CSMD3, a large gene encoding a transmembrane protein with CUB and sushi multiple domains, is expressed mainly in adult and fetal brains [3]. It is considered a putative complement control protein, but its exact function and associated pathways remain to be fully elucidated. Genetic models, such as knockout mice, have been crucial in studying its role.

In male CSMD3 knockout (CSMD3 -/-) mice, genetic deletion led to core autistic-like symptoms and motor dysfunction. The ablation of CSMD3 also caused abnormal cerebellar Purkinje cell (PC) morphology in Crus I/II lobules, increased neuronal activity in PCs, enhanced intrinsic excitability, more excitatory synaptic input, and impaired long-term depression at the parallel fiber-PC synapse [1]. In another study, disruption of Csmd3 in mice induced retarded development and neurodevelopmental disorder (NDD)-related behaviors, impaired synaptogenesis and neurogenesis, and perturbed functional networks in the developing cortex [2].

In summary, CSMD3 plays an important role in the development of cerebellar PCs and synaptogenesis. Mouse models with CSMD3 deficiency have revealed its potential contribution to the pathogenesis of motor deficits, autism-like behaviors, and NDDs, providing novel insights into the pathophysiological mechanisms of these disorders.

References:

1. Xi, Ke, Cai, Si-Qing, Yan, Hui-Fang, Wang, Jing-Min, Xing, Guo-Gang. 2023. CSMD3 Deficiency Leads to Motor Impairments and Autism-Like Behaviors via Dysfunction of Cerebellar Purkinje Cells in Mice. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 43, 3949-3969. doi:10.1523/JNEUROSCI.1835-22.2023. https://pubmed.ncbi.nlm.nih.gov/37037606/

2. Song, Wei, Li, Quan, Wang, Tao, Sun, Zhong Sheng, Wang, Yan. 2022. Putative complement control protein CSMD3 dysfunction impairs synaptogenesis and induces neurodevelopmental disorders. In Brain, behavior, and immunity, 102, 237-250. doi:10.1016/j.bbi.2022.02.027. https://pubmed.ncbi.nlm.nih.gov/35245678/

3. Shimizu, Atsushi, Asakawa, Shuichi, Sasaki, Takashi, Kondo, Ikuko, Shimizu, Nobuyoshi. . A novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains: a candidate gene for benign adult familial myoclonic epilepsy on human chromosome 8q23.3-q24.1. In Biochemical and biophysical research communications, 309, 143-54. doi:. https://pubmed.ncbi.nlm.nih.gov/12943675/