Anne-Fleur van Rootselaar1, Alexander J Groffen1, Boukje de Vries1, Petra M C Callenbach1, Gijs W E Santen1, Stephany Koelewijn1, Lisanne S Vijfhuizen1, Arthur Buijink1, Marina A J Tijssen2, Arn M J M van den Maagdenberg2. 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.
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.
Authors: Tom van den Ende; Sarvi Sharifi; Sandra M A van der Salm; Anne-Fleur van Rootselaar Journal: Tremor Other Hyperkinet Mov (N Y) Date: 2018-01-23
Authors: Rahel T Florian; Florian Kraft; Elsa Leitão; Sabine Kaya; Stephan Klebe; Eloi Magnin; Anne-Fleur van Rootselaar; Julien Buratti; Theresa Kühnel; Christopher Schröder; Sebastian Giesselmann; Nikolai Tschernoster; Janine Altmueller; Anaide Lamiral; Boris Keren; Caroline Nava; Delphine Bouteiller; Sylvie Forlani; Ludmila Jornea; Regina Kubica; Tao Ye; Damien Plassard; Bernard Jost; Vincent Meyer; Jean-François Deleuze; Yannick Delpu; Mario D M Avarello; Lisanne S Vijfhuizen; Gabrielle Rudolf; Edouard Hirsch; Thessa Kroes; Philipp S Reif; Felix Rosenow; Christos Ganos; Marie Vidailhet; Lionel Thivard; Alexandre Mathieu; Thomas Bourgeron; Ingo Kurth; Haloom Rafehi; Laura Steenpass; Bernhard Horsthemke; Eric LeGuern; Karl Martin Klein; Pierre Labauge; Mark F Bennett; Melanie Bahlo; Jozef Gecz; Mark A Corbett; Marina A J Tijssen; Arn M J M van den Maagdenberg; Christel Depienne Journal: Nat Commun Date: 2019-10-29 Impact factor: 14.919
Authors: Yongxing Zhou; Raman Sood; Qun Wang; Blake Carrington; Morgan Park; Alice C Young; Daniel Birnbaum; Zhao Liu; Tetsuo Ashizawa; James C Mullikin; Mohamad Z Koubeissi; Paul Liu Journal: Epilepsia Open Date: 2021-02-02