Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.” Cell Reports, vol. 39, no. 1, 110615, Elsevier, 2022, doi:10.1016/j.celrep.2022.110615.","apa":"Villa, C. E., Cheroni, C., Dotter, C., López-Tóbon, A., Oliveira, B., Sacco, R., … Novarino, G. (2022). CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. Elsevier. https://doi.org/10.1016/j.celrep.2022.110615","ama":"Villa CE, Cheroni C, Dotter C, et al. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. 2022;39(1). doi:10.1016/j.celrep.2022.110615","short":"C.E. Villa, C. Cheroni, C. Dotter, A. López-Tóbon, B. Oliveira, R. Sacco, A.Ç. Yahya, J. Morandell, M. Gabriele, M. Tavakoli, J. Lyudchik, C.M. Sommer, M. Gabitto, J.G. Danzl, G. Testa, G. Novarino, Cell Reports 39 (2022).","ieee":"C. E. Villa et al., “CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories,” Cell Reports, vol. 39, no. 1. Elsevier, 2022."},"user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","author":[{"last_name":"Villa","full_name":"Villa, Carlo Emanuele","first_name":"Carlo Emanuele"},{"full_name":"Cheroni, Cristina","last_name":"Cheroni","first_name":"Cristina"},{"id":"4C66542E-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph","last_name":"Dotter","orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph"},{"last_name":"López-Tóbon","full_name":"López-Tóbon, Alejandro","first_name":"Alejandro"},{"full_name":"Oliveira, Bárbara","last_name":"Oliveira","id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","first_name":"Bárbara"},{"last_name":"Sacco","full_name":"Sacco, Roberto","first_name":"Roberto","id":"42C9F57E-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Aysan Çerağ","id":"365A65F8-F248-11E8-B48F-1D18A9856A87","full_name":"Yahya, Aysan Çerağ","last_name":"Yahya"},{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"full_name":"Gabriele, Michele","last_name":"Gabriele","first_name":"Michele"},{"id":"3A0A06F4-F248-11E8-B48F-1D18A9856A87","first_name":"Mojtaba","full_name":"Tavakoli, Mojtaba","orcid":"0000-0002-7667-6854","last_name":"Tavakoli"},{"first_name":"Julia","id":"46E28B80-F248-11E8-B48F-1D18A9856A87","last_name":"Lyudchik","full_name":"Lyudchik, Julia"},{"full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","last_name":"Sommer","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Gabitto, Mariano","last_name":"Gabitto","first_name":"Mariano"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","first_name":"Johann G","last_name":"Danzl","full_name":"Danzl, Johann G","orcid":"0000-0001-8559-3973"},{"first_name":"Giuseppe","full_name":"Testa, Giuseppe","last_name":"Testa"},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia"}],"article_processing_charge":"Yes","external_id":{"pmid":["35385734"],"isi":["000785983900003"]},"title":"CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories","acknowledgement":"We thank Farnaz Freeman for technical assistance. This research was supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Bioimaging Facility (BIF) and the Life Science Facility (LSF). This work supported by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 to G.N. (REVERSEAUTISM) and grant 825759 to G.T. (ENDpoiNTs); the Fondazione Cariplo 2017-0886 to A.L.T.; E-Rare-3 JTC 2018 IMPACT to M. Gabriele; and the Austrian Science Fund FWF I 4205-B to G.N. Graphical abstract and figures were created using BioRender.com.","publisher":"Elsevier","quality_controlled":"1","oa":1,"isi":1,"has_accepted_license":"1","year":"2022","day":"05","publication":"Cell Reports","date_published":"2022-04-05T00:00:00Z","doi":"10.1016/j.celrep.2022.110615","date_created":"2022-04-15T09:03:10Z","_id":"11160","article_type":"original","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"status":"public","keyword":["General Biochemistry","Genetics and Molecular Biology"],"date_updated":"2024-03-27T23:30:44Z","ddc":["570"],"department":[{"_id":"JoDa"},{"_id":"GaNo"}],"file_date_updated":"2022-04-15T09:06:25Z","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"abstract":[{"text":"Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a frequent cause of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly, implicating cortical abnormalities, how CHD8 haploinsufficiency affects neurodevelopmental is unclear. Here, employing human cerebral organoids, we find that CHD8 haploinsufficiency disrupted neurodevelopmental trajectories with an accelerated and delayed generation of, respectively, inhibitory and excitatory neurons that yields, at days 60 and 120, symmetrically opposite expansions in their proportions. This imbalance