Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA⋅TTC triplet repeat instability.
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.
Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Sherman
S
Ku
Elisabetta
E
Soragni
Erica
E
Campau
Elizabeth A
EA
Thomas
Gulsah
G
Altun
Louise C
LC
Laurent
Jeanne F
JF
Loring
Marek
M
Napierala
Joel M
JM
Gottesfeld
D002478:Cells, Cultured; D042622:DNA Repeat Expansion; D005621:Friedreich Ataxia / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D033862:Iron-Binding Proteins / Q000235:genetics; D053842:Microsatellite Instability; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D000096923:Frataxin
D033862:Iron-Binding Proteins; D000096923:Frataxin