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CTNNB1综合征小鼠模型。

CTNNB1 syndrome mouse models.

作者信息

Lainšček Duško, Forstnerič Vida, Miroševič Špela

机构信息

Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, 1000, Slovenia.

Centre for Technologies of Gene and Cell Therapy, Ljubljana, 1000, Slovenia.

出版信息

Mamm Genome. 2025 Jan 20. doi: 10.1007/s00335-025-10105-3.

DOI:10.1007/s00335-025-10105-3
PMID:39833474
Abstract

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.

摘要

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。

相似文献

1
CTNNB1 syndrome mouse models.CTNNB1综合征小鼠模型。
Mamm Genome. 2025 Jan 20. doi: 10.1007/s00335-025-10105-3.
2
De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.β-连环蛋白(CTNNB1)中的新生突变似乎是智力障碍的一个常见原因:扩展突变和临床谱。
Hum Genet. 2015 Jan;134(1):97-109. doi: 10.1007/s00439-014-1498-1. Epub 2014 Oct 19.
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Establishment of an iPSC line from a NDD patient with a heterozygous mutation in the CTNNB1 gene.建立一个具有 CTNNB1 基因突变的 NDD 患者的 iPSC 系。
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BMC Neurol. 2016 Mar 12;16:35. doi: 10.1186/s12883-016-0554-y.
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Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome.抑制 GSK3α、β 可挽救 CTNNB1 综合征临床前小鼠模型中的认知表型。
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Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects.抑制性神经回路中CTNNB1的缺失导致自闭症相关行为缺陷。
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Identification of a novel de novo mutation in the CTNNB1 gene in an Iranian patient with intellectual disability.在一名伊朗智力障碍患者中鉴定到 CTNNB1 基因中的一个新的从头突变。
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Inhibiting Wnt/beta-catenin in CTNNB1-mutated endometrial cancer.抑制 CTNNB1 突变型子宫内膜癌中的 Wnt/β-连环蛋白。
Mol Carcinog. 2021 Aug;60(8):511-523. doi: 10.1002/mc.23308. Epub 2021 May 26.

本文引用的文献

1
Genetic investigations in cerebral palsy.脑瘫的遗传学研究。
Dev Med Child Neurol. 2025 Feb;67(2):177-185. doi: 10.1111/dmcn.16080. Epub 2024 Aug 29.
2
Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome.抑制 GSK3α、β 可挽救 CTNNB1 综合征临床前小鼠模型中的认知表型。
EMBO Mol Med. 2024 Sep;16(9):2109-2131. doi: 10.1038/s44321-024-00110-5. Epub 2024 Aug 5.
3
Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.CTNNB1 综合征的运动障碍表型:一种复杂但可识别的现象学。
Parkinsonism Relat Disord. 2024 Sep;126:107057. doi: 10.1016/j.parkreldis.2024.107057. Epub 2024 Jul 9.
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Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.CTNNB1 神经发育障碍的临床表型谱。
Clin Genet. 2024 May;105(5):523-532. doi: 10.1111/cge.14487. Epub 2024 Jan 21.
5
Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8 T cell-mediated antitumour immunity and improves anti-PD-1 efficacy.靶向 CTNNB1 突变型肝细胞癌中的 MMP9 可恢复 CD8 T 细胞介导的抗肿瘤免疫并提高抗 PD-1 疗效。
Gut. 2024 May 10;73(6):985-999. doi: 10.1136/gutjnl-2023-331342.
6
Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.CTNNB1 综合征中的先天性心脏缺陷:提高临床意识。
Clin Genet. 2023 Nov;104(5):528-541. doi: 10.1111/cge.14404. Epub 2023 Jul 17.
7
/β-catenin inactivation in UCP1-positive adipocytes augments the browning of white adipose tissue.UCP1阳性脂肪细胞中的β-连环蛋白失活增强了白色脂肪组织的褐变。
iScience. 2023 Apr 1;26(5):106552. doi: 10.1016/j.isci.2023.106552. eCollection 2023 May 19.
8
CTNNB1 in neurodevelopmental disorders.神经发育障碍中的β-连环蛋白1(CTNNB1)
Front Psychiatry. 2023 Mar 16;14:1143328. doi: 10.3389/fpsyt.2023.1143328. eCollection 2023.
9
Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations.CTNNB1 基因突变患者的家族性渗出性玻璃体视网膜病变和全身异常。
Invest Ophthalmol Vis Sci. 2023 Feb 1;64(2):18. doi: 10.1167/iovs.64.2.18.
10
Cortical Parvalbumin-Positive Interneuron Development and Function Are Altered in the APC Conditional Knockout Mouse Model of Infantile and Epileptic Spasms Syndrome.皮质层 Parvalbumin 阳性中间神经元在婴儿痉挛症和癫痫性痉挛综合征 APC 条件性敲除小鼠模型中的发育和功能改变。
J Neurosci. 2023 Feb 22;43(8):1422-1440. doi: 10.1523/JNEUROSCI.0572-22.2022. Epub 2023 Jan 30.