A de novo variant in RAC3 causes severe global developmental delay and a middle interhemispheric variant of holoprosencephaly
A de novo variant in RAC3 causes severe global developmental delay and a middle interhemispheric variant of holoprosencephaly
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DOI：
10.1038/s10038-019-0656-7
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发表时间：
2019-11-01
影响因子：
3.5
通讯作者：
Saitsu, Hirotomo
中科院分区：
文献类型：
--
作者：
Hiraide, Takuya;Yasui, Hikari Kaba;Saitsu, Hirotomo
RAC 3是Rho GTPases家族的成员，在神经元形态发生方面具有重要的调节功能。Rho GTP酶通过GTP结合在两个区域（开关I和II）中显示构象变化，这为与功能多样的蛋白质的选择性相互作用提供了平台。RAC 3开关I和II区域的错义变体最近被认为会导致严重的智力残疾和脑畸形。在这里，我们报告了一个具有新的从头RAC 3变体的个体（c.101 C>G，p.（Pro34Arg）），其取代开关I区域内的进化上保守的氨基酸。患者表现出严重的整体发育迟缓、智力残疾、癫痫和喉肌张力障碍。影像学研究显示特征性脑发育不良，包括前脑无裂畸形和脑干畸形的中纵裂变异共存。我们的研究支持RAC 3变异体导致综合征性神经发育障碍和脑结构异常，并扩大了RAC 3相关疾病的表型谱。
RAC3 is a member of the Rho GTPases family, which has important regulatory functions in aspects of neuronal morphogenesis. Rho GTPases show a conformational change in two regions (switch I and II) through GTP binding, which provides a platform for selective interactions with functionally diverse proteins. Missense variants in the switch I and II regions of RAC3 were recently suggested to cause severe intellectual disability and brain malformations. Here, we report an individual with a novel de novo RAC3 variant (c.101 C>G, p.(Pro34Arg)), which substitutes for an evolutionarily conserved amino acid within the switch I region. The patient showed severe global developmental delay, intellectual disability, epilepsy, and laryngeal dystonia. An imaging study revealed characteristic brain dysplasia, including coexistence of the middle interhemispheric variant of holoprosencephaly and brainstem dysmorphism. Our study supports that RAC3 variants cause syndromic neurodevelopmental disorders and brain structural abnormality, and expands the phenotypic spectrum of RAC3-related disorders.