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.This article is protected by copyright. All rights reserved.
About The Expert
Sugi Panneerselvam
Julia Wang
Wenmiao Zhu
Hongzheng Dai
John G Pappas
Rachel Rabin
Karen J Low
Jill A Rosenfeld
Lisa Emrick
Rui Xiao
Fan Xia
Yaping Yang
Christine M Eng
Anne Anderson
Vann Chau
Claudia Soler-Alfonso
Haley Streff
Seema R Lalani
Saadet Mercimek-Andrews
Weimin Bi
References
PubMed