PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration
Authors: Ferecht√© Razavi
Jelena Martinovic
Sandrine Po√´a-Guyon
Christel Depienne
Agn√®s Rastetter
V√©ronique Rousseau
Jacqueline Cherfils
Tania Atti√©-Bitach
Solveig Heide
Cyril Mignot
Marie Laure Moutard
Caroline Nava
Jean-Vianney Barnier
K√©vin Duarte
Delphine H√©ron
Journal: Neurobiology of Disease (2020)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Cell adhesion; Cell migration; Cell spreading; Corpus callosum agenesis (CCA); Intellectual disability
Affiliations: Department of Cognition and Behavior, Paris-Saclay Institute of Neuroscience (Neuro-PSI CNRS, UMR 9197), Paris-Sud and Paris-Saclay Universities, Orsay, France. Electronic address: ., Department of genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Piti√© Salp√™tri√®re, Paris, France. Electronic address: ., Department of genetics, Reference Center for Intellectual Disabilities of Rare Causes, APHP, GH Piti√© Salp√™tri√®re, Paris, France; Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: ., Unit√© d'Embryofoetopathologie, Service of Histology-Embryology-Cytogenetics, APHP Necker Enfants Malades & Imagine Institute, Inserm U1163, Paris, France. Electronic address: ., Unit√© d'Embryofoetopathologie, Service of Histology-Embryology-Cytogenetics, APHP Necker Enfants Malades & Imagine Institute, Inserm U1163, Paris, France., Unit√© de foetopathologie, APHP Antoine B√©cl√®re, Paris, France., Department of Pediatrics Neurology, Reference Center for Intellectual Disabilities of Rare Causes APHP, Armand-Trousseau Hospital, Paris, France. Electronic address: ., Laboratoire de Biologie et Pharmacologie Appliqu√©e, CNRS and Ecole normale sup√©rieure Paris-Saclay, Cachan, France. Electronic address: .

Abstract:  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 Œ±PIX/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. 

Retracted: No

PubPeer comments:
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