title: MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells.
abstract: MECP2 mutations cause the X-linked neurodevelopmental disorder Rett Syndrome (RTT) by consistently altering the protein encoded by the MECP2e1 alternative transcript. While mutations that simultaneously affect both MECP2e1 and MECP2e2 isoforms have been widely studied, the consequence of MECP2e1 deficiency on human neurons remains unknown. Here we report the first isoform-specific patient induced pluripotent stem cell (iPSC) model of RTT. RTTe1 patient iPS cell-derived neurons retain an inactive X-chromosome and express only the mutant allele. Single-cell mRNA analysis demonstrated they have a molecular signature of cortical neurons. Mutant neurons exhibited a decrease in soma size, reduced dendritic complexity and decreased cell capacitance, consistent with impaired neuronal maturation. The soma size phenotype was rescued cell-autonomously by MECP2e1 transduction in a level-dependent manner but not by MECP2e2 gene transfer. Importantly, MECP2e1 mutant neurons showed a dysfunction in action potential generation, voltage-gated Na(+) currents, and miniature excitatory synaptic current frequency and amplitude. We conclude that MECP2e1 mutation affects soma size, information encoding properties and synaptic connectivity in human neurons that are defective in RTT.
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Ugljesa
authors: U
authors: Djuric
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Aaron Y L
authors: AYL
authors: Cheung
authors: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; University of Toronto Centre for the Study of Pain, University of Toronto, Toronto, ON M5T 1P8, Canada.
authors: Wenbo
authors: W
authors: Zhang
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Rebecca S
authors: RS
authors: Mok
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Wesley
authors: W
authors: Lai
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors: Alina
authors: A
authors: Piekna
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors: Jason A
authors: JA
authors: Hendry
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors: P Joel
authors: PJ
authors: Ross
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors: Peter
authors: P
authors: Pasceri
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors: Dae-Sung
authors: DS
authors: Kim
authors: Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; University of Toronto Centre for the Study of Pain, University of Toronto, Toronto, ON M5T 1P8, Canada.
authors: Michael W
authors: MW
authors: Salter
authors: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jellis@sickkids.ca.
authors: James
authors: J
authors: Ellis
mesh_terms: D000200:Action Potentials; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology* / Q000502:physiology*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D020033:Protein Isoforms; D015518:Rett Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D020033:Protein Isoforms
keywords: MeCP2; Rett syndrome; iPS cell disease models
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