title: Loss of muscleblind-like 1 results in cardiac pathology and persistence of embryonic splice isoforms.
abstract: Cardiac dysfunction is a prominent cause of mortality in myotonic dystrophy I (DM1), a disease where expanded CUG repeats bind and disable the muscleblind-like family of splice regulators. Deletion of muscleblind-like 1 (Mbnl1(ΔE2/ΔE2)) in 129 sv mice results in QRS, QTc widening, bundle block and STc narrowing at 2-4 months of age. With time, cardiac function deteriorates further and at 6 months, decreased R wave amplitudes, sinus node dysfunction, cardiac hypertrophy, interstitial fibrosis, multi-focal myocardial fiber death and calcification manifest. Sudden death, where no end point illness is overt, is observed at a median age of 6.5 and 4.8 months in ~67% and ~86% of male and female Mbnl1(ΔE2/ΔE2) mice, respectively. Mbnl1 depletion results in the persistence of embryonic splice isoforms in a network of cardiac RNAs, some of which have been previously implicated in DM1, regulating sodium and calcium currents, Scn5a, Junctin, Junctate, Atp2a1, Atp11a, Cacna1s, Ryr2, intra and inter cellular transport, Clta, Stx2, Tjp1, cell survival, Capn3, Sirt2, Csda, sarcomere and cytoskeleton organization and function, Trim55, Mapt, Pdlim3, Pdlim5, Sorbs1, Sorbs2, Fhod1, Spag9 and structural components of the sarcomere, Myom1, Tnnt2, Zasp. Thus this study supports a key role for Mbnl1 loss in the initiation of DM1 cardiac disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Dixon
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Jongkyu
authors.initials: J
authors.lastname: Choi
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA [2] Department of Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Ayea
authors.initials: A
authors.lastname: El-Ghazali
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Roos
authors.affiliation: Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jordan
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.affiliation: Department of Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Lucio
authors.initials: L
authors.lastname: Comai
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Sita
authors.initials: S
authors.lastname: Reddy
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001146:Arrhythmia, Sinus; D002114:Calcinosis; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D005355:Fibrosis; D017353:Gene Deletion; D015870:Gene Expression; D023061:Gene Order; D018390:Gene Targeting; D056426:Genetic Loci; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D059368:RNA Isoforms; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: C493663:MBNL1 protein, human; D059368:RNA Isoforms; D016601:RNA-Binding Proteins