is consistent with an enlargement of cerebral organoids as an in vitro correlate of patients’ macrocephaly. Through an isogenic design of patient-specific mutations and mosaic organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Our results define cell-type-specific CHD8-dependent molecular defects related to an abnormal program of proliferation and alternative splicing. By identifying cell-type-specific effects of CHD8 mutations, our study uncovers reproducible developmental alterations that may be employed for neurodevelopmental disease modeling.","lang":"eng"}],"oa_version":"Published Version","pmid":1,"month":"04","intvolume":" 39","publication_identifier":{"issn":["2211-1247"]},"publication_status":"published","file":[{"file_id":"11164","checksum":"b4e8d68f0268dec499af333e6fd5d8e1","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file","date_created":"2022-04-15T09:06:25Z","file_name":"2022_CellReports_Villa.pdf","date_updated":"2022-04-15T09:06:25Z","file_size":"7808644","creator":"dernst"}],"language":[{"iso":"eng"}],"related_material":{"record":[{"relation":"dissertation_contains","status":"public","id":"12364"}]},"volume":39,"issue":"1","ec_funded":1},{"project":[{"call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425","grant_number":"754411","name":"ISTplus - Postdoctoral Fellowships"},{"name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508","call_identifier":"H2020","_id":"25444568-B435-11E9-9278-68D0E5697425"},{"grant_number":"W1232-B24","name":"Molecular Drug Targets","_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"name":"Neural stem cells in autism and epilepsy","grant_number":"F07807","_id":"05A0D778-7A3F-11EA-A408-12923DDC885E"},{"call_identifier":"FWF","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","grant_number":"I03600","name":"Optical control of synaptic function via adhesion molecules"}],"article_number":"3058","external_id":{"isi":["000658769900010"]},"article_processing_charge":"No","author":[{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"id":"29A8453C-F248-11E8-B48F-1D18A9856A87","first_name":"Lena A","full_name":"Schwarz, Lena A","last_name":"Schwarz"},{"orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette","last_name":"Basilico","first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425"},{"last_name":"Tasciyan","orcid":"0000-0003-1671-393X","full_name":"Tasciyan, Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","first_name":"Saren"},{"full_name":"Dimchev, Georgi A","orcid":"0000-0001-8370-6161","last_name":"Dimchev","id":"38C393BE-F248-11E8-B48F-1D18A9856A87","first_name":"Georgi A"},{"id":"2A103192-F248-11E8-B48F-1D18A9856A87","first_name":"Armel","full_name":"Nicolas, Armel","last_name":"Nicolas"},{"last_name":"Sommer","orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Kreuzinger, Caroline","last_name":"Kreuzinger","id":"382077BA-F248-11E8-B48F-1D18A9856A87","first_name":"Caroline"},{"last_name":"Dotter","orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph","first_name":"Christoph","id":"4C66542E-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","last_name":"Knaus","full_name":"Knaus, Lisa"},{"last_name":"Dobler","full_name":"Dobler, Zoe","first_name":"Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F"},{"full_name":"Cacci, Emanuele","last_name":"Cacci","first_name":"Emanuele"},{"orcid":"0000-0003-4790-8078","full_name":"Schur, Florian KM","last_name":"Schur","id":"48AD8942-F248-11E8-B48F-1D18A9856A87","first_name":"Florian KM"},{"last_name":"Danzl","orcid":"0000-0001-8559-3973","full_name":"Danzl, Johann G","first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"}],"title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","citation":{"chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Georgi A Dimchev, Armel Nicolas, Christoph M Sommer, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” Nature Communications. Springer Nature, 2021. https://doi.org/10.1038/s41467-021-23123-x.","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Dimchev GA, Nicolas A, Sommer CM, Kreuzinger C, Dotter C, Knaus L, Dobler Z, Cacci E, Schur FK, Danzl JG, Novarino G. 2021. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 12(1), 3058.","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” Nature Communications, vol. 12, no. 1, 3058, Springer Nature, 2021, doi:10.1038/s41467-021-23123-x.","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, G.A. Dimchev, A. Nicolas, C.M. Sommer, C. Kreuzinger, C. Dotter, L. Knaus, Z. Dobler, E. Cacci, F.K. Schur, J.G. Danzl, G. Novarino, Nature Communications 12 (2021).","ieee":"J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” Nature Communications, vol. 12, no. 1. Springer Nature, 2021.","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Dimchev, G. A., Nicolas, A., … Novarino, G. (2021). