Friedreich's ataxia induced pluripotent stem cells model intergenerational GAAâ
TTC triplet repeat instability.
Cell Stem Cell
; 7(5): 631-7, 2010 Nov 05.
Article
em En
| MEDLINE
| ID: mdl-21040903
ABSTRACT
The inherited neurodegenerative disease Friedreich's ataxia (FRDA) is caused by GAAâ
TTC triplet repeat hyperexpansions within the first intron of the FXN gene, encoding the mitochondrial protein frataxin. Long GAAâ
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. GAAâ
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ataxia de Friedreich
/
Expansão das Repetições de Trinucleotídeos
/
Células-Tronco Pluripotentes Induzidas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cell Stem Cell
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos