title: Compound loss of muscleblind-like function in myotonic dystrophy.
abstract: Myotonic dystrophy (DM) is a multi-systemic disease that impacts cardiac and skeletal muscle as well as the central nervous system (CNS). DM is unusual because it is an RNA-mediated disorder due to the expression of toxic microsatellite expansion RNAs that alter the activities of RNA processing factors, including the muscleblind-like (MBNL) proteins. While these mutant RNAs inhibit MBNL1 splicing activity in heart and skeletal muscles, Mbnl1 knockout mice fail to recapitulate the full-range of DM symptoms in these tissues. Here, we generate mouse Mbnl compound knockouts to test the hypothesis that Mbnl2 functionally compensates for Mbnl1 loss. Although Mbnl1(-/-) ; Mbnl2(-/-) double knockouts (DKOs) are embryonic lethal, Mbnl1(-/-) ; Mbnl2(+/-) mice are viable but develop cardinal features of DM muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in Mbnl1(-/-) knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the hypothesis that compound loss of MBNL function is a critical event in DM pathogenesis and provide novel mouse models to investigate additional pathways disrupted in this RNA-mediated disease.
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, FL, USA; Department of Neurology, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Kuang-Yung
authors.initials: KY
authors.lastname: Lee
authors.forename: Moyi
authors.initials: M
authors.lastname: Li
authors.forename: Mini
authors.initials: M
authors.lastname: Manchanda
authors.forename: Ranjan
authors.initials: R
authors.lastname: Batra
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Charizanis
authors.forename: Apoorva
authors.initials: A
authors.lastname: Mohan
authors.forename: Sonisha A
authors.initials: SA
authors.lastname: Warren
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Chamberlain
authors.forename: Dustin
authors.initials: D
authors.lastname: Finn
authors.forename: Hannah
authors.initials: H
authors.lastname: Hong
authors.forename: Hassan
authors.initials: H
authors.lastname: Ashraf
authors.forename: Hideko
authors.initials: H
authors.lastname: Kasahara
authors.forename: Laura P W
authors.initials: LP
authors.lastname: Ranum
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D053208:Kaplan-Meier Estimate; D008136:Longevity / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; C529512:Mbnl2 protein, mouse; D016601:RNA-Binding Proteins
keywords: Mbnl1; Mbnl2; RNA-mediated disease; muscleblind-like; myotonic dystrophy