ARHGEF9, also known as Collybistin (Cb), is a Cdc42 Guanine Nucleotide Exchange Factor. It is crucial for inhibitory synapse function as it directly interacts with neuroligin-2 and the α2 subunit of GABAA receptors [2]. It also plays a role in regulating cell shape determination, with its activity being essential for melanoma cells to invade 3D matrices and establish filopodial-driven adhesion [1].

Mutations in ARHGEF9 lead to a range of neurodevelopmental disorders. In humans, patients with ARHGEF9 mutations often present with intellectual disability, epilepsy, abnormal EEG activity, behavioral symptoms, and sleep disturbances [2]. In a study of 18 patients, symptoms presented in early childhood, including delayed motor development and seizures. Intellectual disability was severe in most, and males with severe intellectual disability had intractable epilepsy and a particular facial dysmorphism. Those with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy [3]. A mouse model (Gabra2-1 mice) with a mutation that disrupts collybistin binding to the GABAA receptor α2 subunit recapitulated many features of human ARHGEF9 mutation, such as deficits in memory, hyperactivity, anxiety, and spontaneous seizures [2].

In conclusion, ARHGEF9 is essential for inhibitory synapse function and cell shape regulation. Research using mouse models has been crucial in understanding its role in neurodevelopmental disorders, such as intellectual disability and epilepsy. These insights can potentially guide the development of targeted therapies for these complex syndromes.

References:

1. Bousgouni, Vicky, Inge, Oliver, Robertson, David, Clatworthy, Innes, Bakal, Chris. 2022. ARHGEF9 regulates melanoma morphogenesis in environments with diverse geometry and elasticity by promoting filopodial-driven adhesion. In iScience, 25, 104795. doi:10.1016/j.isci.2022.104795. https://pubmed.ncbi.nlm.nih.gov/36039362/

2. Hines, Dustin J, Contreras, April, Garcia, Betsua, Moss, Stephen J, Hines, Rochelle M. 2022. Human ARHGEF9 intellectual disability syndrome is phenocopied by a mutation that disrupts collybistin binding to the GABAA receptor α2 subunit. In Molecular psychiatry, 27, 1729-1741. doi:10.1038/s41380-022-01468-z. https://pubmed.ncbi.nlm.nih.gov/35169261/

3. Alber, Michael, Kalscheuer, Vera M, Marco, Elysa, Najmabadi, Hossein, Minassian, Berge A. 2017. ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation. In Neurology. Genetics, 3, e148. doi:10.1212/NXG.0000000000000148. https://pubmed.ncbi.nlm.nih.gov/28589176/