March 1, 2018

PPP3CA Gene Mutations Cause a Severe Neurodevelopmental Disease and Seizures

The discovery is credited to data from CURE’s Epilepsy Genetics Initiative

De novo mutations in the PPP3CA gene lead to a severe form of neurodevelopmental disease characterized by seizures. These mutations are not inherited from an individual’s parents.

The discovery was based on genomic data from CURE’s Epilepsy Genetics Initiative.

The identification of PPP3CA as an epilepsy-associated gene provides new insight into the possible causes and mechanisms behind epilepsy, opening a new research target for potential PPP3CA-related therapeutics.

The discovery also provides much-needed information to the individuals and families affected by PPP3CA-associated epilepsies because that diagnosis can potentially be used to inform decisions regarding treatments.

Identifying the genes in which mutations can lead to epilepsy can be challenging, especially for the severe and rare forms. The rarity of these disorders is often associated with a lack of sufficient data. However, in pooling genetics data from several different sources, including those from CURE’s Epilepsy Genetics Initiative, Principal Investigator Dr. Erin L. Heinzen and senior co-author Dr. Heather Mefford had the statistical power to successfully identify mutations in the PPP3CA gene as a lead factor in the development of one severe type of PPP3CA-associated neurodevelopmental disease characterized by childhood-onset epilepsy.

The PPP3CA gene is typically responsible for the production of a protein called calcineurin, which is an essential component of proper signaling between neurons in the brain.[1] As the results of the current study demonstrate, mutations interfering with proper neuronal transmission, such as mutations in PPP3CA, can lead to neurodevelopmental disorders and epilepsy. Using a combined genomic dataset, Dr. Heinzen and her team found de novo mutations in PPP3CA in six individuals: 6/6 of these individuals had developmental delays, 5/6 had childhood-onset epilepsy, and 3/6 had an atypical physical appearance.

According to Dr. Laura Lubbers, Chief Scientific Officer at CURE, “The powerful discovery that mutations in the PPP3CA gene can lead to this severe form of disease with childhood-onset epilepsy paves the way for the creation of new treatments for epilepsy, and hopefully, a cure.”

This research, recently published in The American Journal of Human Genetics, was led by Dr. Heinzen from the Institute of Genomic Medicine at Columbia University, and involved the efforts of several other Epilepsy Genetics Initiative researchers including Dr. David B. Goldstein, also from the Institute of Genomic Medicine at Columbia University.

At its core, the CURE Epilepsy Genetics Initiative is a program created to use genetic information from people with epilepsy to uncover the causes of epilepsy and advance precision medicine.

Through the Epilepsy Genetics Initiative, individuals with epilepsy undergo Trio Whole Exome Sequencing – a test that analyzes approximately 20,000 genes simultaneously to identify changes in the person’s DNA that are related to their epilepsy.

The results of this powerful study highlight the importance of the continued work of projects like CURE’s Epilepsy Genetics Initiative in advancing towards a better understanding of the genetic causes of epilepsy. “Begun in 2014, CURE’s Epilepsy Genetics Initiative is already helping people understand the cause of their epilepsy” says CURE CEO Kate Carr. “We are excited about this advance in our search for the genetic causes of epilepsy and will continue in our quest for new treatments and our pursuit of a cure.”
[1] Lai MM, Hong JJ, Rugiero Am et al. The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis. J Biol Chem 1999; 274:25963-25966.