Lainšček Duško, Forstnerič Vida, Miroševič Špela
Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, 1000, Slovenia.
Centre for Technologies of Gene and Cell Therapy, Ljubljana, 1000, Slovenia.
Mamm Genome. 2025 Jan 20. doi: 10.1007/s00335-025-10105-3.
CTNNB1 syndrome is a rare neurodevelopmental disorder, affecting children worldwide with a prevalence of 2.6-3.2 per 100,000 births and often misdiagnosed as cerebral palsy. De novo loss-of-function mutations in the Ctnnb1 gene result in dysfunction of the β-catenin protein, disrupting the canonical Wnt signaling pathway, which plays a key role in cell proliferation, differentiation, and tissue homeostasis. Additionally, these mutations impair the formation of cell junctions, adversely affecting tissue architecture. Motor and speech deficits, cognitive impairment, cardiovascular and visual problems are just some of the key symptoms that occur in CTNNB1 syndrome patients. There is currently no effective treatment option available for patients with CTNNB1 syndrome, with support largely focused on the management of symptoms and physiotherapy, yet recently some therapeutic approaches are being developed. Animal testing is still crucial in the process of new drug development, and mouse models are particularly important. These models provide researchers with new understanding of the disease mechanisms and are invaluable for testing the efficacy and safety of potential treatments. The development of various mouse models with β-catenin loss- and gain-of-function mutations successfully replicates key features of intellectual disability, autism-like behaviors, motor deficits, and more. These models provide a valuable platform for studying disease mechanisms and offer a powerful tool for testing the therapeutic potential and effectiveness of new drug candidates, paving the way for future clinical trials.
CTNNB1综合征是一种罕见的神经发育障碍,全球范围内均有儿童受其影响,每10万例出生中患病率为2.6 - 3.2例,且常被误诊为脑瘫。Ctnnb1基因的新生功能丧失突变导致β - 连环蛋白功能障碍,破坏经典Wnt信号通路,该通路在细胞增殖、分化和组织稳态中起关键作用。此外,这些突变会损害细胞连接的形成,对组织结构产生不利影响。运动和言语缺陷、认知障碍、心血管和视觉问题只是CTNNB1综合征患者出现的部分关键症状。目前,CTNNB1综合征患者尚无有效的治疗选择,主要支持措施集中在症状管理和物理治疗上,但最近正在开发一些治疗方法。在新药研发过程中,动物试验仍然至关重要,小鼠模型尤为重要。这些模型为研究人员提供了对疾病机制的新认识,对于测试潜在治疗方法的疗效和安全性具有不可估量的价值。具有β - 连环蛋白功能丧失和功能获得突变的各种小鼠模型的开发成功复制了智力残疾、自闭症样行为、运动缺陷等关键特征。这些模型为研究疾病机制提供了有价值的平台,并为测试新候选药物的治疗潜力和有效性提供了强大工具,为未来的临床试验铺平了道路。