, 2011). However, more detailed analysis of phenotypic differences was not described. Thus, iPS cell disease modeling of X chromosome-linked disorders in female lines could offer a unique advantage for modeling efforts. Friedrich’s Ataxia (FRDA, MIM 229300), an autosomal-recessive

disorder, is the most common inherited ataxic disorder with an age of onset in the teenage years. Clinical characteristics include progressive ataxia of gait and limbs, dysarthria, muscle weakness, spasticity in the legs, scoliosis, bladder dysfunction, and loss of position and vibration sense. Cardiomyopathy and diabetes mellitus are systemic complications in some patients (Pandolfo, 2009). FRDA individuals have a GAA triple-repeat Smad2 signaling expansion in intron 1 of the Frataxin (FXN) gene of greater than 66 repeats whereas normal individuals selleck chemical may have between six and 34 ( Campuzano et al., 1996). Pathological expansion of the GAA triplet leads to transcriptional silencing of FXN, resulting

from heterochromatin formation, adoption of an abnormal DNA-RNA hybrid structure, or triplex DNA formation ( Wells, 2008). Length of GAA expansion correlates with Frataxin deficiency and disease severity and progression ( Dürr et al., 1996 and Filla et al., 1996). Frataxin is localized to the inner mitochondrial membrane where it is involved in biogenesis of iron-sulfur either clusters and thus in the respiratory chain complex. Frataxin deficiency leads to mitochondrial dysfunction and increased oxidative damage ( Pandolfo and Pastore, 2009). Iron accumulation is seen in affected tissues such as neurons and cardiomyocytes ( Ye and Rouault, 2010). FRDA-iPS cell lines have been established from patients (Ku et al., 2010 and Liu et al., 2010). While a specific disease-related phenotype was not reported, the phenomenon of repeat-length instability that characterizes

many of the repeat expansion disorders could be recapitulated in FRDA-iPS cells (Ku et al., 2010). Analysis of global gene expression of FRDA-iPS lines (two clones from two patients) demonstrated that disease lines cluster with wild-type iPS and ES cell lines but with small differences (5%–7% global expression difference between FRDA-iPS lines and WT-iPS/ES lines). Interestingly, analysis of the most differentially expressed genes had known functions related to mitochondrial function, DNA repair, and DNA damage. With regard to GAA repeat instability, iPS cells showed repeat expansions whereas parental fibroblasts did not (Ku et al., 2010). Instability was specific to the abnormally expanded FXN as GAA expansions in WT FXN allele or at two unrelated loci with short GAA repeats remained unchanged. Repeat length changed over iPS cell passages in culture.