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-021-23123-x","ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 2021;12(1). doi:10.1038/s41467-021-23123-x"},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","oa":1,"quality_controlled":"1","publisher":"Springer Nature","acknowledgement":"We thank A. Coll Manzano, F. Freeman, M. Ladron de Guevara, and A. Ç. Yahya for technical assistance, S. Deixler, A. Lepold, and A. Schlerka for the management of our animal colony, as well as M. Schunn and the Preclinical Facility team for technical assistance. We thank K. Heesom and her team at the University of Bristol Proteomics Facility for the proteomics sample preparation, data generation, and analysis support. We thank Y. B. Simon for kindly providing the plasmid for lentiviral labeling. Further, we thank M. Sixt for his advice regarding cell migration and the fruitful discussions. This work was supported by the ISTPlus postdoctoral fellowship (Grant Agreement No. 754411) to B.B., by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM), and by the Austrian Science Fund (FWF) to G.N. (DK W1232-B24 and SFB F7807-B) and to J.G.D (I3600-B27).","date_created":"2021-05-28T11:49:46Z","date_published":"2021-05-24T00:00:00Z","doi":"10.1038/s41467-021-23123-x","year":"2021","has_accepted_license":"1","isi":1,"publication":"Nature Communications","day":"24","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_type":"original","keyword":["General Biochemistry","Genetics and Molecular Biology"],"status":"public","_id":"9429","department":[{"_id":"GaNo"},{"_id":"JoDa"},{"_id":"FlSc"},{"_id":"MiSi"},{"_id":"LifeSc"},{"_id":"Bio"}],"file_date_updated":"2021-05-28T12:39:43Z","date_updated":"2024-03-27T23:30:23Z","ddc":["572"],"intvolume":" 12","month":"05","acknowledged_ssus":[{"_id":"PreCl"}],"abstract":[{"text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.","lang":"eng"}],"oa_version":"Published Version","ec_funded":1,"issue":"1","volume":12,"related_material":{"link":[{"relation":"press_release","url":"https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/"}],"record":[{"id":"7800","status":"public","relation":"earlier_version"},{"relation":"dissertation_contains","status":"public","id":"12401"}]},"publication_status":"published","publication_identifier":{"eissn":["2041-1723"]},"language":[{"iso":"eng"}],"file":[{"date_created":"2021-05-28T12:39:43Z","file_name":"2021_NatureCommunications_Morandell.pdf","date_updated":"2021-05-28T12:39:43Z","file_size":9358599,"creator":"kschuh","file_id":"9430","checksum":"337e0f7959c35ec959984cacdcb472ba","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file"}]},{"day":"12","has_accepted_license":"1","year":"2020","doi":"10.15479/AT:ISTA:8620","date_published":"2020-10-12T00:00:00Z","date_created":"2020-10-07T14:53:13Z","page":"138","acknowledgement":"I would like to especially thank Armel Nicolas from the Proteomics and Christoph Sommer from the Bioimaging Facilities for the data analysis, and to thank the team of the Preclinical Facility, especially Sabina Deixler, Angela Schlerka, Anita Lepold, Mihalea Mihai and Michael Schun for taking care of the mouse line maintenance and their great support.","publisher":"Institute of Science and Technology Austria","oa":1,"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","citation":{"ista":"Morandell J. 2020. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. Institute of Science and Technology Austria.","chicago":"Morandell, Jasmin. “Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:8620.","ieee":"J. Morandell, “Illuminating the role of Cul3 in autism spectrum disorder pathogenesis,” Institute of Science and Technology Austria, 2020.","short":"J. Morandell, Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis, Institute of Science and Technology Austria, 2020.","apa":"Morandell, J. (2020). Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:8620","ama":"Morandell J. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. 2020. doi:10.15479/AT:ISTA:8620","mla":"Morandell, Jasmin. Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:8620."