MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells

Ugljesa Djuric, Aaron Y.L. Cheung, Wenbo Zhang, Rebecca S. Mok, Wesley Lai, Alina Piekna, Jason A. Hendry, P. Joel Ross, Peter Pasceri, Dae-Sung Kim, Michael W. Salter, James Ellis

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)37-45
Number of pages9
JournalNeurobiology of Disease
Volume76
DOIs
Publication statusPublished - 2015 Apr 1
Externally publishedYes

Fingerprint

Rett Syndrome
Protein Isoforms
Neurons
Mutation
Carisoprodol
Single-Cell Analysis
Induced Pluripotent Stem Cells
X Chromosome
Action Potentials
Alleles
Phenotype
Messenger RNA
Genes
Proteins

Keywords

  • IPS cell disease models
  • MeCP2
  • Rett syndrome

ASJC Scopus subject areas

  • Neurology

Cite this

MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells. / Djuric, Ugljesa; Cheung, Aaron Y.L.; Zhang, Wenbo; Mok, Rebecca S.; Lai, Wesley; Piekna, Alina; Hendry, Jason A.; Ross, P. Joel; Pasceri, Peter; Kim, Dae-Sung; Salter, Michael W.; Ellis, James.

In: Neurobiology of Disease, Vol. 76, 01.04.2015, p. 37-45.

Research output: Contribution to journalArticle

Djuric, U, Cheung, AYL, Zhang, W, Mok, RS, Lai, W, Piekna, A, Hendry, JA, Ross, PJ, Pasceri, P, Kim, D-S, Salter, MW & Ellis, J 2015, 'MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells', Neurobiology of Disease, vol. 76, pp. 37-45. https://doi.org/10.1016/j.nbd.2015.01.001
Djuric, Ugljesa ; Cheung, Aaron Y.L. ; Zhang, Wenbo ; Mok, Rebecca S. ; Lai, Wesley ; Piekna, Alina ; Hendry, Jason A. ; Ross, P. Joel ; Pasceri, Peter ; Kim, Dae-Sung ; Salter, Michael W. ; Ellis, James. / MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells. In: Neurobiology of Disease. 2015 ; Vol. 76. pp. 37-45.
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