The giant 532 kDa HERC1 protein is a ubiquitin ligase that interacts with tuberous sclerosis complex subunit 2 (TSC2), a negative upstream regulator of the mammalian target of rapamycin complex 1 (mTORC1). TSC2 regulates anabolic cell growth through its influence on protein synthesis, cell growth, proliferation, autophagy, and differentiation. TSC subunit 1 (TSC1) stabilizes TSC2 by inhibiting the interaction between TSC2 and HERC1, forming a TSC1-TSC2 complex that negatively regulates mTORC1. HERC1-TSC2 interaction destabilizes and degrades TSC2. Recessive mutations in HERC1 have been reported in patients with intellectual disability. Some patients exhibit epilepsy, macrocephaly, somatic overgrowth, and dysmorphic facial features as well. Here we describe two sisters from a consanguineous marriage with a novel homozygous missense variant in the C-terminal HECT domain of HERC1 [chr15:g63,907,989C > G GRCh37.p11|c.14,072G > C NM_003922|p.(Arg4,691Pro)]. Symptoms comprised global developmental delay, macrocephaly, somatic overgrowth, intellectual disability, seizures, schizoaffective disorder, and pyramidal tract signs. We functionally assessed the HERC1 mutation by investigation of patient and control fibroblasts under normal and nutrient starving conditions. During catabolic state, mTORC1 activity remained high in patient fibroblasts, which stands in stark contrast to its downregulation in controls. This was corroborated by an abnormally high phosphorylation of S6K1-kinase, a direct downstream target of mTORC1, in patients. Moreover, autophagy, usually enhanced in catabolic states, was down-regulated in patient fibroblasts. These data confirm that the missense variant found in both patients results in a gain-of-function for the mutant HERC1 protein.

巨大的532 kDa HERC1蛋白是一种泛素连接酶，可与结节性硬化复合物亚基2（TSC2）相互作用，后者是雷帕霉素复合物1（mTORC1）哺乳动物靶标的负上游调节子。TSC2通过影响蛋白合成，细胞生长，增殖，自噬和分化来调节合成代谢细胞的生长。TSC亚基1（TSC1）通过抑制TSC2与HERC1之间的相互作用来稳定TSC2，从而形成负调控mTORC1的TSC1-TSC2复合物。HERC1-TSC2相互作用使TSC2不稳定并降解。HERC1中的隐性突变有智力障碍患者的报道。一些患者还表现出癫痫，大头畸形，躯体过度生长和面部畸形。在这里，我们描述了来自近亲结婚的两个姐妹，它们在HERC1的C端HECT域中具有新型的纯合错义变体[chr15：g63,907,989C> G GRCh37.p11 | c.14,072G> C NM_003922 | p。（Arg4， 691Pro）]。症状包括整体发育迟缓，大头畸形，躯体过度生长，智力残疾，癫痫发作，精神分裂症和锥体束征。我们通过在正常和营养缺乏的情况下研究患者和对照成纤维细胞，功能上评估了HERC1突变。在分解代谢状态下，患者成纤维细胞中mTORC1的活性仍然很高，这与其对照中的下调形成鲜明对比。在患者中，mTORC1的直接下游靶点S6K1激酶异常高的磷酸化证实了这一点。此外，通常在分解代谢状态下增强的自噬在患者成纤维细胞中被下调。这些数据证实在两个患者中发现的错义变体导致突变的HERC1蛋白的功能获得。