},"title":"Illuminating the role of Cul3 in autism spectrum disorder pathogenesis","author":[{"first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","last_name":"Morandell","full_name":"Morandell, Jasmin"}],"article_processing_charge":"No","project":[{"name":"Molecular Drug Targets","grant_number":"W1232-B24","call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425"},{"_id":"05A0D778-7A3F-11EA-A408-12923DDC885E","name":"Neural stem cells in autism and epilepsy","grant_number":"F07807"}],"file":[{"embargo":"2021-10-15","checksum":"7ee83e42de3e5ce2fedb44dff472f75f","file_id":"8621","content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_name":"Jasmin_Morandell_Thesis-2020_final.pdf","date_created":"2020-10-07T14:41:49Z","file_size":16155786,"date_updated":"2021-10-16T22:30:04Z","creator":"jmorande"},{"file_id":"8622","checksum":"5e0464af453734210ce7aab7b4a92e3a","relation":"source_file","access_level":"closed","embargo_to":"open_access","content_type":"application/x-zip-compressed","file_name":"Jasmin_Morandell_Thesis-2020_final.zip","date_created":"2020-10-07T14:45:07Z","creator":"jmorande","file_size":24344152,"date_updated":"2021-10-16T22:30:04Z"}],"language":[{"iso":"eng"}],"publication_identifier":{"issn":["2663-337X"]},"publication_status":"published","degree_awarded":"PhD","related_material":{"record":[{"status":"public","id":"7800","relation":"part_of_dissertation"},{"status":"public","id":"8131","relation":"part_of_dissertation"}]},"oa_version":"Published Version","abstract":[{"text":"The development of the human brain occurs through a tightly regulated series of dynamic and adaptive processes during prenatal and postnatal life. A disruption of this strictly orchestrated series of events can lead to a number of neurodevelopmental conditions, including Autism Spectrum Disorders (ASDs). ASDs are a very common, etiologically and phenotypically heterogeneous group of disorders sharing the core symptoms of social interaction and communication deficits and restrictive and repetitive interests and behaviors. They are estimated to affect one in 59 individuals in the U.S. and, over the last three decades, mutations in more than a hundred genetic loci have been convincingly linked to ASD pathogenesis. Yet, for the vast majority of these ASD-risk genes their role during brain development and precise molecular function still remain elusive.\r\nDe novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin 3 (CUL3) lead to ASD. In the study described here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 heterozygous knockout mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3+/-, Cul3+/fl Emx1-Cre and Cul3fl/fl Emx1-Cre mutant brains display cortical lamination abnormalities due to defective migration of post-mitotic excitatory neurons, as well as reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal cortical organization, Cul3 heterozygous deletion is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level we show that Cul3 regulates cytoskeletal and adhesion protein abundance in the mouse embryonic cortex. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neural cells results in atypical organization of the actin mesh at the cell leading edge. Of note, heterozygous deletion of Cul3 in adult mice does not induce the majority of the behavioral defects observed in constitutive Cul3 haploinsufficient animals, pointing to a critical time-window for Cul3 deficiency.\r\nIn conclusion, our data indicate that Cul3 plays a critical role in the regulation of cytoskeletal proteins and neuronal migration. ASD-associated defects and behavioral abnormalities are primarily due to dosage sensitive Cul3 functions at early brain developmental stages.","lang":"eng"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"PreCl"}],"month":"10","alternative_title":["ISTA Thesis"],"ddc":["610"],"supervisor":[{"full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"date_updated":"2023-09-07T13:22:14Z","file_date_updated":"2021-10-16T22:30:04Z","department":[{"_id":"GaNo"}],"_id":"8620","status":"public","type":"dissertation"},{"status":"public","type":"preprint","tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"_id":"7800","department":[{"_id":"JoDa"},{"_id":"GaNo"},{"_id":"LifeSc"}],"file_date_updated":"2020-07-14T12:48:03Z","ddc":["570"],"date_updated":"2024-03-27T23:30:14Z","month":"01","oa_version":"Preprint","abstract":[{"lang":"eng","text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages."