Department of Neuroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.
Deptartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Dev Med Child Neurol. 2021 Jul;63(7):802-807. doi: 10.1111/dmcn.14831. Epub 2021 Feb 4.
Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ligase that is critical for typical postnatal brain development. Emerging evidence indicates that UBE3A plays a particularly important role in the nucleus. However, the critical substrates that are controlled by UBE3A remain elusive, which hinders the search for effective treatments. Moreover, given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. Therefore, expectations are very high for approaches that aim to restore UBE3A protein levels. A particular promising strategy is an antisense oligonucleotide approach, which activates the silenced paternal UBE3A gene. When successful, such treatments potentially offer a disease-modifying therapy for Angelman syndrome and several other neurodevelopmental disorders. What this paper adds Loss of UBE3A affects multiple signalling pathways in the brain. Emerging evidence suggests that UBE3A plays a critical role in the cell nucleus. Trials using antisense oligonucleotides to restore UBE3A levels are continuing.
半个世纪前，Harry Angelman 报道了三例具有重叠临床特征的患者，现在众所周知的是 Angelman 综合征。Angelman 综合征是由影响母系遗传 UBE3A 基因的突变引起的，该基因编码一种 E3-泛素连接酶，对典型的产后大脑发育至关重要。新出现的证据表明，UBE3A 在核内发挥着特别重要的作用。然而，受 UBE3A 控制的关键底物仍难以捉摸，这阻碍了寻找有效治疗方法的努力。此外，鉴于有许多信号转导机制被打乱，靶向单一途径不太可能非常有效。因此，人们对旨在恢复 UBE3A 蛋白水平的方法寄予厚望。一种特别有前途的策略是反义寡核苷酸方法，它可以激活沉默的父系 UBE3A 基因。如果成功，这些治疗方法可能为 Angelman 综合征和其他几种神经发育障碍提供一种疾病修饰疗法。本文的新发现UBE3A 的缺失会影响大脑中的多个信号通路。新出现的证据表明，UBE3A 在细胞核中起着关键作用。正在继续使用反义寡核苷酸来恢复 UBE3A 水平的试验。
