{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T16:29:19Z","timestamp":1782577759841,"version":"3.54.5"},"reference-count":55,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente 2019, 2020, 2021, 5x1000"],"award-info":[{"award-number":["Ricerca Corrente 2019, 2020, 2021, 5x1000"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018982","name":"Fondazione Bambino Ges\u00f9","doi-asserted-by":"publisher","award":["Vite Coraggiose"],"award-info":[{"award-number":["Vite Coraggiose"]}],"id":[{"id":"10.13039\/501100018982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>PCDH19-related epilepsy is a rare genetic disease caused by defective function of PCDH19, a calcium-dependent cell\u2013cell adhesion protein of the cadherin superfamily. This disorder is characterized by a heterogeneous phenotypic spectrum, with partial and generalized febrile convulsions that are gradually increasing in frequency. Developmental regression may occur during disease progression. Patients may present with intellectual disability (ID), behavioral problems, motor and language delay, and a low motor tone. In most cases, seizures are resistant to treatment, but their frequency decreases with age, and some patients may even become seizure-free. ID generally persists after seizure remission, making neurological abnormalities the main clinical issue in affected individuals. An effective treatment is lacking. In vitro studies using patient-derived induced pluripotent stem cells (iPSCs) reported accelerated neural differentiation as a major endophenotype associated with PCDH19 mutations. By using this in vitro model system, we show that accelerated in vitro neurogenesis is associated with a defect in the cell division plane at the neural progenitors stage. We also provide evidence that altered PCDH19 function affects proper mitotic spindle orientation. Our findings identify an altered equilibrium between symmetric versus asymmetric cell division as a previously unrecognized mechanism contributing to the pathogenesis of this rare epileptic encephalopathy.<\/jats:p>","DOI":"10.3390\/jcm10132754","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T11:28:41Z","timestamp":1624447721000},"page":"2754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis"],"prefix":"10.3390","volume":"10","author":[{"given":"Rossella","family":"Borghi","sequence":"first","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"},{"name":"Department of Science, University \u201cRoma Tre\u201d, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Magliocca","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"},{"name":"Department of Science, University \u201cRoma Tre\u201d, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3249-0003","authenticated-orcid":false,"given":"Stefania","family":"Petrini","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Core Facility, Research Laboratories, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9466-5473","authenticated-orcid":false,"given":"Libenzio Adrian","family":"Conti","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Core Facility, Research Laboratories, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1079-3222","authenticated-orcid":false,"given":"Sandra","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Science, University \u201cRoma Tre\u201d, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0877-6172","authenticated-orcid":false,"given":"Claudia","family":"Compagnucci","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/S0022-3476(71)80382-7","article-title":"A new familial form of convulsive disorder and mental retardation limited to females","volume":"79","author":"Juberg","year":"1971","journal-title":"J. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1111\/epi.14003","article-title":"PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum","volume":"59","author":"Smith","year":"2018","journal-title":"Epilepsia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/s41380-018-0066-9","article-title":"A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity","volume":"24","author":"Kolc","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1002\/humu.23701","article-title":"A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern","volume":"40","author":"Niazi","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.gde.2020.06.012","article-title":"Disentangling the paradox of the PCDH19 clustering epilepsy, a disorder of cellular mosaics","volume":"65","author":"Gecz","year":"2020","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Depienne, C., Bouteiller, D., Keren, B., Cheuret, E., Poirier, K., Trouillard, O., Benyahia, B., Quelin, C., Carpentier, W., and Julia, S. (2009). Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet., 5.","DOI":"10.1371\/annotation\/314060d5-06da-46e0-b9e4-57194e8ece3a"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1212\/WNL.0b013e3181ed9e67","article-title":"Protocadherin 19 mutations in girls with infantile-onset epilepsy","volume":"75","author":"Marini","year":"2010","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1002\/humu.22029","article-title":"PCDH19-related infantile epileptic encephalopathy: An unusual X-linked inheritance disorder","volume":"33","author":"Depienne","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s13353-014-0243-8","article-title":"Epilepsy and mental retardation restricted to females: X-linked epileptic infantile encephalopathy of unusual inheritance","volume":"56","author":"Duszyc","year":"2015","journal-title":"J. Appl. