Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA⋅TTC triplet repeat instability.
Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA⋅TTC triplet repeat instability.
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DOI：
10.1016/j.stem.2010.09.014
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发表时间：
2010-11-05
期刊：
影响因子：
23.9
通讯作者：
Gottesfeld, Joel M.
中科院分区：
文献类型：
--
作者：
Ku, Sherman;Soragni, Elisabetta;Campau, Erica;Thomas, Elizabeth A.;Altun, Gulsah;Laurent, Louise C.;Loring, Jeanne F.;Napierala, Marek;Gottesfeld, Joel M.
The inherited neurodegenerative disease Friedreich’s ataxia (FRDA) is caused by GAA•TTC triplet repeat hyper-expansions within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAA•TTC repeats causes 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, occupies FXN intron 1, and shRNA silencing of MSH2 impedes repeat expansion, providing a possible molecular explanation for repeat expansion in FRDA.
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