Clinical and Molecular Characterization of Three Novel ARHGEF9 Mutations in Patients with Developmental Delay and Epilepsy
Clinical and Molecular Characterization of Three Novel ARHGEF9 Mutations in Patients with Developmental Delay and Epilepsy
复制标题
发育迟缓和癫痫患者中三种新的 ARHGEF9 突变的临床和分子特征。
DOI：
10.1007/s12031-019-01465-y
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发表时间：
2020-01-15
影响因子：
3.1
通讯作者：
Yu, Tingting
中科院分区：
文献类型：
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作者：
Yao, Ruen;Zhang, Yi;Yu, Tingting
rho鸟嘌呤核苷酸交换因子9基因（ARHGEF 9）的突变存在于具有异质性表型的患者中，包括精神发育迟缓和不同程度的癫痫。由ARHGEF 9编码的collybistin（CB）的功能障碍导致桥蛋白依赖性甘氨酸受体和γ-氨基丁酸A型（GABA α）受体的聚集受损是一种重要的致病机制。在这里，我们报告三例癫痫和精神发育迟滞。我们研究了三名男性癫痫患者和轻度至中度精神发育迟滞。我们对已知引起遗传性疾病的基因进行了靶向测序。体外研究和转录实验进行评估的功能和剪接的影响，这些变异体对CB。在3例患者中分别鉴定出ARHGEF 9的两个新错义变体（p.I294T和p.R357I）和一个新剪接变体（c.381+3A>G）。体外研究证实，这两个错义变体破坏CB介导的桥蛋白在膜下微簇中的积累。剪接变体的转录实验揭示了导致截短蛋白产物的异常转录物的存在。意义：我们的病例和功能研究丰富了我们对ARHGEF 9表型和基因型谱的理解。
Mutations in the rho guanine nucleotide exchange factor 9 gene (ARHGEF9) are present in patients with heterogeneous phenotypes including psychomotor developmental delay and variable degrees of epilepsy. Malfunction of collybistin (CB) encoded by ARHGEF9 leading to impaired clustering of gephyrin-dependent glycine receptors and gamma-aminobutyric acid type A (GABA alpha) receptors is a crucial pathogenic mechanism. Here, we report on three patients with epilepsy and mental retardation. We studied three male patients with epilepsy and mild to moderate mental retardation. We conducted targeted panel sequencing of genes known to cause inherited disorders. In vitro studies and transcriptional experiments were performed to evaluate the functional and splicing effects of these variants on CB. Two novel missense variants (p.I294T and p.R357I) and one novel splicing variant (c.381+3A>G) in ARHGEF9 were identified in the three patients, respectively. In vitro studies confirmed that the two missense variants disrupted CB-mediated accumulation of gephyrin in submembrane microclusters. Transcriptional experiments of the splicing variant revealed the presence of aberrant transcripts leading to truncated protein product. Significance: Our cases and functional studies enrich our understanding of the phenotypic and genotypic spectrum of ARHGEF9.