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Neurology. 2017 Dec 5;89(23):2341-2350. doi: 10.1212/WNL.0000000000004709. Epub 2017 Nov 10.

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

Author information

1
From the Departments of Neurology and Clinical Neurophysiology (A.-F.v.R., A.B., M.A.J.T.), Academic Medical Centre, Amsterdam Neuroscience, University of Amsterdam; Departments of Functional Genomics and Clinical Genetics (A.J.G.), CNCR, Neuroscience Campus Amsterdam, VU University and VU Medical Centre; Departments of Human Genetics (B.d.V., S.K., L.S.V., A.M.J.M.v.d.M.), Clinical Genetics (G.W.E.S.), and Neurology (A.M.J.M.v.d.M.), Leiden University Medical Centre; and Department of Neurology (P.M.C.C., M.A.J.T.), University Medical Centre Groningen, University of Groningen, the Netherlands.
2
From the Departments of Neurology and Clinical Neurophysiology (A.-F.v.R., A.B., M.A.J.T.), Academic Medical Centre, Amsterdam Neuroscience, University of Amsterdam; Departments of Functional Genomics and Clinical Genetics (A.J.G.), CNCR, Neuroscience Campus Amsterdam, VU University and VU Medical Centre; Departments of Human Genetics (B.d.V., S.K., L.S.V., A.M.J.M.v.d.M.), Clinical Genetics (G.W.E.S.), and Neurology (A.M.J.M.v.d.M.), Leiden University Medical Centre; and Department of Neurology (P.M.C.C., M.A.J.T.), University Medical Centre Groningen, University of Groningen, the Netherlands. m.a.j.de.koning-tijssen@umcg.nl maagdenberg@lumc.nl.

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 δ-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.

PMID:
29127138
DOI:
10.1212/WNL.0000000000004709
[Indexed for MEDLINE]

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