}],"acknowledged_ssus":[{"_id":"PreCl"}],"related_material":{"record":[{"id":"9429","status":"public","relation":"later_version"},{"id":"8620","status":"public","relation":"dissertation_contains"}]},"file":[{"file_size":2931370,"date_updated":"2020-07-14T12:48:03Z","creator":"rsix","file_name":"2020.01.10.902064v1.full.pdf","date_created":"2020-05-05T14:31:19Z","content_type":"application/pdf","relation":"main_file","access_level":"open_access","file_id":"7801","checksum":"c6799ab5daba80efe8e2ed63c15f8c81"}],"language":[{"iso":"eng"}],"publication_status":"submitted","project":[{"call_identifier":"FWF","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","name":"Optical control of synaptic function via adhesion molecules","grant_number":"I03600"},{"call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets","grant_number":"W1232-B24"}],"title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","author":[{"first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","last_name":"Morandell","full_name":"Morandell, Jasmin"},{"last_name":"Schwarz","full_name":"Schwarz, Lena A","first_name":"Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","last_name":"Basilico","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173"},{"id":"4323B49C-F248-11E8-B48F-1D18A9856A87","first_name":"Saren","orcid":"0000-0003-1671-393X","full_name":"Tasciyan, Saren","last_name":"Tasciyan"},{"full_name":"Nicolas, Armel","last_name":"Nicolas","first_name":"Armel","id":"2A103192-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","last_name":"Sommer","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"id":"382077BA-F248-11E8-B48F-1D18A9856A87","first_name":"Caroline","last_name":"Kreuzinger","full_name":"Kreuzinger, Caroline"},{"full_name":"Knaus, Lisa","last_name":"Knaus","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","first_name":"Lisa"},{"first_name":"Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F","last_name":"Dobler","full_name":"Dobler, Zoe"},{"first_name":"Emanuele","last_name":"Cacci","full_name":"Cacci, Emanuele"},{"last_name":"Danzl","full_name":"Danzl, Johann G","orcid":"0000-0001-8559-3973","first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","last_name":"Novarino"}],"article_processing_charge":"No","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv. doi:10.1101/2020.01.10.902064 ","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Nicolas, A., Sommer, C. M., … Novarino, G. (n.d.). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.01.10.902064 ","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, A. Nicolas, C.M. Sommer, C. Kreuzinger, L. Knaus, Z. Dobler, E. Cacci, J.G. Danzl, G. Novarino, BioRxiv (n.d.).","ieee":"J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” bioRxiv. Cold Spring Harbor Laboratory.","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2020.01.10.902064 .","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Nicolas A, Sommer CM, Kreuzinger C, Knaus L, Dobler Z, Cacci E, Danzl JG, Novarino G. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv, 10.1101/2020.01.10.902064 .","chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph M Sommer, Caroline Kreuzinger, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2020.01.10.902064 ."},"publisher":"Cold Spring Harbor Laboratory","oa":1,"date_published":"2020-01-11T00:00:00Z","doi":"10.1101/2020.01.10.902064 ","date_created":"2020-05-05T14:31:33Z","day":"11","publication":"bioRxiv","has_accepted_license":"1","year":"2020"},{"scopus_import":"1","month":"12","intvolume":" 65","abstract":[{"lang":"eng","text":"The possibility to generate construct valid animal models enabled the development and testing of therapeutic strategies targeting the core features of autism spectrum disorders (ASDs). At the same time, these studies highlighted the necessity of identifying sensitive developmental time windows for successful therapeutic interventions. Animal and human studies also uncovered the possibility to stratify the variety of ASDs in molecularly distinct subgroups, potentially facilitating effective treatment design. Here, we focus on the molecular pathways emerging as commonly affected by mutations in diverse ASD-risk genes, on their role during critical windows of brain development and the potential treatments targeting these biological processes."