ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks

Maria W A Teunissen, Elly Lewerissa, Eline J H van Hugte, Shan Wang, Charlotte W Ockeloen, David A Koolen, Rolph Pfundt, Carlo L M Marcelis, Eva Brilstra, Jennifer L Howe, Stephen W Scherer, Xavier Le Guillou, Frédéric Bilan, Michelle Primiano, Jasmin Roohi, Amelie Piton, Anne de Saint Martin, Sarah Baer, Simone Seiffert, Konrad PlatzerRami Abou Jamra, Steffen Syrbe, Jan Henje Doering, Shenela Lakhani, Srishti Nangia, Christian Gilissen, R Jeroen Vermeulen, Rob P W Rouhl, Han G Brunner, Marjolein H Willemsen, Nael Nadif Kasri*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

PURPOSE: To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and homeostatic plasticity in human-induced pluripotent stem cell-derived neurons. METHODS: We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human-induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated into excitatory neurons, and we measured their spontaneous electrophysiological responses using micro-electrode arrays (MEAs). We also characterized their somatodendritic morphology and axon initial segment (AIS) structure and plasticity. RESULTS: We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation. CONCLUSIONS: Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.

Original languageEnglish
Pages (from-to)2373-2385
Number of pages13
JournalHuman molecular genetics
Volume32
Issue number14
Early online date17 May 2023
DOIs
Publication statusPublished - 4 Jul 2023

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