@article{61d81704ab5d4ff4b347e5b46ef2e073,
title = "Friedreich's ataxia induced pluripotent stem cells model intergenerational GAATTC triplet repeat instability",
abstract = "The inherited neurodegenerative disease Friedreich's ataxia (FRDA) is caused by GAATTC triplet repeat hyperexpansions within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAATTC 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. GAATTC 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.",
author = "Sherman Ku and Elisabetta Soragni and Erica Campau and Thomas, {Elizabeth A.} and Gulsah Altun and Laurent, {Louise C.} and Loring, {Jeanne F.} and Marek Napierala and Gottesfeld, {Joel M.}",
note = "Funding Information: We thank S. Perlman (UCLA) for providing skin biopsies and I. Singec, J. Clark, and C. Desponts for valuable advice and guidance. Additionally, we thank V. Lukiyanchuk for virus expertise, K. Clingerman for veterinary assistance, and C. Lynch for microarray analysis. This work was supported by the National Institutes of Neurological Disorders and Stroke (NIH), The Friedreich's Ataxia Research Alliance (FARA), GoFAR, Ataxia UK, Friedreich's Ataxia Society Ireland, and Repligen Corporation (Waltham, MA) to J.M.G. and by a fellowship from Families of Spinal Muscular Atrophy (to S.K.). L.C.L. is supported by NIH WRHR K12 Career Development Award and the Hartwell Foundation, and G.A. and J.F.L. are supported by CIRM (CL1-00502, RT1-01108, TR1-01250), NIH (R21MH087925), the Millipore Foundation, and the Esther O'Keefe Foundation. M.N. is supported by the National Ataxia Foundation and the FARA “Kyle Bryant Translational Research Award.” J.M.G. serves as a consultant to Repligen Corporation, which is involved in the development of therapeutics for FRDA, and has a competing financial interest in this work. ",
year = "2010",
month = nov,
day = "5",
doi = "10.1016/j.stem.2010.09.014",
language = "English (US)",
volume = "7",
pages = "631--637",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "5",
}