PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy
Sugi Panneerselvam1, Julia Wang2, Wenmiao Zhu3
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
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.
Insights
New research identifies specific PPP3CA gene truncating variants in a regulatory domain region. These variants are linked to severe early-onset epilepsy, distinguishing them from other known loss-of-function or gain-of-function mutations.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Developmental Biology
Background:
- PPP3CA encodes the catalytic subunit of calcineurin, a crucial phosphatase involved in cellular signaling.
- Known loss-of-function (LoF) variants in the catalytic domain are associated with epilepsy.
- Gain-of-function (GoF) variants in the auto-inhibitory domain are linked to congenital abnormalities.
Purpose of the Study:
- To investigate the clinical and molecular characteristics of novel de novo PPP3CA variants.
- To differentiate the phenotypic impact of truncating variants in the regulatory domain from previously described LoF and GoF variants.
Main Methods:
- Clinical evaluation of five new patients with de novo PPP3CA variants.
- Analysis of variant locations, focusing on a specific 26-amino acid region in the regulatory domain (RD).
- Comparison of seizure severity and associated neurodevelopmental features between different variant types.
- Expression studies to assess the impact of a truncating variant on RNA and protein levels.
Main Results:
- Five new patients with de novo PPP3CA variants were identified.
- Frameshift and truncating variants were clustered within a 26-amino acid region of the RD.
- Patients with truncating variants exhibited more severe, early-onset seizures compared to those with LoF missense variants.
- Autism spectrum disorder was more prevalent in patients with LoF missense variants.
- Expression studies indicated RNA expression but no detectable mutant protein for a truncating variant.
Conclusions:
- PPP3CA truncating variants clustered in the RD represent a distinct class of pathogenic variants.
- These variants are strongly associated with severe, early-onset refractory epilepsy.
- The findings differentiate the clinical spectrum of PPP3CA-related disorders based on variant type and location.
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