Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2

Roberta De Mori, Mariasavina Severino, Maria Margherita Mancardi, Danila Anello, Silvia Tardivo, Tommaso Biagini, Valeria Capra, Antonella Casella, Cristina Cereda, Brett R Copeland, Stella Gagliardi, Alessandra Gamucci, Monia Ginevrino, Barbara Illi, Elisa Lorefice, Damir Musaev, Valentina Stanley, Alessia Micalizzi, Joseph G Gleeson, Tommaso MazzaAndrea Rossi, Enza Maria Valente

Research output: Contribution to journalArticle

Abstract

Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.

Original languageEnglish
Pages (from-to)2965-78
Number of pages14
JournalBrain : a journal of neurology
Volume142
Issue number(10)
Early online dateAug 14 2019
DOIs
Publication statusPublished - 2019

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Globus Pallidus
Homeobox Genes
Putamen
Basal Ganglia
Mutation
Classical Lissencephalies and Subcortical Band Heterotopias
Genes
Exome
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Telencephalon
Median Eminence
Pyramidal Tracts
Proteins
Genitalia
Muscle Spasticity
Dystonia
Caudate Nucleus
Olfactory Bulb
Neurogenesis
Brain

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Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2. / De Mori, Roberta; Severino, Mariasavina; Mancardi, Maria Margherita; Anello, Danila; Tardivo, Silvia; Biagini, Tommaso; Capra, Valeria; Casella, Antonella; Cereda, Cristina; Copeland, Brett R; Gagliardi, Stella; Gamucci, Alessandra; Ginevrino, Monia; Illi, Barbara; Lorefice, Elisa; Musaev, Damir; Stanley, Valentina; Micalizzi, Alessia; Gleeson, Joseph G; Mazza, Tommaso; Rossi, Andrea; Valente, Enza Maria.

In: Brain : a journal of neurology, Vol. 142 , No. (10), 2019, p. 2965-78.

Research output: Contribution to journalArticle

De Mori, R, Severino, M, Mancardi, MM, Anello, D, Tardivo, S, Biagini, T, Capra, V, Casella, A, Cereda, C, Copeland, BR, Gagliardi, S, Gamucci, A, Ginevrino, M, Illi, B, Lorefice, E, Musaev, D, Stanley, V, Micalizzi, A, Gleeson, JG, Mazza, T, Rossi, A & Valente, EM 2019, 'Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2', Brain : a journal of neurology, vol. 142 , no. (10), pp. 2965-78. https://doi.org/10.1093/brain/awz247
De Mori, Roberta ; Severino, Mariasavina ; Mancardi, Maria Margherita ; Anello, Danila ; Tardivo, Silvia ; Biagini, Tommaso ; Capra, Valeria ; Casella, Antonella ; Cereda, Cristina ; Copeland, Brett R ; Gagliardi, Stella ; Gamucci, Alessandra ; Ginevrino, Monia ; Illi, Barbara ; Lorefice, Elisa ; Musaev, Damir ; Stanley, Valentina ; Micalizzi, Alessia ; Gleeson, Joseph G ; Mazza, Tommaso ; Rossi, Andrea ; Valente, Enza Maria. / Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2. In: Brain : a journal of neurology. 2019 ; Vol. 142 , No. (10). pp. 2965-78.
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abstract = "Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.",
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T1 - Agenesis of the putamen and globus pallidus caused by recessive mutations in the homeobox gene GSX2

AU - De Mori, Roberta

AU - Severino, Mariasavina

AU - Mancardi, Maria Margherita

AU - Anello, Danila

AU - Tardivo, Silvia

AU - Biagini, Tommaso

AU - Capra, Valeria

AU - Casella, Antonella

AU - Cereda, Cristina

AU - Copeland, Brett R

AU - Gagliardi, Stella

AU - Gamucci, Alessandra

AU - Ginevrino, Monia

AU - Illi, Barbara

AU - Lorefice, Elisa

AU - Musaev, Damir

AU - Stanley, Valentina

AU - Micalizzi, Alessia

AU - Gleeson, Joseph G

AU - Mazza, Tommaso

AU - Rossi, Andrea

AU - Valente, Enza Maria

N1 - © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2019

Y1 - 2019

N2 - Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.

AB - Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.

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DO - 10.1093/brain/awz247

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