背景:15q11.2缺失和重复与自闭症谱系障碍(ASD)有关,精神分裂症,智力残疾(ID)。最近的证据表明,功能失调的细胞质FMR1相互作用蛋白1(CYFIP1)有助于在15q11.2缺失/重复综合征的个体中观察到的临床表型。CYFIP1在神经元发育和大脑连接中起着至关重要的作用,促进肌动蛋白聚合和调节局部蛋白质合成。然而,CYFIP1单核苷酸变异体对神经发育障碍的影响有限.
方法:这里,我们报告了一个有两个先证者的家庭,ASD,痉挛性四轻瘫,和携带CYFIP1基因双等位基因错义点突变的脑形态缺陷。我们使用了先证者之一的皮肤成纤维细胞,父母,以及通常发育中的个体,以研究变体对CYFIP1功能的影响。此外,我们产生了果蝇敲入突变体,以解决体内变异的影响,并深入了解临床表型的分子机制.
结果:我们的研究表明,这两个错义变体位于负责维持波调节复合物(WRC)内相互作用的蛋白质结构域中。来自一个先证者的皮肤成纤维细胞的分子和细胞分析显示肌动蛋白聚合不足。这些突变的苍蝇模型表现出异常的大脑形态和F-肌动蛋白丢失,并概括了核心行为症状,例如社会交往和运动协调的缺陷。
结论:我们的研究结果表明,两种CYFIP1变体有助于在先证者中观察到的临床表型,反映了肌动蛋白介导的脑发育过程中的缺陷。
BACKGROUND: 15q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional
CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes to the clinical phenotypes observed in individuals with 15q11.2 deletion/duplication syndrome.
CYFIP1 plays crucial roles in neuronal development and brain connectivity, promoting actin polymerization and regulating local protein synthesis. However, information about the impact of single nucleotide variants in
CYFIP1 on neurodevelopmental disorders is limited.
METHODS: Here, we report a family with 2 probands exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects and who carry biallelic missense point mutations in the
CYFIP1 gene. We used skin fibroblasts from one of the probands, the parents, and typically developing individuals to investigate the effect of the variants on the functionality of
CYFIP1. In addition, we generated Drosophila knockin mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism that underlies the clinical phenotype.
RESULTS: Our study revealed that the 2 missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex. Molecular and cellular analyses in skin fibroblasts from one proband showed deficits in actin polymerization. The fly model for these mutations exhibited abnormal brain morphology and F-actin loss and recapitulated the core behavioral symptoms, such as deficits in social interaction and motor coordination.
CONCLUSIONS: Our findings suggest that the 2 CYFIP1 variants contribute to the clinical phenotype in the probands that reflects deficits in actin-mediated brain development processes.