Expanded CTG repeats were shown to alter chromatin structure and have regional effects on gene expression (Otten and Tapscott 1995; Wang et al. 1994). The CTG expansion in the DMPK 3'UTR are located immediately upstream of the SIX5 promoter region and were shown to lower SIX5 expression (Gennarelli et al. 1999; Inukai et al. 2000; Klesert et al. 1997; Thornton et al. 1997). Six5 is a transcription factor required for eye development in Drosophila, and the mouse homologue is implicated in distal limb muscle development (Harris et al. 2000). Six5 knockout mice develop ocular cataracts and infertility resembling some features of DM1 (Klesert et al. 2000; Sarkar et al. 2000). Cardiac conduction abnormalities were also noted in Six5 knockout mice (Wakimoto et al. 2002). However, the most common symptoms of DM1 such as muscle weakness, wasting, and myotonia were not reproduced in Six5 knockout mice (Klesert et al. 2000; Sarkar et al. 2000). The identification of a second locus causing DM2 reduced the likelihood that loss of function of DMPK or flanking genes was the determinative mechanism for at least the symptoms common for DM1 and DM2.
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