Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.
Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
Am J Med Genet A. 2021 Oct;185(10):2895-2902. doi: 10.1002/ajmg.a.62363. Epub 2021 May 28.
The HECT, C2, and WW domain containing E3 ubiquitin protein ligase 2 gene (HECW2) is involved in protein ubiquitination. Several genes associated with protein ubiquitination have been linked to neurodevelopmental disorders. HECW2-related disorder has been established through the identification of de novo variants in HECW2 in patients with neurodevelopmental disorders with hypotonia, seizures, and absent language. Recently, we identified novel HECW2 variants in four Japanese patients with neurodevelopmental disorders. Regarding motor development, two of the patients cannot walk, whereas the other two can walk with an unsteady gait, owing to hypotonia. All HECW2 variants, including those that were previously reported, are missense, and no loss-of-function variants have been identified. Most of the identified variants are located around the HECT domain. These findings suggest that the dominant negative effects of missense variants around the HECT domain may be the mechanism underlying HECW2-related disorder.
HECT、C2 和 WW 结构域包含 E3 泛素蛋白连接酶 2 基因（HECW2）参与蛋白质泛素化。一些与蛋白质泛素化相关的基因与神经发育障碍有关。通过在伴有肌张力低下、癫痫发作和语言缺失的神经发育障碍患者中鉴定新的 HECW2 变异，确定了 HECW2 相关疾病。最近，我们在四名患有神经发育障碍的日本患者中发现了新型 HECW2 变异体。在运动发育方面，两名患者无法行走，而另外两名患者由于肌张力低下，行走步态不稳。所有 HECW2 变异体，包括以前报道过的，均为错义变异体，未发现功能丧失变异体。大多数鉴定出的变异体位于 HECT 结构域附近。这些发现表明，HECT 结构域附近错义变异体的显性负效应可能是 HECW2 相关疾病的机制。