}],"pmid":1,"oa_version":"Published Version","volume":65,"issue":"12","related_material":{"record":[{"id":"8620","status":"public","relation":"dissertation_contains"}]},"ec_funded":1,"publication_identifier":{"eissn":["18790380"],"issn":["0959437X"]},"publication_status":"published","file":[{"file_name":"2020_CurrentOpGenetics_Basilico.pdf","date_created":"2020-07-22T06:47:45Z","file_size":1381545,"date_updated":"2020-07-22T06:47:45Z","creator":"dernst","success":1,"file_id":"8146","content_type":"application/pdf","relation":"main_file","access_level":"open_access"}],"language":[{"iso":"eng"}],"article_type":"original","type":"journal_article","tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"status":"public","_id":"8131","file_date_updated":"2020-07-22T06:47:45Z","department":[{"_id":"GaNo"}],"date_updated":"2024-03-27T23:30:14Z","ddc":["570"],"quality_controlled":"1","publisher":"Elsevier","oa":1,"page":"126-137","date_published":"2020-12-01T00:00:00Z","doi":"10.1016/j.gde.2020.06.004","date_created":"2020-07-19T22:00:58Z","has_accepted_license":"1","isi":1,"year":"2020","day":"01","publication":"Current Opinion in Genetics and Development","project":[{"name":"ISTplus - Postdoctoral Fellowships","grant_number":"754411","call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425"},{"_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Molecular Drug Targets","grant_number":"W1232-B24"},{"name":"Neural stem cells in autism and epilepsy","grant_number":"F07807","_id":"05A0D778-7A3F-11EA-A408-12923DDC885E"}],"author":[{"id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette","orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette","last_name":"Basilico"},{"first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","last_name":"Morandell","full_name":"Morandell, Jasmin"},{"first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino"}],"article_processing_charge":"Yes (via OA deal)","external_id":{"pmid":["32659636"],"isi":["000598918900019"]},"title":"Molecular mechanisms for targeted ASD treatments","citation":{"ista":"Basilico B, Morandell J, Novarino G. 2020. Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. 65(12), 126–137.","chicago":"Basilico, Bernadette, Jasmin Morandell, and Gaia Novarino. “Molecular Mechanisms for Targeted ASD Treatments.” Current Opinion in Genetics and Development. Elsevier, 2020. https://doi.org/10.1016/j.gde.2020.06.004.","ieee":"B. Basilico, J. Morandell, and G. Novarino, “Molecular mechanisms for targeted ASD treatments,” Current Opinion in Genetics and Development, vol. 65, no. 12. Elsevier, pp. 126–137, 2020.","short":"B. Basilico, J. Morandell, G. Novarino, Current Opinion in Genetics and Development 65 (2020) 126–137.","apa":"Basilico, B., Morandell, J., & Novarino, G. (2020). Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. Elsevier. https://doi.org/10.1016/j.gde.2020.06.004","ama":"Basilico B, Morandell J, Novarino G. Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. 2020;65(12):126-137. doi:10.1016/j.gde.2020.06.004","mla":"Basilico, Bernadette, et al. “Molecular Mechanisms for Targeted ASD Treatments.” Current Opinion in Genetics and Development, vol. 65, no. 12, Elsevier, 2020, pp. 126–37, doi:10.1016/j.gde.2020.06.004."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8"},{"page":"S11-S12","date_created":"2020-01-30T10:07:41Z","doi":"10.1016/j.euroneuro.2019.09.040","date_published":"2019-12-13T00:00:00Z","issue":"Supplement 6","volume":29,"year":"2019","publication_status":"published","publication_identifier":{"issn":["0924-977X"]},"isi":1,"language":[{"iso":"eng"}],"publication":"European Neuropsychopharmacology","day":"13","quality_controlled":"1","publisher":"Elsevier","intvolume":" 29","month":"12","oa_version":"None","external_id":{"isi":["000502657500021"]},"article_processing_charge":"No","author":[{"first_name":"Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"last_name":"Nicolas","full_name":"Nicolas, Armel","first_name":"Armel","id":"2A103192-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Schwarz","full_name":"Schwarz, Lena A","first_name":"Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","last_name":"Novarino"}],"title":"S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism","department":[{"_id":"GaNo"},{"_id":"LifeSc"}],"date_updated":"2023-09-07T14:56:17Z","citation":{"ista":"Morandell J, Nicolas A, Schwarz LA, Novarino G. 2019. S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism. European Neuropsychopharmacology. 29(Supplement 6), S11–S12.","chicago":"Morandell, Jasmin, Armel Nicolas, Lena A Schwarz, and Gaia Novarino. “S.16.05 Illuminating the Role of the E3 Ubiquitin Ligase Cullin3 in Brain Development and Autism.” European Neuropsychopharmacology. Elsevier, 2019. https://doi.org/10.1016/j.euroneuro.2019.09.040.","apa":"Morandell, J., Nicolas, A., Schwarz, L. A., & Novarino, G. (2019). S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism. European Neuropsychopharmacology. Elsevier. https://doi.org/10.1016/j.euroneuro.2019.09.040","ama":"Morandell J, Nicolas A, Schwarz LA, Novarino G. S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism. European Neuropsychopharmacology. 