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. 2022 Apr 21;23(9):4622. doi: 10.3390/ijms23094622

Table 1.

DM1 mouse models used for studying pathogenetic mechanisms and/or molecular therapies.

(A) Knockout and Overexpressing Models
Mouse Model Generation Strategy DM1-Like Features Limitations Research Application Ref
DMPK-/- Dmpk KO via replacement of 5′-UTR and exons 1-7 with hygromycin cassette Late-onset mild myopathy and altered Ca++ homeostasis Mild phenotype; possible confounding insertional effects on flanking genes; mixed genetic background Relevance of absence of DMPK protein to DM1 phenotype [52,66]
DMPK-/- Dmpk KO via replacement of 5′-UTR and exons 1-7 with neomycin cassette Late-onset mild myopathy; decreased force generation; altered Na+ currents in skeletal muscles; cardiac conduction defects Mild phenotype; possible confounding insertional effects on flanking genes; mixed genetic background Relevance of absence of DMPK protein to DM1 phenotype [51,67]
DMPK-/- Dmpk KO via replacement of 5′-UTR and exons 1-7 with hygromycin cassette No phenotype Failure to replicate the DM1 phenotype Relevance of absence of DMPK protein to DM1 phenotype [53]
Mbnl1ΔE3/ΔE3 Mbnl1 KO via targeted deletion of Mbnl1 exon 3 Mild myotonia and myopathy (centralized nuclei, split fibers); heart conduction defects; progressive cataracts; AS alterations Mild muscle phenotype; mild brain alterations; limited spliceopathy Evaluation of MBNL1 splicing regulation to DM1 phenotype [56,57]
Mbnl2ΔE2/ΔE2 Mbnl2 KO via targeted deletion of Mbnl2 exon 2 Development of several CNS alterations (REM sleep propensity, deficit in spatial memory, decreased synaptic plasticity), AS alterations Failure to replicate the DM1 muscular phenotype Evaluation of MBNL2 splicing regulation to DM1 phenotype [55]
Mbnl3ΔE2 Mbnl3 KO via targeted deletion of Mbnl3 exon 2 (X-linked) Progressive delay in muscle regeneration; abnormalities in embryonic muscle differentiation leading to neonatal hypotonia Possible compensation by MBNL3 truncated isoform or other MBNl family members Evaluation of MBNL3 contribution to DM1 phenotype [58]
Mbnl1ΔE3/ΔE3;
Mbnl2C/C;
Myo-Cre+/- 		Mbnl1 KO; skeletal-muscle specific Cre-mediated Mbnl2 KO Small size at birth and skeletal abnormalities; myopathy and severe motor deficits; AS alterations also in brain tissues High neonatal mortality and reduced lifespan Evaluation of MBNL1 and MBNL2 contribution to DM1 muscular phenotype [60]
Mbnl1ΔE3/ΔE3;
Mbnl3ΔE2 		Mbnl1 and Mbnl3 KO via targeted deletion of Mbnl1 exon 3 and Mbnl3 exon 2 Myotonia and myopathy; reduction in muscle strength; chloride currents alteration; AS alterations; translation defects AS alterations similar to Mbnl1 single knock out; lack of brain alterations Evaluation of MBNL1 and MBNL3 contribution to DM1 phenotype [59]
Mbnl1ΔE3/ΔE3;
Mbnl2C/C;
Mbnl3C;
Myo-Cre+/- 		Mbnl1 KO; muscle-specific Cre-mediated Mbnl2 and Mbnl3 KO Severe congenital myopathy and spliceopathy, severe respiratory difficulties and muscle wasting in adults; gene expression changes High neonatal mortality and reduced lifespan Evaluation of all MBNL proteins loss contribution to DM1 muscular phenotype [61]
MCKCUGBP1 Insertion of human CELF1 transgene under striated-muscle-specific MCK mouse promoter Chains of central nuclei in myofibers, increased NADH reactivity, degenerating fibers and AS alterations Neonatal lethality in mice expressing high levels of CELF1 Contribution of CELF1 overexpression to DM1 muscular phenotype [62]
TRECUGBP1 Insertion of Tet-responsive human CELF1 transgene; heart-specific rtTA expression Left ventricular systolic dysfunction and dilatation, AS alterations DM1-like phenotype limited to heart defects Contribution of CELF1 overexpression to DM1 heart phenotype [63]
TRECUGBP1 Insertion of Tet-responsive human CELF1 transgene; skeletal-muscle-specific rtTA expression Myofibers containing central nuclei, decreased muscle weight, impaired muscle function, AS alterations DM1-like phenotype limited to skeletal-muscle defects Contribution of CELF1 overexpression to DM1 skeletal-muscle phenotype [65]
TRECUGBP2 Insertion of Tet-responsive human CELF2 transgene; heart-specific rtTA expression No observed heart pathology; AS alterations similar to those observed in TRECUBP1 mice Mild heart phenotype Contribution of CELF2 overexpression to DM1 heart phenotype [64]
(B) Transgenic Models with Repeat Expansion
Mouse Model Generation Strategy (CTG)n DM1-Like Features Limitations Research Application Ref
