Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
Department of Medical Genetics, University of Alberta, Edmonton, Canada.
Clin Genet. 2021 Nov;100(5):637-640. doi: 10.1111/cge.14039. Epub 2021 Aug 9.
HECT And RLD Domain-Containing E3 Ubiquitin Protein Ligase 2, or HERC2, codes an ubiquitin ligase that has an important role in key cellular processes including cell cycle regulation, DNA repair, mitochondrial functions, and spindle formation during mitosis. While HERC2 Neurodevelopmental Disorder in Old Order Amish is a well characterized human disorder involving HERC2, bi-allelic HERC2 loss of function has only been described in three families and results in a more severe neurodevelopmental disorder. Herein, we delineate the HERC2 loss of function phenotype by describing three previously unreported patients, and by summarizing the molecular and phenotypic information of all known HERC2 missense variants and biallelic loss of function patients. Collectively, these twelve individuals present with recurring features that define a syndrome with varying combinations of severe neurodevelopmental delay, structural brain anomalies, seizures, hypotonia, feeding difficulties, hearing and vision issues, and renal anomalies. This study describes a distinct neurodevelopmental disorder, emphasizing the importance of further characterization of HERC2-related disorders, as well as highlighting the importance of ongoing work into understanding these critical neurodevelopmental pathways.
HECT 和 RLD 结构域包含 E3 泛素蛋白连接酶 2（也称为 HERC2），编码一种泛素连接酶，在包括细胞周期调控、DNA 修复、线粒体功能和有丝分裂期间纺锤体形成在内的关键细胞过程中发挥重要作用。虽然旧秩序阿米什人中的 HERC2 神经发育障碍是一种特征明确的人类疾病，涉及 HERC2，但双等位基因 HERC2 功能丧失仅在三个家族中描述过，会导致更严重的神经发育障碍。在此，我们通过描述三个以前未报道过的患者，以及总结所有已知的 HERC2 错义变异和双等位基因功能丧失患者的分子和表型信息，来描述 HERC2 功能丧失表型。总的来说，这 12 个人具有反复出现的特征，定义了一种综合征，具有严重神经发育迟缓、结构性脑异常、癫痫、张力减退、喂养困难、听力和视力问题以及肾脏异常等不同组合。本研究描述了一种独特的神经发育障碍，强调了进一步描述 HERC2 相关疾病的重要性，以及强调了不断努力理解这些关键神经发育途径的重要性。
