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

Grütz, Karen, Seibler, Philip, Weissbach, Anne, Lohmann, Katja, Carlisle, Francesca ORCID: https://orcid.org/0000-0002-9734-113X, Blake, Derek J ORCID: https://orcid.org/0000-0002-5005-4731, Westenberger, Ana, Klein, Christine and Grünewald, Anne 2017. Faithful SGCE imprinting in iPSC-derived cortical neurons: an endogenous cellular model of myoclonus-dystonia. Scientific Reports 7 , 41156. 10.1038/srep41156

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
ISSN:	2045-2322
Date of First Compliant Deposit:	22 February 2017
Date of Acceptance:	14 December 2016
Last Modified:	04 May 2023 13:40
URI:	https://orca.cardiff.ac.uk/id/eprint/98464

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