Faithful SGCE imprinting in iPSC-derived cortical neurons: an endogenous cellular model of myoclonus-dystonia

Sci Rep. 2017 Feb 3;7:41156. doi: 10.1038/srep41156.

Abstract

In neuropathology research, induced pluripotent stem cell (iPSC)-derived neurons are considered a tool closely resembling the patient brain. Albeit in respect to epigenetics, this concept has been challenged. We generated iPSC-derived cortical neurons from myoclonus-dystonia patients with mutations (W100G and R102X) in the maternally imprinted ε-sarcoglycan (SGCE) gene and analysed properties such as imprinting, mRNA and protein expression. Comparison of the promoter during reprogramming and differentiation showed tissue-independent differential methylation. DNA sequencing with methylation-specific primers and cDNA analysis in patient neurons indicated selective expression of the mutated paternal SGCE allele. While fibroblasts only expressed the ubiquitous mRNA isoform, brain-specific SGCE mRNA and ε-sarcoglycan protein were detected in iPSC-derived control neurons. However, neuronal protein levels were reduced in both mutants. Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA Methylation
  • Dystonic Disorders / genetics*
  • Dystonic Disorders / metabolism
  • Female
  • Genomic Imprinting*
  • HEK293 Cells
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Models, Biological
  • Mutation
  • Neurons / cytology*
  • Neurons / metabolism
  • Promoter Regions, Genetic
  • Sarcoglycans / genetics*
  • Sarcoglycans / metabolism
  • Sequence Analysis, DNA

Substances

  • SGCE protein, human
  • Sarcoglycans

Supplementary concepts

  • Myoclonic dystonia