DM200 Insertion of a Tet-responsive expanded DMPK transgene where DMPK coding region is replaced by GFP 200 Ribonuclear foci; MBNL1 sequestration; AS alterations; myotonia, progressive cardiac conduction abnormalities Splicing alterations in the heart have not been described Study of DM1 phenotype associated with toxic CUG repeats; modeling muscle regeneration; test of therapeutic strategies [68,69,70]
DM300 Insertion of a 45Kb human genomic fragment containing DMWD, DMPK and SIX5 genes from a DM1 patient ~300 Ribonuclear foci (skeletal muscle, heart and brain); myotonia; muscle atrophy; morphological abnormalities; changes in the distribution of MAPT/Tau protein isoform; defect in glucose metabolism High mortality; mild splicing alterations; intergenerational instability of CTG-repeat numbers Evaluation of DMPK transcript toxicity in different tissues [71,72]
DMSXL Insertion of a 45Kb human genomic fragment containing DMWD, DMPK and SIX5 genes from a DM1 patient >1000 Ribonuclear foci; MBNL1 sequestration; AS alterations; deficits in motor performance; behavioral abnormalities; synaptic dysfunction; inhibition of exploratory activity and cerebellar glial dysfunction High mortality; severe body-weight reduction; interindividual variability; decreased transgene expression with aging; mild muscular phenotype Evaluation of DMPK transcript toxicity in different tissues and in multiple brain cell types; test of therapeutic strategies [23,73,74]
HSALR Insertion of the human skeletal actin (HSA) gene including CTG repeats in the 3’ UTR ~250 Ribonuclear foci; AS alterations;
myotonia and muscle histopathology abnormalities (increase in central nuclei and variability in fiber size) after six months of age		 Limited to skeletal muscle; does not contain DMPK gene sequence; absence of muscle weakness Investigation of expanded-CUG-repeat toxicity
in muscle fibers; test of therapeutic strategies		 [75,76]
LC15 Insertion of CTG expanded DMPK 3’ UTR downstream Luciferase gene driven by CMV-βA promoter 250–400 Ribonuclear foci, AS alteration and MBNL2 upregulation in the heart; reduced Na+ and K+ channel activity; ventricular arrhythmias DM1-like phenotype limited to heart defects Evaluation of biophysical mechanisms reproducing DM1-like electrocardiograph abnormalities [77]
EpA960/
𝛼 -MHC-Cre 		Insertion of CTG expanded DMPK exon 15 transgene containing Cre-responsive loxP sequences; heart-specific myosin Cre expression 960
(CTCGA-interrupted)		 Ribonuclear foci; MBNL1 sequestration; CELF1 protein upregulation; AS alterations;
cardiomyopathy, arrhythmias; systolic and diastolic dysfunction		 Does not reproduce CTG-repeat continuity; mouse model no longer available Evaluation of DMPK transcript toxicity and CELF1 overexpression in heart tissue [78]
EpA960/
HSA-Cre 		Insertion of CTG expanded DMPK exon 15 transgene containing Cre-responsive loxP sequence; skeletal-muscle-specific Cre expression 960
(CTCGA-interrupted) 		Ribonuclear foci; MBNL1 sequestration; CELF1 protein upregulation; AS defects; myotonia and progressive muscle wasting, deficits in muscle performance and histopathological abnormalities Does not reproduce CTG-repeat continuity; mouse model no longer available Evaluation of DMPK transcript toxicity and CELF1 overexpression in skeletal tissue [79]
EpA960/
CamKII-Cre 		Insertion of CTG expanded DMPK exon 15 transgene containing Cre-responsive loxP sequence; brain-specific Cre expression 960
(CTCGA-interrupted) 		Ribonuclear foci; MBNL1 sequestration; AS alterations; learning disability; neurotransmission dysfunction; brain atrophy and aging Does not reproduce CTG-repeat continuity; mouse model no longer available Identify mechanisms involved in CTG-dependent neuronal degeneration [80]
TREDT960I/ 𝛼 -MHC-rtTA Insertion of Tet-responsive expanded DMPK exons 11–15 transgene; heart-specific rtTA expression 960
(CTCGA-interrupted) 		Ribonuclear foci; MBNL1 sequestration; CELF1 protein upregulation; AS alterations ; arrhythmias Does not reproduce CTG-repeat continuity Study of alteration of ion transport and action potential in cardiomyocytes expressing toxic CUG [81,82]
TREDT960I/
MDAF-rtTA 		Insertion of Tet-responsive expanded DMPK exons 11–15 transgene; skeletal-muscle-specific rtTA expression 960
(CTCGA-interrupted) 		Ribonuclear foci; MBNL1 sequestration; CELF1 protein upregulation; AS alterations; muscle wasting and myopathy Does not reproduce CTG-repeat continuity Study the mechanisms of CUG-repeat-induced muscle tissue loss [83]

Abbreviations: AS = alternative splicing; ChP = brain choroid plexus; CMVβA = cytomegalovirus enhancer/β-actin; GFP = green fluorescent protein; KO = knockout; MDAF = expression vector carrying regulatory sequences for the rat myosin light chain 1/3 gene; MHC = myosin heavy chain; Myo = myogenin; NADH = nicotinamide adenine dinucleotide; polyA = polyadenylation; rtTA = reverse tet transactivator.