Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jun 26, 2015; 7(5): 823-838
Published online Jun 26, 2015. doi: 10.4252/wjsc.v7.i5.823
Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells
Shira Yanovsky-Dagan, Hagar Mor-Shaked, Rachel Eiges
Shira Yanovsky-Dagan, Hagar Mor-Shaked, Rachel Eiges, Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel
Author contributions: Yanovsky-Dagan S and Mor-Shaked H equally contributed to the preparation of the review; Eiges R designed the aim of the editorial and wrote the manuscript.
Conflict-of-interest: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Rachel Eiges, PhD, Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, 12 Shmu’el Bait Street, PO Box 3235, Jerusalem 91031, Israel. rachela@szmc.org.il
Telephone: +972-2-6555129 Fax: +972-2-6666135
Received: December 5, 2014
Peer-review started: December 6, 2014
First decision: February 7, 2015
Revised: March 5, 2015
Accepted: April 1, 2015
Article in press: April 7, 2015
Published online: June 26, 2015
Abstract

Pathogenic mutations involving DNA repeat expansions are responsible for over 20 different neuronal and neuromuscular diseases. All result from expanded tracts of repetitive DNA sequences (mostly microsatellites) that become unstable beyond a critical length when transmitted across generations. Nearly all are inherited as autosomal dominant conditions and are typically associated with anticipation. Pathologic unstable repeat expansions can be classified according to their length, repeat sequence, gene location and underlying pathologic mechanisms. This review summarizes the current contribution of mutant pluripotent stem cells (diseased human embryonic stem cells and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. Among this class of disorders are Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome, myotonic dystrophy type 1 and myotonic dystrophy type 2, Friedreich ataxia and C9 related amyotrophic lateral sclerosis and/or frontotemporal dementia, Facioscapulohumeral Muscular Dystrophy and potentially more. Common features that are typical to this subclass of conditions are RNA toxic gain-of-function, epigenetic loss-of-function, toxic repeat-associated non-ATG translation and somatic instability. For each mechanism we summarize the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.

Keywords: Unstable repeat associated disorders, Human embryonic stem cells, Patient-derived induced pluripotent stem cells, Disease modeling, Epigenetics, repeat-associated non-ATG translation, RNA toxicity, Repeat somatic instability

Core tip: This review summarizes the current contribution of mutant pluripotent stem cells (diseased HESCs and patient-derived induced pluripotent stem cells) to the research of unstable repeat pathologies by focusing on particularly large unstable noncoding expansions. It demonstrates their importance as an unlimited cell source for generating rarely available impaired cells in culture, and as a model system for exploring the mechanisms that are involved with this class of mutations. For each mechanism we describe the currently available stem cell based models, highlight how they contributed to better understanding of the related mechanism, and discuss how they may be utilized in future investigations.