Viviane Tran, Marie-Anne Goyette, Mónica Martínez-García, Ana Jiménez de Domingo, Daniel Martín Fernández-Mayoralas, Ana Laura Fernández-Perrone, Pilar Tirado, Beatriz Calleja-Pérez, Sara Álvarez, Jean-François Côté, Alberto Fernández-Jaén
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引用次数: 3
摘要
吞噬和细胞运动3 (ELMO3)蛋白属于elmo蛋白家族。ELMO蛋白与DOCK1-5鸟嘌呤核苷酸交换因子形成紧密复合物,调控RAC1的时空激活和信号传导。众所周知,DOCK蛋白和RAC1在中枢神经系统发育中起着重要作用。在这里,我们在与遗传起源相容的神经发育障碍个体的390个全外显子组中寻找ELMO3基因的纯合或复合杂合突变。我们在ELMO3中发现了一个复合杂合突变(c.1153A>T, p.Ser385Cys和c.1009)G > A, p.Val337Ile) 1例5岁男性自闭症谱系障碍(ASD)并发发育迟缓。这些突变不会干扰ELMO3/DOCK1复合物的形成,但会显著削弱该复合物促进rac1 - gtp加载的能力。因此,表达DOCK1和任何一种ELMO3突变体的细胞表现出迁移和侵袭受损。总之,我们的研究结果表明,ELMO3的双等位基因功能缺失突变可能导致发育迟缓,并为ELMO3在神经发育中的作用以及ELMO3突变的病理后果提供了新的见解。
Biallelic ELMO3 mutations and loss of function for DOCK-mediated RAC1 activation result in intellectual disability.
The engulfment and cell motility 3 (ELMO3) protein belongs to the ELMO-family of proteins. ELMO proteins form a tight complex with the DOCK1-5 guanine nucleotide exchange factors that regulate RAC1 spatiotemporal activation and signalling. DOCK proteins and RAC1 are known to have fundamental roles in central nervous system development. Here, we searched for homozygous or compound heterozygous mutations in the ELMO3 gene in 390 whole exomes sequenced in trio in individuals with neurodevelopmental disorders compatible with a genetic origin. We found a compound heterozygous mutation in ELMO3 (c.1153A>T, p.Ser385Cys and c.1009 G > A, p.Val337Ile) in a 5 year old male child with autism spectrum disorder (ASD) and developmental delay. These mutations did not interfere with the formation of an ELMO3/DOCK1 complex, but markedly impaired the ability of the complex to promote RAC1-GTP-loading. Consequently, cells expressing DOCK1 and either of the ELMO3 mutants displayed impaired migration and invasion. Collectively, our results suggest that biallelic loss-of-function mutations in ELMO3 may cause a developmental delay and provide new insight into the role of ELMO3 in neurodevelopmental as well as the pathological consequences of ELMO3 mutations.