The RhoB p.S73F mutation leads to cerebral palsy through dysregulation of lipid homeostasis.

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. Synopsis: A novel rabbit model was successfully developed to replicate the genetic changes observed in human CP cases. The model exhibited typical symptoms of CP, providing further insights between RhoB and lipid metabolism, and therapeutic targets for human CP. The first precise point mutation mammalian model of genetic CP disease based on human cases was constructed using the SpG-BE4max system. The rabbit model successfully replicated key features of motor impairment in CP cases that are not found in existing models, including a forward tilt of the trunk, hypertonia of the lower limbs, and a scissor-like gait. The RhoB p.S73F mutation could disrupt lipid homeostasis via the LYN-ACAT1 pathway, leading to lipid peroxidation, calcium overload, and subsequent damage to neuronal cells and myelin. A novel rabbit model was successfully developed to replicate the genetic changes observed in human CP cases. The model exhibited typical symptoms of CP, providing further insights between RhoB and lipid metabolism, and therapeutic targets for human CP. [ABSTRACT FROM AUTHOR]