<i>RNF216</i>, encoding an E3 ubiquitin ligase, has been identified as a causative gene for Gordon Holmes syndrome, characterized by ataxia, dementia, and hypogonadotropic hypogonadism.
We propose that RNF138 plays a critical role in the homeostatic regulation of Ca<sub>V</sub>2.1 protein level and functional expression and that RNF138 serves as the primary E3 ubiquitin ligase promoting EA2-associated aberrant degradation of human Ca<sub>V</sub>2.1 subunits.<b>SIGNIFICANCE STATEMENT</b> Loss-of-function mutations in the human Ca<sub>V</sub>2.1 subunit are linked to episodic ataxia type 2 (EA2), a dominantly inherited disease characterized by paroxysmal attacks of ataxia and nystagmus.
Transcriptional analysis of endophilin-A mutant mice, complemented by proteomics, highlighted ataxia- and protein-homeostasis-related genes and revealed upregulation of the E3-ubiquitin ligase FBXO32/atrogin-1 and its transcription factor FOXO3A.