δ-Catenin (<i>CTNND2</i>) missense mutation in familial cortical myoclonic tremor and epilepsy.

Abstract

To identify the causative gene in a large Dutch family with familial cortical myoclonic tremor and epilepsy (FCMTE). We performed exome sequencing for 3 patients of our FCMTE family. Next, we performed knock-down (shRNA) and rescue experiments by overexpressing wild-type and mutant human δ-catenin (CTNND2) proteins in cortical mouse neurons and compared the results with morphologic abnormalities in the postmortem FCMTE brain. We identified a missense mutation, p.Glu1044Lys, in the <i>CTNND2</i> gene that cosegregated with the FCMTE phenotype. The knock-down of <i>Ctnnd2</i> in cultured cortical mouse neurons revealed increased neurite outgrowth that was rescued by overexpression of wild-type, but not mutant, CTNND2 and was reminiscent of the morphologic abnormalities observed in cerebellar Purkinje cells from patients with FCMTE. We propose <i>CTNND2</i> as the causal gene in FCMTE3. Functional testing of the mutant protein revealed abnormal neuronal sprouting, consistent with the abnormal cerebellar Purkinje cell morphology in patients with FCMTE.