PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration
Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119303845 |
| id |
doaj-21ff7dea18624a998bce2e24ef51db82 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Kévin Duarte Solveig Heide Sandrine Poëa-Guyon Véronique Rousseau Christel Depienne Agnès Rastetter Caroline Nava Tania Attié-Bitach Ferechté Razavi Jelena Martinovic Marie Laure Moutard Jacqueline Cherfils Cyril Mignot Delphine Héron Jean-Vianney Barnier |
| spellingShingle |
Kévin Duarte Solveig Heide Sandrine Poëa-Guyon Véronique Rousseau Christel Depienne Agnès Rastetter Caroline Nava Tania Attié-Bitach Ferechté Razavi Jelena Martinovic Marie Laure Moutard Jacqueline Cherfils Cyril Mignot Delphine Héron Jean-Vianney Barnier PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration Neurobiology of Disease Corpus callosum agenesis (CCA) Cell adhesion Cell migration Cell spreading Intellectual disability Kinase |
| author_facet |
Kévin Duarte Solveig Heide Sandrine Poëa-Guyon Véronique Rousseau Christel Depienne Agnès Rastetter Caroline Nava Tania Attié-Bitach Ferechté Razavi Jelena Martinovic Marie Laure Moutard Jacqueline Cherfils Cyril Mignot Delphine Héron Jean-Vianney Barnier |
| author_sort |
Kévin Duarte |
| title |
PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration |
| title_short |
PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration |
| title_full |
PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration |
| title_fullStr |
PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration |
| title_full_unstemmed |
PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration |
| title_sort |
pak3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration |
| publisher |
Elsevier |
| series |
Neurobiology of Disease |
| issn |
1095-953X |
| publishDate |
2020-03-01 |
| description |
Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two “severe” G424R and K389N variants (responsible for severe ID and CCA) and the “mild” A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects. |
| topic |
Corpus callosum agenesis (CCA) Cell adhesion Cell migration Cell spreading Intellectual disability Kinase |
| url |
http://www.sciencedirect.com/science/article/pii/S0969996119303845 |
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doaj-21ff7dea18624a998bce2e24ef51db822021-03-22T08:41:20ZengElsevierNeurobiology of Disease1095-953X2020-03-01136104709PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migrationKévin Duarte0Solveig Heide1Sandrine Poëa-Guyon2Véronique Rousseau3Christel Depienne4Agnès Rastetter5Caroline Nava6Tania Attié-Bitach7Ferechté Razavi8Jelena Martinovic9Marie Laure Moutard10Jacqueline Cherfils11Cyril Mignot12Delphine Héron13Jean-Vianney Barnier14Department of Cognition and Behavior, Paris-Saclay Institute of Neuroscience (Neuro-PSI CNRS, UMR 9197), Paris-Sud and Paris-Saclay Universities, Orsay, FranceDepartment of genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Pitié Salpêtrière, Paris, FranceDepartment of Cognition and Behavior, Paris-Saclay Institute of Neuroscience (Neuro-PSI CNRS, UMR 9197), Paris-Sud and Paris-Saclay Universities, Orsay, FranceDepartment of Cognition and Behavior, Paris-Saclay Institute of Neuroscience (Neuro-PSI CNRS, UMR 9197), Paris-Sud and Paris-Saclay Universities, Orsay, FranceDepartment of genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Pitié Salpêtrière, Paris, France; Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, GermanyDepartment of genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Pitié Salpêtrière, Paris, FranceDepartment of genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Pitié Salpêtrière, Paris, FranceUnité d'Embryofoetopathologie, Service of Histology-Embryology-Cytogenetics, APHP Necker Enfants Malades & Imagine Institute, Inserm U1163, Paris, FranceUnité d'Embryofoetopathologie, Service of Histology-Embryology-Cytogenetics, APHP Necker Enfants Malades & Imagine Institute, Inserm U1163, Paris, FranceUnité de foetopathologie, APHP Antoine Béclère, Paris, FranceDepartment of Pediatrics Neurology, Reference Center for Intellectual Disabilities of Rare Causes APHP, Armand-Trousseau Hospital, Paris, FranceLaboratoire de Biologie et Pharmacologie Appliquée, CNRS and Ecole normale supérieure Paris-Saclay, Cachan, FranceDepartment of genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Pitié Salpêtrière, Paris, FranceDepartment of genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Pitié Salpêtrière, Paris, France; Correspondence to: D. Héron, Department of Genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Pitié Salpêtrière, 75013 Paris, France.Department of Cognition and Behavior, Paris-Saclay Institute of Neuroscience (Neuro-PSI CNRS, UMR 9197), Paris-Sud and Paris-Saclay Universities, Orsay, France; Correspondence to: J.-V. Barnier, Department of Cognition and Behavior, Paris-Saclay Institute of Neuroscience (Neuro-PSI CNRS, UMR 9197), Paris-Sud and Paris-Saclay Universities, 91400 Orsay, France.Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two “severe” G424R and K389N variants (responsible for severe ID and CCA) and the “mild” A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.http://www.sciencedirect.com/science/article/pii/S0969996119303845Corpus callosum agenesis (CCA)Cell adhesionCell migrationCell spreadingIntellectual disabilityKinase |