δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy

Anne Fleur Van Rootselaar, Alexander J. Groffen, Boukje De Vries, Petra M.C. Callenbach, Gijs W.E. Santen, Stephany Koelewijn, Lisanne S. Vijfhuizen, Arthur Buijink, Marina A.J. Tijssen, Arn M.J.M. Van Den Maagdenberg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective: To identify the causative gene in a large Dutch family with familial cortical myoclonic tremor and epilepsy (FCMTE). Methods: 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 d-catenin (CTNND2) proteins in cortical mouse neurons and compared the results with morphologic abnormalities in the postmortem FCMTE brain. Results: We identified a missense mutation, p.Glu1044Lys, in the CTNND2 gene that cosegregated with the FCMTE phenotype. The knock-down of Ctnnd2 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. Conclusions: We propose CTNND2 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.

Original languageEnglish
Pages (from-to)2341-2350
Number of pages10
JournalNeurology
Volume89
Issue number23
DOIs
Publication statusPublished - 1 Dec 2017

Cite this

Van Rootselaar, A. F., Groffen, A. J., Vries, B. D., Callenbach, P. M. C., Santen, G. W. E., Koelewijn, S., ... Van Den Maagdenberg, A. M. J. M. (2017). δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy. Neurology, 89(23), 2341-2350. https://doi.org/10.1212/WNL.0000000000004709