PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration.
Neurobiol Dis
; 136: 104709, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-31843706
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 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Índice de Gravidade de Doença
/
Movimento Celular
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Quinases Ativadas por p21
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Agenesia do Corpo Caloso
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Deficiência Intelectual
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Child
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article