2019;29(Supplement 6):S11-S12. doi:10.1016/j.euroneuro.2019.09.040","ieee":"J. Morandell, A. Nicolas, L. A. Schwarz, and G. Novarino, “S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism,” European Neuropsychopharmacology, vol. 29, no. Supplement 6. Elsevier, pp. S11–S12, 2019.","short":"J. Morandell, A. Nicolas, L.A. Schwarz, G. Novarino, European Neuropsychopharmacology 29 (2019) S11–S12.","mla":"Morandell, Jasmin, et al. “S.16.05 Illuminating the Role of the E3 Ubiquitin Ligase Cullin3 in Brain Development and Autism.” European Neuropsychopharmacology, vol. 29, no. Supplement 6, Elsevier, 2019, pp. S11–12, doi:10.1016/j.euroneuro.2019.09.040."},"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","article_type":"original","type":"journal_article","status":"public","_id":"7415"},{"day":"19","publication":"Nature Neuroscience","has_accepted_license":"1","isi":1,"year":"2018","date_published":"2018-11-19T00:00:00Z","doi":"10.1038/s41593-018-0266-2","date_created":"2018-12-11T11:44:05Z","page":"1717 - 1727","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.","quality_controlled":"1","publisher":"Nature Publishing Group","oa":1,"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","citation":{"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.","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.","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.","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","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","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.","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."},"title":"Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition","publist_id":"8054","author":[{"full_name":"Deliu, Elena","orcid":"0000-0002-7370-5293","last_name":"Deliu","first_name":"Elena","id":"37A40D7E-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Niccoló","full_name":"Arecco, Niccoló","last_name":"Arecco"},{"full_name":"Morandell, Jasmin","last_name":"Morandell","id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin"},{"last_name":"Dotter","orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph","id":"4C66542E-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph"},{"id":"475990FE-F248-11E8-B48F-1D18A9856A87","first_name":"Ximena","last_name":"Contreras","full_name":"Contreras, Ximena"},{"full_name":"Girardot, Charles","last_name":"Girardot","first_name":"Charles"},{"last_name":"Käsper","full_name":"Käsper, Eva","first_name":"Eva"},{"full_name":"Kozlova, Alena","last_name":"Kozlova","id":"C50A9596-02D0-11E9-976E-E38CFE5CBC1D","first_name":"Alena"},{"last_name":"Kishi","full_name":"Kishi, Kasumi","id":"3065DFC4-F248-11E8-B48F-1D18A9856A87","first_name":"Kasumi"},{"orcid":"0000-0002-9529-4464","full_name":"Chiaradia, Ilaria","last_name":"Chiaradia","id":"B6467F20-02D0-11E9-BDA5-E960C241894A","first_name":"Ilaria"},{"full_name":"Noh, Kyung","last_name":"Noh","first_name":"Kyung"},{"full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"external_id":{"isi":["000451324700010"]},"article_processing_charge":"No","project":[{"_id":"254BA948-B435-11E9-9278-68D0E5697425","name":"Probing development and reversibility of autism spectrum disorders","grant_number":"401299"}],"file":[{"content_type":"application/pdf","access_level":"open_access","relation":"main_file","checksum":"60abd0f05b7cdc08a6b0ec460884084f","file_id":"6255","date_updated":"2020-07-14T12:45:58Z","file_size":8167169,"creator":"dernst","date_created":"2019-04-09T07:41:57Z","file_name":"2017_NatureNeuroscience_Deliu.pdf"}],"language":[{"iso":"eng"}],"publication_status":"published","issue":"12","related_material":{"link":[{"description":"News on IST Homepage","url":"https://ist.ac.at/en/news/mutation-that-causes-autism-and-intellectual-disability-makes-brain-less-flexible/","relation":"press_release"}],"record":[{"id":"6074","status":"public","relation":"popular_science"},{"relation":"dissertation_contains","id":"12364","status":"public"}]},"volume":21,"oa_version":"Submitted Version","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"}],"month":"11","intvolume":" 21","scopus_import":"1","ddc":["570"],"date_updated":"2024-03-27T23:30:44Z","department":[{"_id":"GaNo"},{"_id":"EdHa"}],"file_date_updated":"2020-07-14T12:45:58Z","_id":"3","status":"public","pubrep_id":"1071","type":"journal_article","article_type":"original"},{"_id":"1106","type":"journal_article","status":"public","citation":{"chicago":"Isrie, Mala, Martin Breuss, Guoling Tian, Andi H Hansen, Francesca Cristofoli, Jasmin Morandell, Zachari A Kupchinsky, et al. “Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.” The American Journal of Human Genetics. Cell Press, 2015. https://doi.org/10.1016/j.ajhg.2015.10.014.","ista":"Isrie M, Breuss M, Tian G, Hansen AH, Cristofoli F, Morandell J, Kupchinsky ZA, Sifrim A, Rodriguez Rodriguez C, Dapena EP, Doonanco K, Leonard N, Tinsa F, Moortgat S, Ulucan H, Koparir E, Karaca E, Katsanis N, Marton V, Vermeesch JR, Davis EE, Cowan NJ, Keays D, Van Esch H. 2015. Mutations in either TUBB or MAPRE2 cause circumferential skin creases Kunze type. The American Journal of Human Genetics. 