In a study published online in Annals of Neurology, researchers from the University of South Australia in Adelaide have identified mutations in GATOR1 complex as the most significant cause of familial focal epilepsy identified to date.
The research team led by Associate Professor Leanne Dibbens studied 404 unrelated probands with focal epilepsy and performed exome sequencing on 2 families in which multiple members had focal epilepsy.
The group had previously published on the association between DEPDC5 gene mutations and familial focal epilepsy (Dibbens et al., 2013). The hypothesis for their current study was that if DEPDC5 mutations result in hyperactivity of mTOR signalling, then mutations in other genes that bind with it to form the GATOR 1 protein complex, NPRL2 and NPRL3, may also be implicated.
In the current study they decided to look at the DEPDC5's GATOR1 protein complex partners, a master regulator of cell growth and metabolism and the mechanistic target of rapamycin (mTOR) regulators NPRL2 and NPRL3, and have uncovered associations between mutations in these genes and focal epilepsy
They have identified 5 mutations each in NPRL2 (4 familial and 1 sporadic) and NPRL3 (all familial) and 18 new mutations in DEPDC5 (17 familial and 1 sporadic). The 2 sporadic cases were a case of frontal lobe epilepsy with a tumour-like brain lesion and the other a case of focal epilepsy with a bilateral brain malformation. According to the researchers the dysregulation of mTOR-mediated control of cell growth could have resulted in irregular growth which disrupted neural circuitry, leading to epilepsy.
There were 272 familial and 132 sporadic cases among their cohort. 239 (59%) had temporal lobe epilepsy and 91 (23%) had nocturnal frontal lobe epilepsy. The remaining cases had frontal (7%), occipital (4%), parietal lobe epilepsy (1%), benign epilepsy with centrotemporal spikes (4%), focal epilepsy associated with structural brain lesions (1%) and focal epilepsy and developmental delay (<1%).
All study participants were negative for KCNT1 mutations and mutations of CHRNA2, CHRNB2, and or CHRNA4 were not identified in any of the participants with nocturnal frontal lobe epilepsy.
These studies seem to implicate mutations in the GATOR1 complex are the most significant genetic cause of focal epilepsy via dysregulation of cell growth. In addition these findings suggest therapeutic prospects for mTOR inhibitors in focal epilepsies.
Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, Crompton DE, Hughes JN, Bellows ST, Klein KM, Callenbach PM, Corbett MA, Gardner AE, Kivity S, Iona X, Regan BM, Weller CM, Crimmins D, O'Brien TJ, Guerrero-López R, Mulley JC, Dubeau F, Licchetta L, Bisulli F, Cossette P, Thomas PQ, Gecz J, Serratosa J, Brouwer OF, Andermann F, Andermann E, van den Maagdenberg AM, Pandolfo M, Berkovic SF, Scheffer IE. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013 May;45(5):546-51. doi: 10.1038/ng.2599. Epub 2013 Mar 31. PubMed PMID: 23542697.
Ricos MG, Hodgson BL, Pippucci T, et al. Mutations in the mTOR pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2015; doi:10.1002/ana.24547.