Ppp3ca, encoding the catalytic subunit of calcineurin, is a serine/threonine phosphatase. Calcineurin is crucial in connecting calcium signaling to the phosphorylation states of numerous substrates like transcription factors, receptors, and proteins associated with mitochondria and microtubules. It is activated by increased intracellular calcium concentrations and calmodulin binding to its regulatory domain [2].

Pathogenic variants in Ppp3ca are linked to severe diseases. Truncating variants in the regulatory domain of Ppp3ca lead to early-onset refractory epilepsy, with patients showing more severe and earlier-onset seizures compared to those with loss-of-function missense variants. In addition, Ppp3ca-related developmental and epileptic encephalopathy presents two distinct electro-clinical phenotypes depending on the location of pathogenic variants. Variants in the calmodulin-binding domain result in childhood-onset epilepsy with focal and generalized seizures, while those in the regulatory domain cause early-onset drug-resistant severe epilepsy and potentially fatal outcomes [1,3].

In conclusion, Ppp3ca plays a vital role in calcium-mediated signaling and protein phosphorylation. Its dysfunction, especially due to specific pathogenic variants, is strongly associated with severe epileptic and encephalopathic conditions. The study of Ppp3ca through genetic models helps in understanding the underlying pathophysiological mechanisms of these diseases, potentially paving the way for new treatment strategies.