title: Muscleblind-like 3 deficit results in a spectrum of age-associated pathologies observed in myotonic dystrophy.
abstract: Myotonic dystrophy type I (DM1) exhibits distinctive disease specific phenotypes and the accelerated onset of a spectrum of age-associated pathologies. In DM1, dominant effects of expanded CUG repeats result in part from the inactivation of the muscleblind-like (MBNL) proteins. To test the role of MBNL3, we deleted Mbnl3 exon 2 (Mbnl3(ΔE2)) in mice and examined the onset of age-associated diseases over 4 to 13 months of age. Accelerated onset of glucose intolerance with elevated insulin levels, cardiac systole deficits, left ventricle hypertrophy, a predictor of a later onset of heart failure and the development of subcapsular and cortical cataracts is observed in Mbnl3(ΔE2) mice. Retention of embryonic splice isoforms in adult organs, a prominent defect in DM1, is not observed in multiple RNAs including the Insulin Receptor (Insr), Cardiac Troponin T (Tnnt2), Lim Domain Binding 3 (Ldb3) RNAs in Mbnl3(ΔE2) mice. Although rare DM1-like splice errors underlying the observed phenotypes cannot be excluded, our data in conjunction with the reported absence of alternative splice errors in embryonic muscles of a similar Mbnl3(ΔE2) mouse by RNA-seq studies, suggest that mechanisms distinct from the adult retention of embryonic splice patterns may make important contributions to the onset of age-associated pathologies in DM1.
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: 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: Warunee
authors.initials: W
authors.lastname: Dansithong
authors.affiliation: USC Eye Institute, Los Angeles, CA 90033, USA.|Department of Ophthalmology, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
authors.forename: Walid F
authors.initials: WF
authors.lastname: Abdallah
authors.affiliation: Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751, 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 90095-1751, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jordan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Trac
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Han Shin
authors.initials: HS
authors.lastname: Lee
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: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017398:Alternative Splicing; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D018149:Glucose Intolerance; D060588:LIM Domain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009223:Myotonic Dystrophy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D016601:RNA-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D060588:LIM Domain Proteins; C485639:Ldb3 protein, mouse; C522920:MBNL3 protein, mouse; D016601:RNA-Binding Proteins