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Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis

PCDH19-related epilepsy is a rare genetic disease caused by defective function of PCDH19, a calcium-dependent cell–cell adhesion protein of the cadherin superfamily. This disorder is characterized by a heterogeneous phenotypic spectrum, with partial and generalized febrile convulsions that are gradu...

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Autores principales: Borghi, Rossella, Magliocca, Valentina, Petrini, Stefania, Conti, Libenzio Adrian, Moreno, Sandra, Bertini, Enrico, Tartaglia, Marco, Compagnucci, Claudia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268119/
https://www.ncbi.nlm.nih.gov/pubmed/34201522
http://dx.doi.org/10.3390/jcm10132754
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author Borghi, Rossella
Magliocca, Valentina
Petrini, Stefania
Conti, Libenzio Adrian
Moreno, Sandra
Bertini, Enrico
Tartaglia, Marco
Compagnucci, Claudia
author_facet Borghi, Rossella
Magliocca, Valentina
Petrini, Stefania
Conti, Libenzio Adrian
Moreno, Sandra
Bertini, Enrico
Tartaglia, Marco
Compagnucci, Claudia
author_sort Borghi, Rossella
collection PubMed
description PCDH19-related epilepsy is a rare genetic disease caused by defective function of PCDH19, a calcium-dependent cell–cell 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.
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spelling pubmed-82681192021-07-10 Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis Borghi, Rossella Magliocca, Valentina Petrini, Stefania Conti, Libenzio Adrian Moreno, Sandra Bertini, Enrico Tartaglia, Marco Compagnucci, Claudia J Clin Med Article PCDH19-related epilepsy is a rare genetic disease caused by defective function of PCDH19, a calcium-dependent cell–cell 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. MDPI 2021-06-23 /pmc/articles/PMC8268119/ /pubmed/34201522 http://dx.doi.org/10.3390/jcm10132754 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Borghi, Rossella
Magliocca, Valentina
Petrini, Stefania
Conti, Libenzio Adrian
Moreno, Sandra
Bertini, Enrico
Tartaglia, Marco
Compagnucci, Claudia
Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis
title Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis
title_full Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis
title_fullStr Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis
title_full_unstemmed Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis
title_short Dissecting the Role of PCDH19 in Clustering Epilepsy by Exploiting Patient-Specific Models of Neurogenesis
title_sort dissecting the role of pcdh19 in clustering epilepsy by exploiting patient-specific models of neurogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268119/
https://www.ncbi.nlm.nih.gov/pubmed/34201522
http://dx.doi.org/10.3390/jcm10132754
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