Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.

2015-04-09

Carvill, Gemma L

McMahon, Jacinta M

Schneider, Amy

Zemel, Matthew

Myers, Candace T

Saykally, Julia

Nguyen, John

Robbiano, Angela

Zara, Federico

Specchio, Nicola

Mecarelli, Oriano

Smith, Robert L

Leventer, Richard J

Møller, Rikke S

Nikanorova, Marina

Dimova, Petia

Jordanova, Albena

Petrou, Steven

Helbig, Ingo

Striano, Pasquale

Weckhuysen, Sarah

Berkovic, Samuel F

Scheffer, Ingrid E

Mefford, Heather C

EuroEPINOMICS Rare Epilepsy Syndrome Myoclonic-Astatic Epilepsy & Dravet working group

Journal Article

10.1016/j.ajhg.2015.02.016

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for ∼4% of unsolved MAE cases.

link

American Journal of Human Genetics 2015; 96(5): 808-15

American journal of human genetics