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

被引：15

作者：

Gruetz, Karen ^{[1
]}

Seibler, Philip ^{[1
]}

Weissbach, Anne ^{[1
]}

Lohmann, Katja ^{[1
]}

Carlisle, Francesca A. ^{[2
]}

Blake, Derek J. ^{[2
]}

Westenberger, Ana ^{[1
]}

Klein, Christine ^{[1
]}

Gruenewald, Anne ^{[1
,3
]}

机构：

[1] Univ Lubeck, Inst Neurogenet, D-23562 Lubeck, Germany

[2] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff CF24 4HQ, S Glam, Wales

[3] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Mol & Funct Neurobiol Grp, L-4367 Belvaux, Luxembourg

来源：

SCIENTIFIC REPORTS | 2017年 / 7卷

关键词：

PLURIPOTENT STEM-CELLS; EPSILON-SARCOGLYCAN; DIFFERENTIATION; TRAFFICKING; MEMBRANE; MUTATION;

D O I：

10.1038/srep41156

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 epsilon-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 e-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.

引用

页数：9

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