The family of Tre2‐Bub2‐Cdc16 (TBC)‐domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP‐independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss‐of‐function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B‐deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.

中文翻译：

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TBC1D2B 中的双等位基因功能丧失变异导致癫痫发作和牙龈过度生长的神经发育障碍。

Tre2-Bub2-Cdc16 (TBC) 结构域包含 GTPase 激活蛋白 (RABGAPs) 家族不仅被称为 RAB GTPase 活性的关键调节因子，而且还具有独立于 GAP 的功能。Rab GTP 酶与膜运输途径有关，例如囊泡运输。我们报告了TBC1D2B 中的双等位基因功能丧失变异，编码 TBC/RABGAP 家族成员但功能未知，这是三个来自无关家族的个体认知障碍、癫痫发作和/或牙龈过度生长的根本原因。TBC1D2B信使 RNA 量急剧减少，两名患者的成纤维细胞中不存在该蛋白质。在免疫荧光分析中，异位表达的 TBC1D2B 与 RAB5 阳性囊泡共定位，RAB5 是一种协调早期内吞囊泡运输的小 GTPase。在用作TBC1D2B缺陷细胞模型的两个独立的TBC1D2B CRISPR/Cas9 敲除 HeLa 细胞系中，与亲本 HeLa 细胞系相比，表皮生长因子内化显着降低，表明 TBC1D2B 在早期内吞作用中发挥作用。TBC1D2B 缺陷型HeLa 细胞系的血清剥夺导致细胞活力降低和细胞凋亡增加。我们的数据显示，TBC1D2B 的丢失 导致牙龈过度生长的神经发育障碍，可能是由于囊泡运输和/或细胞存活的缺陷。