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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.
Pubmed ID: 24293317
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TREAT-NMD is a network for the neuromuscular field that is creating the infrastructure to ensure that the most promising new therapies reach patients as quickly as possible. Since its launch in January 2007 the network''s focus has been on the development of tools that industry, clinicians and scientists need to bring novel therapeutic approaches through preclinical development and into the clinic, and on establishing best-practice care for neuromuscular patients worldwide.
View all literature mentionslaboratory mouse with name 129/Sv x C57BL from MGI.
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View all literature mentionsAllele Detail: Targeted This is a legacy resource.
View all literature mentionsAllele Detail: Targeted This is a legacy resource.
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