News and Events : 2015 : March

Geneticists discover new gene associated with epileptic encephalopathy

Miller School researchers were part of an international team that identified a new gene linked to epileptic encephalopathy. Published March 9, 2015, in Nature Genetics, the researchers identified four different de novo mutations in the potassium channel gene KCNA2 that caused mild to severe epileptic encephalopathy by two different mechanisms, predicting either hyperexcitability or electrical silencing of the Kv1.2 potassium channel.

Epileptic encephalopathies are a rare phenotypically and genetically heterogeneous group of epilepsy syndromes often accompanied by severe cognitive, behavioral, and neurological deficits. Mutations in potassium channel-encoding genes have been found to cause various neurological diseases, including benign familial neonatal seizures, neonatal epileptic encephalopathy, episodic ataxia, and peripheral nerve disease. Utilizing massive next-generation sequencing in epilepsy cohorts collected within the European EuroEPINOMICS research consortium and several other universities throughout the world, the research team identified four different de novo mutations in KCNA2, encoding the potassium channel Kv1.2. While two of the mutations led to a loss-of-function of Kv1.2, the other two gave rise to a drastic gain-of-function effect, leading to permanently open channels. These differences are critically important for future drug development.

“Many epileptic drugs currently target ion channels,” said Rebecca Schüle, M.D., neurologist and scientist at the Hertie Institute for Clinical Brain Research at the University of Tübingen, Germany, a Marie Curie fellow conducting research at the Miller School, and study coauthor. “By linking a gene that encodes a potassium channel with epileptic encephalopathy, our findings could lead to new targets for drug development.”

“The success of this study is prove of our innovative approaches to global sharing of genetic data in real-time. We were able to connect multiple competitive groups and contribute to the broader phenotypic spectrum of KCNA2,” said Stephan Züchner, M.D., Ph.D., professor of human genetics and neurology, interim chair of the Dr. John T. Macdonald Foundation Department of Human Genetics, and coauthor of the study.

Michael Gonzalez, Ph.D., a 2014 alumnus of the Human Genetics and Genomics Ph.D. program at the Miller School, was also a coauthor on the study.

The study was led by Sarah Weckhuysen, M.D., at the University of Antwerp (Antwerp, Belgium); Holger Lerche, M.D., at the University of Tübingen (Tübingen, Germany); and Johannes R. Lemke, M.D., at the University of Leipzig (Leipzig, Germany).