Calcineurin is a calcium-calmodulin-regulated serine–threonine phosphatase consisting catalytic subunit calcineurin A and regulatory subunit calcineurin B. PPP3CA encodes a major isoform of calcineurin A that contains a catalytic domain (CD), a binding site for calcineurin regulatory subunit - calcineurin B, and a regulatory domain (RD) that contains a calmodulin binding domain (CaMB) and an auto-inhibitory domain (AID). Calcineurin activation needs calmodulin binding which triggers protein conformation changes and displacement of AID.
Heterozygous pathogenic or likely pathogenic variants in PPP3CA are rare and so far, all reported patients had a de novo variant. Inheritance mode is autosomal dominant.
Missense variants in the CD and missense variants in the AID have been associated with two distinct disorders. Studies in yeast models suggested that the variants in the CD decreased calcineurin signaling resulting in LoF, whereas the variants in the AID increased calcineurin signaling resulting in GoF. Truncating variants including nonsense and frameshift variants are clustered in the RD and their disease-causing mechanism is not well understood at this time. Deletion or duplication of this gene has not been reported yet.
Diagnostic testing
Variants in PPP3CA can be identified using molecular genetic testing, either direct sequencing of PPP3CA, or by exome or genome sequencing or targeted next generation sequencing panel for epilepsy.
PPP3CA