Friedreich's Ataxia Induced Pluripotent Stem Cells Model Intergenerational GAA.TTC Triplet Repeat Instability

被引：175

作者：

Ku, Sherman ^{[1
]}

Soragni, Elisabetta ^{[1
]}

Campau, Erica ^{[1
]}

Thomas, Elizabeth A. ^{[1
]}

Altun, Gulsah ^{[2
]}

Laurent, Louise C. ^{[2
,3
]}

Loring, Jeanne F. ^{[2
]}

Napierala, Marek ^{[4
]}

Gottesfeld, Joel M. ^{[1
]}

机构：

[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Dept Physiol Chem, Ctr Regenerat Med, La Jolla, CA 92037 USA

[3] Univ Calif San Diego, Dept Reprod Med, San Diego, CA 92035 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA

来源：

CELL STEM CELL | 2010年 / 7卷 / 05期

关键词：

MISMATCH REPAIR; DEFINED FACTORS; DEFICIENT MICE; SOMATIC-CELLS; EXPANSION; GENE; DISEASE; TRANSCRIPTION; REPLICATION; FIBROBLASTS;

D O I：

10.1016/j.stem.2010.09.014

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

The inherited neurodegenerative disease Friedreich's ataxia (FRDA) is caused by GAA.TTC triplet repeat hyperexpansions within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAA.TTC repeats cause heterochromatin-mediated gene silencing and loss of frataxin in affected individuals. We report the derivation of induced pluripotent stem cells (iPSCs) from FRDA patient fibroblasts by transcription factor reprogramming. FXN gene repression is maintained in the iPSCs, as are the global gene expression signatures reflecting the human disease. GAA.TTC repeats uniquely in FXN in the iPSCs exhibit repeat instability similar to patient families, where they expand and/or contract with discrete changes in length between generations. The mismatch repair enzyme MSH2, implicated in repeat instability in other triplet repeat diseases, is highly expressed in pluripotent cells and occupies FXN intron 1, and shRNA silencing of MSH2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.

引用

页码：631 / 637

页数：7

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