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. Stock No. 037288 contains the TREDT960I transgene found in Stock No. <a href="https://www.jax.org/strain/032050">032050</a>. Specifically, the transgene harbors a human genomic segment containing exons 11-15 of 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. The donating investigator reports that the CTG repeats (CUG960) on the TREDT960I transgene are stable in mice after more than 20 generations. In October 2020, The Jackson Laboratory was notified by the donating investigator of Stock No. 032050 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. Stock No. 037288 also contains the MDAFrtTA transgene found in Stock No. <a href="https://www.jax.org/strain/032637">032637</a>. Specifically, this transgene is a Tet-On tool that allows conditional, doxycycline-inducible expression of the reverse tetracycline-controlled transactivator (rtTA) protein in skeletal muscle using the rat myosin light chain (Myl1) promoter. MYL1 is an ATPase cellular motor protein expressed in slow twitch muscles such as the soleus that is involved in the development of fast skeletal muscle. The expression of CUG960 RNA may be regulated with tetracycline or its analog doxycycline (dox) in TREDT960I (TRE) double transgenic mice. After dox induction, these 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 for the MDAFrtTA transgene reports that no homozygous mice are born from hemizygous breeding of MDAFrtTA mice, indicating that homozygous MDAFrtTA mice may not be viable. Homozygous and hemizygous TREDT960I mice are viable and fertile.

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TREDT960I (TRE) double transgenic mice express a human genomic segment containing exons 11-15 of the DMPK gene with 960 interrupted CTG repeats (CUG960) under direction of the tetO (tet-responsive element) promoter. They also express the reverse tetracycline-controlled transactivator (rtTA) protein in skeletal muscle using the rat myosin light chain (Myl1) promoter. Together these two transgenes are useful when studying potential molecular mechanisms underlying skeletal muscle loss associated with Myotonic dystrophy type 1 (DM1).

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