PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration

NEUROBIOLOGY OF DISEASE

卷:136

Article

Duarte, Kevin^1,2  Heide, Solveig³  Poea-Guyon, Sandrine^1,2  Rousseau, Veronique^1,2  Depienne, Christel^3,4  Rastetter, Agnes³  Nava, Caroline³  Attie-Bitach, Tania⁵  Razavi, Ferechte⁵  Martinovic, Jelena⁶  Moutard, Marie Laure⁷  Cherfils, Jacqueline^8,9  Mignot, Cyril³  Heron, Delphine³  Barnier, Jean-Vianney^1,2 

[1] Paris Sud Univ, Paris Saclay Inst Neurosci Neuro PSI CNRS, Dept Cognit & Behav, UMR 9197, F-91400 Orsay, France

[2] Paris Saclay Univ, Paris Saclay Inst Neurosci Neuro PSI CNRS, Dept Cognit & Behav, UMR 9197, F-91400 Orsay, France

[3] GH Pitie Salpetriere, AP HP, Dept Genet, Reference Ctr Intellectual Disabil Rare Causes, F-75013 Paris, France

[4] Univ Duisburg Essen, Univ Hosp Essen, Inst Human Genet, Essen, Germany

[5] APHP Necker Enfants Malad & Imagine Inst, Serv Histol Embryol Cytogenet, Unite Embryofoetopathol, Inserm U1163, Paris, France

[6] APHP Antoine Beclere, Unite Foetopathol, Paris, France

[7] Armand Trousseau Hosp, AP HP, Reference Ctr Intellectual Disabil Rare Causes, Dept Pediat Neurol, Paris, France

[8] CNRS, Lab Biol & Pharmacol Appl, Cachan, France

[9] Ecole Normale Super Paris Saclay, Cachan, France

关键词: Corpus callosum agenesis (CCA);    Cell adhesion;    Cell migration;    Cell spreading;    Intellectual disability;    Kinase;    Neurodevelopmental disorder;    PAK3;    alpha PIX/ARHGEF6;   

DOI  :  10.1016/j.nbd.2019.104709

来源: Elsevier

【 摘 要 】

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 alpha 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.