The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.

中文翻译：

---

TRIO 中的突变对 RAC1 的相反调节与不同的、特定领域的神经发育障碍有关。

Rho-鸟嘌呤核苷酸交换因子 (RhoGEF) TRIO 通过激活 GTPase RAC1 和调节肌动蛋白细胞骨架重塑，充当神经元迁移、轴突生长、轴突引导和突触发生的关键调节因子。TRIO 中的致病变异与神经发育疾病有关，包括智力障碍 (ID) 和自闭症谱系障碍 (ASD)。在这里，我们报告了 TRIO 中最大的国际队列，该队列由 24 名确诊的致病性错义或无义变异个体组成。无义突变沿着 TRIO 序列传播，受影响的个体表现出可变的神经发育表型。相反，错义变体在 TRIO 序列中聚集成两个突变热点，一个在第七个 Spectrin 重复序列中，一个在 RAC1 激活 GEFD1 中。尽管该队列中的所有个体都存在发育迟缓和神经行为表型，但在第七个血影蛋白重复序列​​中具有致病性变异的个体与大头畸形相关的 ID 比大多数 GEFD1 变异个体更严重，后者表现出较轻的 ID 和小头畸形。功能研究表明，血影蛋白和 GEFD1 变体分别导致 TRIO 介导的 RAC1 过度激活或过度激活，我们观察到 RAC1 激活水平与受影响个体的头部大小之间存在显着的相关性。此外，脊椎动物模型 X.tropicalis 中 TRIO GEFD1 的截断会导致与人类表型一致的缺陷。