Modeling diseases of noncoding unstable repeat expansionsusing mutant pluripotent stem cells

• 作者: Shira Yanovsky-Dagan Hagar Mor-Shaked Rachel Eiges
• 来源期刊: 世界干细胞杂志：英文版（电子版）
• 学科: 医学
• 关键词: UNSTABLE REPEAT ASSOCIATED disorders Human embryonic STEM CELLS Patient-derived inducedpluripotent STEM CELLS Disease MODELING Epigenetics repeat-associated non-ATG translation RNA toxicity REPEAT somatic instability
• 年，卷（期）: 2015,（5）
• 页码范围: 823-838
• 页数: 16页
• 分类号: R

摘要

Pathogenic mutations involving DNA repeat expansionsare responsible for over 20 different neuronal andneuromuscular diseases. All result from expanded tractsof repetitive DNA sequences （mostly microsatellites）that become unstable beyond a critical length when transmitted across generations. Nearly all are inheritedas autosomal dominant conditions and are typicallyassociated with anticipation. Pathologic unstablerepeat expansions can be classified according to theirlength, repeat sequence, gene location and underlyingpathologic mechanisms. This review summarizesthe current contribution of mutant pluripotent stemcells （diseased human embryonic stem cells andpatient-derived induced pluripotent stem cells） to theresearch of unstable repeat pathologies by focusingon particularly large unstable noncoding expansions.Among this class of disorders are Fragile X syndromeand Fragile X-associated tremor/ataxia syndrome,myotonic dystrophy type 1 and myotonic dystrophytype 2, Friedreich ataxia and C9 related amyotrophiclateral sclerosis and/or frontotemporal dementia,Facioscapulohumeral Muscular Dystrophy and potentiallymore. Common features that are typical to this subclassof conditions are RNA toxic gain-of-function, epigeneticloss-of-function, toxic repeat-associated non-ATGtranslation and somatic instability. For each mechanismwe summarize the currently available stem cell basedmodels, highlight how they contributed to betterunderstanding of the related mechanism, and discusshow they may be utilized in future investigations.