97(6), 790–800.","mla":"Isrie, Mala, et al. “Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.” The American Journal of Human Genetics, vol. 97, no. 6, Cell Press, 2015, pp. 790–800, doi:10.1016/j.ajhg.2015.10.014.","ieee":"M. Isrie et al., “Mutations in either TUBB or MAPRE2 cause circumferential skin creases Kunze type,” The American Journal of Human Genetics, vol. 97, no. 6. Cell Press, pp. 790–800, 2015.","short":"M. Isrie, M. Breuss, G. Tian, A.H. Hansen, F. Cristofoli, J. Morandell, Z.A. Kupchinsky, A. Sifrim, C. Rodriguez Rodriguez, E.P. Dapena, K. Doonanco, N. Leonard, F. Tinsa, S. Moortgat, H. Ulucan, E. Koparir, E. Karaca, N. Katsanis, V. Marton, J.R. Vermeesch, E.E. Davis, N.J. Cowan, D. Keays, H. Van Esch, The American Journal of Human Genetics 97 (2015) 790–800.","apa":"Isrie, M., Breuss, M., Tian, G., Hansen, A. H., Cristofoli, F., Morandell, J., … Van Esch, H. (2015). Mutations in either TUBB or MAPRE2 cause circumferential skin creases Kunze type. The American Journal of Human Genetics. Cell Press. https://doi.org/10.1016/j.ajhg.2015.10.014","ama":"Isrie M, Breuss M, Tian G, et al. Mutations in either TUBB or MAPRE2 cause circumferential skin creases Kunze type. The American Journal of Human Genetics. 2015;97(6):790-800. doi:10.1016/j.ajhg.2015.10.014"},"date_updated":"2021-01-12T06:48:19Z","extern":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","author":[{"full_name":"Isrie, Mala","last_name":"Isrie","first_name":"Mala"},{"full_name":"Breuss, Martin","last_name":"Breuss","first_name":"Martin"},{"first_name":"Guoling","last_name":"Tian","full_name":"Tian, Guoling"},{"first_name":"Andi H","id":"38853E16-F248-11E8-B48F-1D18A9856A87","full_name":"Hansen, Andi H","last_name":"Hansen"},{"first_name":"Francesca","last_name":"Cristofoli","full_name":"Cristofoli, Francesca"},{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"full_name":"Kupchinsky, Zachari A","last_name":"Kupchinsky","first_name":"Zachari A"},{"last_name":"Sifrim","full_name":"Sifrim, Alejandro","first_name":"Alejandro"},{"first_name":"Celia","full_name":"Rodriguez Rodriguez, Celia","last_name":"Rodriguez Rodriguez"},{"last_name":"Dapena","full_name":"Dapena, Elena P","first_name":"Elena P"},{"first_name":"Kurston","full_name":"Doonanco, Kurston","last_name":"Doonanco"},{"first_name":"Norma","last_name":"Leonard","full_name":"Leonard, Norma"},{"full_name":"Tinsa, Faten","last_name":"Tinsa","first_name":"Faten"},{"first_name":"Stéphanie","full_name":"Moortgat, Stéphanie","last_name":"Moortgat"},{"last_name":"Ulucan","full_name":"Ulucan, Hakan","first_name":"Hakan"},{"full_name":"Koparir, Erkan","last_name":"Koparir","first_name":"Erkan"},{"first_name":"Ender","last_name":"Karaca","full_name":"Karaca, Ender"},{"full_name":"Katsanis, Nicholas","last_name":"Katsanis","first_name":"Nicholas"},{"first_name":"Valeria","full_name":"Marton, Valeria","last_name":"Marton"},{"first_name":"Joris R","full_name":"Vermeesch, Joris R","last_name":"Vermeesch"},{"first_name":"Erica E","full_name":"Davis, Erica E","last_name":"Davis"},{"first_name":"Nicholas J","full_name":"Cowan, Nicholas J","last_name":"Cowan"},{"first_name":"David","last_name":"Keays","full_name":"Keays, David"},{"first_name":"Hilde","full_name":"Van Esch, Hilde","last_name":"Van Esch"}],"publist_id":"6264","title":"Mutations in either TUBB or MAPRE2 cause circumferential skin creases Kunze type","abstract":[{"lang":"eng","text":"Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect."}],"oa_version":"None","publisher":"Cell Press","quality_controlled":"1","month":"12","intvolume":" 97","year":"2015","publication_status":"published","day":"03","publication":"The American Journal of Human Genetics","language":[{"iso":"eng"}],"page":"790 - 800","date_published":"2015-12-03T00:00:00Z","issue":"6","volume":97,"doi":"10.1016/j.ajhg.2015.10.014","date_created":"2018-12-11T11:50:11Z"}]