Myotonic dystrophy type 1 (DM1) is a multisystemic disease affecting skeletal muscle, heart, the central nervous system, gastrointestinal track and other organs. DM1 is caused by expansion of CTG repeats in the 3'-UTR of the dystrophia myotonica-protein kinase (DMPK) gene to 50-3000 repeats compared to 5-37 repeats in the general population. TREDT960I transgenic mice contain a human genomic segment containing exons 11-15 of the DMPK gene with 960 interrupted CTG repeats (CUG960) in exon 15 at the site of the CTG repeats present in the endogenous gene. These interrupted repeats are generated to contain 20 CTGs separated by five nucleotide spacers. The construct also contains 307 bp of the DMPK 3' flanking region containing the natural polyadenylation signals, and two copies of the cHS4 insulator flanking the 5' and 3' ends of the expression construct to prevent effects of the chromosomal insertion site. This mutant DMPK gene is under direction of the tetO (tet-responsive element) promoter. When mated to a mutant strain expressing tetracycline-controlled transactivator protein (tTA) or reverse tTA (rtTA), expression of CUG960 RNA may be regulated with the tetracycline or its analog doxycycline (dox) in the double mutant offspring. When bred to mice expressing tetracycline-controlled transactivator protein (rtTA) specifically in muscle fibers, and treated with doxycycline, mice display clear, measurable reversible muscle wasting accompanied by severe histological defects including central myonuclei, reduced fiber cross sectional area, increased percentage of oxidative myofibers, and the presence of nuclear RNA foci that colocalize with Mbnl1 protein. The donating investigator reports that the repeats are stable in mice after more than 20 generations. In October 2020, The Jackson Laboratory was notified by the donating investigator that more than 20 copies of the TREDT960I transgene integrated in chromosome 1 (9,622,984-9,660,005; mouse mm10) accompanied by a 37 kb genomic duplication. The integration site is located in the intronic region of 2610203C22Rik. It was also noted at that time that five nucleotide changes are in the TREDT960I transgene compared to the human DMPK sequence. Four of these changes (in intron 11 [CCCTTGGCAgCCCCTCTCGT], intron 14 [CACCCGCCCCgTGCCACCCG], and exon 15 [TTGCCAAACCtGCTTTTTCG and CCCAGCCGGCcCCGCCCGCT]) have no known effect on the Tg. One change, in exon 15 [CCTCGGTATcTATTGT], may affect the binding site for an antisense oligo. Similar to the human gene, it was discovered that two exons in the transgene undergo alternative splicing.

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TREDT960I transgenic mice contain a human genomic segment containing exons 11-15 of DMPK gene with 960 interrupted CTG repeats (CUG960) under direction of the tetO (tet-responsive element) promoter. These mice are useful when studying potential molecular mechanisms underlying skeletal muscle loss associated with Myotonic dystrophy type 1 (DM1).

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