PPP3CA truncating variants clustered in the regulatory domain cause early‐onset refractory epilepsy

Abstract

PPP3CA encodes the catalytic subunit of calcineurin, a calcium‐calmodulin‐regulated serine–threonine phosphatase. Loss‐of‐function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain‐of‐function (GoF) variants in the auto‐inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26‐amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early‐onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.

Astroglial calcium signaling and homeostasis in tuberous sclerosis complex

“…Protein Phosphatase 3 Catalytic Subunit Alpha ( PPP3CA, Log 2 FC = − 0.72; p.adj = 0.026) enables several functions, including ATPase binding activity, CaM binding activity, and CaM -dependent protein phosphatase activity, calcineurin-NFAT signaling cascade, peptidyl–serine dephosphorylation and response to Ca 2+ ion. RCAN3 (Log 2 FC = 0.73; p.adj = 0.004) encodes for RCAN Family Member 3 and is involved in Ca 2+ -mediated signaling, inhibiting calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A [ 72 , 76 ].…”

Vascular endothelial growth factor B regulates insulin secretion in β cells of type 2 diabetes mellitus mice via PLCγ and the IP3R‑evoked Ca2+/CaMK2 signaling pathway

“…In 2008, Wang et al reported that PPP3CA modulates the VEGF-stimulated cell proliferation and signaling cascades in cells ( 47 ). PPP3CA is a serine/threonine phosphatase regulated by Ca 2+ /CaM ( 48 , 49 ). Gelernter et al found that PPP3CA encodes a calcium-dependent, calmodulin-stimulated protein phosphatase involved in calcium signaling ( 50 ).…”

Clinical evaluation of rare copy number variations identified by chromosomal microarray in a Hungarian neurodevelopmental disorder patient cohort

“…Loss-of-function pathogenic variants cause autosomal dominant developmental and epileptic encephalopathy 91 (OMIM#617,711). This disorder is characterized by early-onset epilepsy (severity is variable and may be correlated with the specific variant), moderate/severe DD/ID, developmental regression, autistic behavior, generalized muscular hypotonia or spasticity, talipes equinovarus, feeding difficulties, cortical vision loss, cerebral atrophy and delayed myelinization [ 28 – 30 ]. Gain-of-function pathogenic variants lead to a syndrome characterized by arthrogryposis, cleft palate, craniosynostosis and ID (OMIM#618,265).…”