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/ng.149","article-title":"X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment","volume":"40","author":"Dibbens","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1093\/brain\/awm338","article-title":"Epilepsy and mental retardation limited to females: An under-recognized dis-order","volume":"131","author":"Scheffer","year":"2008","journal-title":"Brain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1006\/geno.2001.6592","article-title":"Identification and characterization of three members of a novel subclass of protocadherins","volume":"76","author":"Wolverton","year":"2001","journal-title":"Genomics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.1007\/s00018-005-5320-z","article-title":"Delta-protocadherins: Unique structures and functions","volume":"62","author":"Redies","year":"2005","journal-title":"Cell Mol. Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4161\/cam.5.2.14374","article-title":"Non-clustered protocadherin","volume":"5","author":"Kim","year":"2011","journal-title":"Cell Adhes. Migr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3389\/fnmol.2020.00117","article-title":"Protocadherins at the crossroad of signaling pathways","volume":"13","author":"Pancho","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ydbio.2009.07.008","article-title":"Protocadherin-19 is essential for early steps in brain morphogenesis","volume":"334","author":"Emond","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1083\/jcb.201007008","article-title":"Protocadherin-19 and N-cadherin interact to control cell movements during anterior neurulation","volume":"191","author":"Biswas","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/mp.2016.106","article-title":"A chromosome 16p13.11 microduplication causes hyperactivity through dysregulation of miR-484\/protocadherin-19 signaling","volume":"22","author":"Fujitani","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26765","DOI":"10.1038\/srep26765","article-title":"Pcdh19 loss-of-function increases neuronal migration in vitro but is dispensable for brain development in mice","volume":"6","author":"Pederick","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5801","DOI":"10.1038\/s41598-017-06374-x","article-title":"Loss of X-linked Protocadherin-19 differentially affects the behavior of heterozygous female and hemizygous male mice","volume":"7","author":"Hayashi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neuron.2017.12.005","article-title":"Abnormal cell sorting underlies the unique X-Linked Inheritance of PCDH19 Epilepsy","volume":"97","author":"Pederick","year":"2018","journal-title":"Neuron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.nbd.2018.05.004","article-title":"PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 girls clustering epilepsy","volume":"116","author":"Homan","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1093\/hmg\/ddy019","article-title":"The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and mor-phological maturation of hippocampal neurons","volume":"27","author":"Bassani","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1083\/jcb.201108115","article-title":"A complex of Protocadherin-19 and N-cadherin mediates a novel mechanism of cell adhesion","volume":"195","author":"Emond","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"eaaz3893","DOI":"10.1126\/science.aaz3893","article-title":"Female-specific synaptic dysfunction and cognitive im-pairment in a mouse model of PCDH19 disorder","volume":"372","author":"Hoshina","year":"2021","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e51","DOI":"10.1111\/epi.13295","article-title":"PCDH19-related epilepsy in two mosaic male patients","volume":"57","author":"Terracciano","year":"2016","journal-title":"Epilepsia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s10048-017-0517-5","article-title":"Male patients affected by mosaic PCDH19 mutations: Five new cases","volume":"18","author":"Rump","year":"2017","journal-title":"Neurogenetics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/5584_2020_574","article-title":"PCDH19 Pathogenic Variants in males: Expanding the phenotypic spectrum","volume":"1298","author":"Kolc","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13041-019-0519-3","article-title":"Autism-like behaviors in male mice with a Pcdh19 deletion","volume":"12","author":"Lim","year":"2019","journal-title":"Mol. Brain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.eplepsyres.2018.06.008","article-title":"PCDH19 -related epilepsy in a male with Klinefelter syndrome: Additional evidence supporting PCDH19 cellular interference disease mechanism","volume":"145","author":"Romasko","year":"2018","journal-title":"Epilepsy Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s11910-015-0588-3","article-title":"Using patient-derived induced pluripotent stem cells to model and treat epilepsies","volume":"15","author":"Du","year":"2015","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1007\/s00018-013-1511-1","article-title":"In vitro