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.

中文翻译：

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PAK3突变导致严重的智力残疾和call发育不全抑制细胞迁移。

us体发育不全（CCA）是与广泛的临床范围相关的脑畸形，包括智力残疾（ID）和病因复杂性。我们在一个患有严重ID，小头畸形和CCA及其胎儿同胞患有CCA和严重脑积水的男孩中，在X连锁的p21活化激酶3（PAK3）基因中发现了一个新的错义G424R突变。已知PAK3激酶可控制突触可塑性和树突棘动力学，但其在脑本体发育中的作用较少。为了鉴定受负责CCA的突变影响的PAK3的发育功能，我们比较了位于催化域中的三个PAK3突变的生化和生物学效应。这些突变包括两个“严重” G424R和K389N变体（负责严重的ID和CCA），而“ 并严重影响细胞迁移。我们的发现突出了与导致严重临床表型和发育性脑缺陷的突变相关的新分子缺陷。并严重影响细胞迁移。我们的发现突出了与导致严重临床表型和发育性脑缺陷的突变相关的新分子缺陷。