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

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.

LanguageEnglish
Pages2341-2350
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
Van Rootselaar, Anne Fleur ; Groffen, Alexander J. ; Vries, Boukje De ; Callenbach, Petra M.C. ; Santen, Gijs W.E. ; Koelewijn, Stephany ; Vijfhuizen, Lisanne S. ; Buijink, Arthur ; Tijssen, Marina A.J. ; Van Den Maagdenberg, Arn M.J.M. / δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy. In: Neurology. 2017 ; Vol. 89, No. 23. pp. 2341-2350.
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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.",
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Van Rootselaar, AF, Groffen, AJ, Vries, BD, Callenbach, PMC, Santen, GWE, Koelewijn, S, Vijfhuizen, LS, Buijink, A, Tijssen, MAJ & Van Den Maagdenberg, AMJM 2017, 'δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy', Neurology, vol. 89, no. 23, pp. 2341-2350. https://doi.org/10.1212/WNL.0000000000004709

δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy. / Van Rootselaar, Anne Fleur; Groffen, Alexander J.; Vries, Boukje De; Callenbach, Petra M.C.; Santen, Gijs W.E.; Koelewijn, Stephany; Vijfhuizen, Lisanne S.; Buijink, Arthur; Tijssen, Marina A.J.; Van Den Maagdenberg, Arn M.J.M.

In: Neurology, Vol. 89, No. 23, 01.12.2017, p. 2341-2350.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy

AU - Van Rootselaar, Anne Fleur

AU - Groffen, Alexander J.

AU - Vries, Boukje De

AU - Callenbach, Petra M.C.

AU - Santen, Gijs W.E.

AU - Koelewijn, Stephany

AU - Vijfhuizen, Lisanne S.

AU - Buijink, Arthur

AU - Tijssen, Marina A.J.

AU - Van Den Maagdenberg, Arn M.J.M.

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N2 - 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.

AB - 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.

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Van Rootselaar AF, Groffen AJ, Vries BD, Callenbach PMC, Santen GWE, Koelewijn S et al. δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy. Neurology. 2017 Dec 1;89(23):2341-2350. https://doi.org/10.1212/WNL.0000000000004709