neurogenesis: Development and functional implications of iPSC technology","volume":"71","author":"Compagnucci","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nmeth.1591","article-title":"A more efficient method to generate integration-free human iPS cells","volume":"8","author":"Okita","year":"2011","journal-title":"Nat. Methods"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zeng, H., Guo, M., Martins-Taylor, K., Wang, X., Zhang, Z., Park, J.W., Zhan, S., Kronenberg, M.S., Lichtler, A., and Liu, H.X. (2010). Specification of region-specific neurons including forebrain glutamatergic neurons from human induced plu-ripotent stem cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0011853"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"Lancaster","year":"2013","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1038\/nprot.2014.158","article-title":"Generation of cerebral organoids from human pluripotent stem cells","volume":"9","author":"Lancaster","year":"2014","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/7651_2015_271","article-title":"Intracellular calcium measurements for functional characterization of neuronal phenotypes","volume":"1341","author":"Glaser","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.seizure.2016.01.006","article-title":"Effectiveness of antiepileptic therapy in patientswith PCDH19 mutations","volume":"35","author":"Lotte","year":"2016","journal-title":"Seizure"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.pediatrneurol.2019.10.009","article-title":"PCDH19-related epilepsy syndrome: A comprehensive clinical review","volume":"105","author":"Samanta","year":"2020","journal-title":"Pediatr. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1152\/physrev.00014.2011","article-title":"Cadherins in Brain Morphogenesis and Wiring","volume":"92","author":"Hirano","year":"2012","journal-title":"Physiol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.cell.2013.11.048","article-title":"The WAVE regulatory complex links diverse Receptors to the actin cytoskeleton","volume":"156","author":"Chen","year":"2014","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1212\/WNL.0000000000002704","article-title":"Loss of function of PCDH12 un-derlies recessive microcephaly mimicking intrauterine infection","volume":"86","author":"Aran","year":"2016","journal-title":"Neurology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1111\/j.1528-1167.2011.03063.x","article-title":"Spectrum of phenotypes in female patients with epilepsy due to protocadherin 19 mutations","volume":"52","author":"Specchio","year":"2011","journal-title":"Epilepsia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/mp.2010.54","article-title":"Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia","volume":"16","author":"Piton","year":"2011","journal-title":"Mol. Psychiatry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.yebeh.2016.04.009","article-title":"Autism spectrum disorder phenotype and intellectual disability in females with epilepsy and PCDH-19 mutations","volume":"60","author":"Breuillard","year":"2016","journal-title":"Epilepsy Behav."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"E1959","DOI":"10.1002\/humu.21373","article-title":"Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females","volume":"32","author":"Depienne","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/dmcn.13595","article-title":"Focal cortical malformations in children with early infantile epilepsy and PCDH19 mutations: Case report","volume":"60","author":"Kurian","year":"2017","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5336","DOI":"10.1007\/s12035-020-02099-7","article-title":"The epilepsy-related protein PCDH19 regulates tonic inhibition, GABAAR Kinetics, and the intrinsic excitability of hippocampal neurons","volume":"57","author":"Serratto","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"26804","DOI":"10.18632\/oncotarget.5757","article-title":"Characterizing PCDH19 in human induced pluripotent stem cells (iPSCs) and iPSC-derived developing neurons: Emerging role of a protein involved in controlling polarity during neurogenesis","volume":"6","author":"Compagnucci","year":"2015","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-11854-x","article-title":"TBR2 coordinates neurogenesis expansion and precise microcircuit organization via Protocadherin 19 in the mammalian cortex","volume":"10","author":"Lv","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/ncb2746","article-title":"Centrosome amplification causes microcephaly","volume":"15","author":"Marthiens","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_53","first-page":"48","article-title":"Cell diversity and network dynamics in photosensitive human brain organoids","volume":"545","author":"Quadrato","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_54","first-page":"523","article-title":"Individual brain organoids reproducibly form cell diversity of the human cerebral cortex","volume":"570","author":"Velasco","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"21487","DOI":"10.1038\/s41598-020-78130-7","article-title":"Multiscale 3D phenotyping of human cerebral organoids","volume":"10","author":"Albanese","year":"2020","journal-title":"Sci. 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