Cerebral palsy (CP) is a prevalent neurological disorder that imposes a significant burden on children, families, and society worldwide. Recently, the RhoB p.S73F mutation was identified as a de novo mutation associated with CP. However, the mechanism by which the RhoB p.S73F mutation causes CP is currently unclear. In this study, rabbit models were generated to mimic the human RhoB p.S73F mutation using the SpG-BE4max system, and exhibited the typical symptoms of human CP, such as periventricular leukomalacia and spastic-dystonic diplegia. Further investigation revealed that the RhoB p.S73F mutation could activate ACAT1 through the LYN pathway, and the subsequently altered lipid levels may lead to neuronal and white matter damage resulting in the development of CP. This study presented the first mammalian model of genetic CP that accurately replicates the RhoB p.S73F mutation in humans, provided further insights between RhoB and lipid metabolism, and novel therapeutic targets for human CP.

中文翻译：

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RhoB p.S73F 突变通过脂质稳态失调导致脑瘫。


脑瘫（CP）是一种常见的神经系统疾病，给全世界的儿童、家庭和社会带来了巨大的负担。最近，RhoB p.S73F 突变被鉴定为与 CP 相关的从头突变。然而，RhoB p.S73F突变导致CP的机制目前尚不清楚。在本研究中，使用 SpG-BE4max 系统模拟人类 RhoB p.S73F 突变的兔模型，并表现出人类 CP 的典型症状，如脑室周围白质软化和痉挛性肌张力障碍性瘫痪。进一步研究发现，RhoB p.S73F突变可以通过LYN途径激活ACAT1，随后脂质水平的改变可能导致神经元和白质损伤，从而导致CP的发生。这项研究提出了第一个遗传性 CP 的哺乳动物模型，该模型准确地复制了人类中的 RhoB p.S73F 突变，提供了 RhoB 和脂质代谢之间的进一步见解，以及人类 CP 的新治疗靶点。