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Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the...

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Autores principales: Accogli, Andrea, Lu, Shenzhao, Musante, Ilaria, Scudieri, Paolo, Rosenfeld, Jill A., Severino, Mariasavina, Baldassari, Simona, Iacomino, Michele, Riva, Antonella, Balagura, Ganna, Piccolo, Gianluca, Minetti, Carlo, Roberto, Denis, Xia, Fan, Razak, Razaali, Lawrence, Emily, Hussein, Mohamed, Chang, Emmanuel Yih-Herng, Holick, Michelle, Calì, Elisa, Aliberto, Emanuela, De-Sarro, Rosalba, Gambardella, Antonio, Network, Undiagnosed Diseases, Group, SYNaPS Study, Emrick, Lisa, McCaffery, Peter J. A., Clagett-Dame, Margaret, Marcogliese, Paul C., Bellen, Hugo J., Lalani, Seema R., Zara, Federico, Striano, Pasquale, Salpietro, Vincenzo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9985553/
https://www.ncbi.nlm.nih.gov/pubmed/35218524
http://dx.doi.org/10.1007/s12311-022-01379-3
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author Accogli, Andrea
Lu, Shenzhao
Musante, Ilaria
Scudieri, Paolo
Rosenfeld, Jill A.
Severino, Mariasavina
Baldassari, Simona
Iacomino, Michele
Riva, Antonella
Balagura, Ganna
Piccolo, Gianluca
Minetti, Carlo
Roberto, Denis
Xia, Fan
Razak, Razaali
Lawrence, Emily
Hussein, Mohamed
Chang, Emmanuel Yih-Herng
Holick, Michelle
Calì, Elisa
Aliberto, Emanuela
De-Sarro, Rosalba
Gambardella, Antonio
Network, Undiagnosed Diseases
Group, SYNaPS Study
Emrick, Lisa
McCaffery, Peter J. A.
Clagett-Dame, Margaret
Marcogliese, Paul C.
Bellen, Hugo J.
Lalani, Seema R.
Zara, Federico
Striano, Pasquale
Salpietro, Vincenzo
author_facet Accogli, Andrea
Lu, Shenzhao
Musante, Ilaria
Scudieri, Paolo
Rosenfeld, Jill A.
Severino, Mariasavina
Baldassari, Simona
Iacomino, Michele
Riva, Antonella
Balagura, Ganna
Piccolo, Gianluca
Minetti, Carlo
Roberto, Denis
Xia, Fan
Razak, Razaali
Lawrence, Emily
Hussein, Mohamed
Chang, Emmanuel Yih-Herng
Holick, Michelle
Calì, Elisa
Aliberto, Emanuela
De-Sarro, Rosalba
Gambardella, Antonio
Network, Undiagnosed Diseases
Group, SYNaPS Study
Emrick, Lisa
McCaffery, Peter J. A.
Clagett-Dame, Margaret
Marcogliese, Paul C.
Bellen, Hugo J.
Lalani, Seema R.
Zara, Federico
Striano, Pasquale
Salpietro, Vincenzo
author_sort Accogli, Andrea
collection PubMed
description Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In this study, we identified a female affected with neurodevelopmental impairment and a complex brain and cardiac malformations in which clinical exome sequencing led to the identification of NAV2 biallelic truncating variants. Through protein expression analysis and cell migration assay in patient-derived fibroblasts, we provide evidence linking NAV2 deficiency to cellular migration deficits. In model organisms, the overall CNS histopathology of the Nav2 hypomorphic mouse revealed developmental anomalies including cerebellar hypoplasia and dysplasia, corpus callosum hypo-dysgenesis, and agenesis of the olfactory bulbs. Lastly, we show that the NAV2 ortholog in Drosophila, sickie (sick) is widely expressed in the fly brain, and sick mutants are mostly lethal with surviving escapers showing neurobehavioral phenotypes. In summary, our results unveil a novel human neurodevelopmental disorder due to genetic loss of NAV2, highlighting a critical conserved role of the NAV2 gene in brain and cerebellar development across species. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12311-022-01379-3.
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spelling pubmed-99855532023-03-06 Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development Accogli, Andrea Lu, Shenzhao Musante, Ilaria Scudieri, Paolo Rosenfeld, Jill A. Severino, Mariasavina Baldassari, Simona Iacomino, Michele Riva, Antonella Balagura, Ganna Piccolo, Gianluca Minetti, Carlo Roberto, Denis Xia, Fan Razak, Razaali Lawrence, Emily Hussein, Mohamed Chang, Emmanuel Yih-Herng Holick, Michelle Calì, Elisa Aliberto, Emanuela De-Sarro, Rosalba Gambardella, Antonio Network, Undiagnosed Diseases Group, SYNaPS Study Emrick, Lisa McCaffery, Peter J. A. Clagett-Dame, Margaret Marcogliese, Paul C. Bellen, Hugo J. Lalani, Seema R. Zara, Federico Striano, Pasquale Salpietro, Vincenzo Cerebellum Original Article Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In this study, we identified a female affected with neurodevelopmental impairment and a complex brain and cardiac malformations in which clinical exome sequencing led to the identification of NAV2 biallelic truncating variants. Through protein expression analysis and cell migration assay in patient-derived fibroblasts, we provide evidence linking NAV2 deficiency to cellular migration deficits. In model organisms, the overall CNS histopathology of the Nav2 hypomorphic mouse revealed developmental anomalies including cerebellar hypoplasia and dysplasia, corpus callosum hypo-dysgenesis, and agenesis of the olfactory bulbs. Lastly, we show that the NAV2 ortholog in Drosophila, sickie (sick) is widely expressed in the fly brain, and sick mutants are mostly lethal with surviving escapers showing neurobehavioral phenotypes. In summary, our results unveil a novel human neurodevelopmental disorder due to genetic loss of NAV2, highlighting a critical conserved role of the NAV2 gene in brain and cerebellar development across species. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12311-022-01379-3. Springer US 2022-02-26 2023 /pmc/articles/PMC9985553/ /pubmed/35218524 http://dx.doi.org/10.1007/s12311-022-01379-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Accogli, Andrea
Lu, Shenzhao
Musante, Ilaria
Scudieri, Paolo
Rosenfeld, Jill A.
Severino, Mariasavina
Baldassari, Simona
Iacomino, Michele
Riva, Antonella
Balagura, Ganna
Piccolo, Gianluca
Minetti, Carlo
Roberto, Denis
Xia, Fan
Razak, Razaali
Lawrence, Emily
Hussein, Mohamed
Chang, Emmanuel Yih-Herng
Holick, Michelle
Calì, Elisa
Aliberto, Emanuela
De-Sarro, Rosalba
Gambardella, Antonio
Network, Undiagnosed Diseases
Group, SYNaPS Study
Emrick, Lisa
McCaffery, Peter J. A.
Clagett-Dame, Margaret
Marcogliese, Paul C.
Bellen, Hugo J.
Lalani, Seema R.
Zara, Federico
Striano, Pasquale
Salpietro, Vincenzo
Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development
title Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development
title_full Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development
title_fullStr Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development
title_full_unstemmed Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development
title_short Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development
title_sort loss of neuron navigator 2 impairs brain and cerebellar development
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9985553/
https://www.ncbi.nlm.nih.gov/pubmed/35218524
http://dx.doi.org/10.1007/s12311-022-01379-3
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