Three to eight percent of female carriers of Duchenne muscular dystrophy (DMD) develop dystrophic symptoms ranging from\nmild muscle weakness to a rapidly progressive DMD-like muscular dystrophy due to skewed inactivation of X chromosomes\nduring early development. Here, we generated human induced pluripotent stem cells (hiPSCs) from a manifesting female carrier\nusing retroviral or Sendai viral (SeV) vectors and determined their X-inactivation status. Although manifesting carrier-derived\niPS cells showed normal expression of human embryonic stem cell markers and formed well-differentiated teratomas in vivo,\nmany hiPS clones showed bi-allelic expression of the androgen receptor (AR) gene and loss of X-inactivation-specific transcript\nand trimethyl-histone H3 (Lys27) signals on X chromosomes, suggesting that both X chromosomes of the hiPS cells are in an\nactive state. Importantly, normal dystrophin was expressed in multinucleated myotubes differentiated from a manifesting carrier\nof DMD-hiPS cells with XaXa pattern. AR transcripts were also equally transcribed from both alleles in induced myotubes. Our\nresults indicated that the inactivated X chromosome in the patient�s fibroblasts was activated during reprogramming, and XCI\noccurred randomly during differentiation.
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