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Huntington's disease (HD) and myotonic dystrophy (DM1) are caused by trinucleotide repeat expansions. The repeats show different instability patterns according to the disorder, cell type and developmental stage. Here we studied the behavior of these repeats in DM1- and HD-derived human embryonic stem cells (hESCs) before and after differentiation, and its relationship to the DNA mismatch repair (MMR). The relatively small (CAG)44 HD expansion was stable in undifferentiated and differentiated HD hESCs. In contrast, the DM1 repeat showed instability from the earliest passages onwards in DM1 hESCs with (CTG)250 or (CTG)1800. Upon differentiation the DM1 repeat was stabilized. MMR genes, including hMSH2, hMSH3 and hMSH6 were assessed at the transcript and protein levels in differentiated cells. The coincidence of differentiation-induced down-regulated MMR expression with reduced instability of the long expanded repeats in hESCs is consistent with a known requirement of MMR proteins for repeat instability in transgenic mice. This is the first demonstration of a correlation between altered repeat instability of an endogenous DM1 locus and natural MMR down-regulation, in contrast to the commonly used murine knock-down systems.
|Number of pages||10|
|Journal||Human Molecular Genetics|
|Publication status||Published - 1 Jan 2011|
- human embryonic stem cell
- myotonic dystrophy
- huntington's disease
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- 2 Finished
GIFT95: Human embryonic stem cells and induced pluripotent cells as models for research of human genetic diseases
1/09/09 → 31/08/16
FWOAL362: Derivation and characterisation of human embryonic stem cells (hESC) with myotonic dystrophy, DUchennes muscular dystrophy or facioscapulohumeral dystrophy and differentiation of normal and affected hESC to myocytes.
1/01/06 → 31/12/09