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. 2013 Dec;5(12):1887-900.
doi: 10.1002/emmm.201303275. Epub 2013 Oct 8.

Compound loss of muscleblind-like function in myotonic dystrophy

Kuang-Yung Lee  1 , Moyi Li, Mini Manchanda, Ranjan Batra, Konstantinos Charizanis, Apoorva Mohan, Sonisha A Warren, Christopher M Chamberlain, Dustin Finn, Hannah Hong, Hassan Ashraf, Hideko Kasahara, Laura P W Ranum, Maurice S Swanson
Affiliations

Compound loss of muscleblind-like function in myotonic dystrophy

Kuang-Yung Lee et al. EMBO Mol Med. 2013 Dec.

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.

Keywords: Mbnl1; Mbnl2; RNA-mediated disease; muscleblind-like; myotonic dystrophy.

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Figures

Figure 1
Figure 1
Reduced viability of Mbnl1; Mbnl2 KO mice.
Figure 2
Figure 2
DM-associated muscle wasting/weakness in Mbnl1; Mbnl2 KOs.
Figure 3
Figure 3
DM-associated splicing deficits following Mbnl1 and Mbnl2 depletion.
Figure 4
Figure 4
Compound mouse knockout model for DM heart disease.
Figure 5
Figure 5
Splicing alterations of cardiac RNA targets in Mbnl1−/−; Mbnl2+/− KOs.
Figure 6
Figure 6
Enhanced muscle pathology in Mbnl1; Mbnl2 muscle-specific KO mice.
Figure 7
Figure 7
HITS-CLIP analysis in Mbnl1 KO mice.
See this image and copyright information in PMC

References

    1. Chamberlain CM, Ranum LP. Mouse model of muscleblind-like 1 overexpression: Skeletal muscle effects and therapeutic promise. Hum Mol Genet. 2012;21:4645–4654. - PMC - PubMed
    1. Charizanis K, Lee KY, Batra R, Goodwin M, Zhang C, Yuan Y, Shiue L, Cline M, Scotti MM, Xia G, et al. Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron. 2012;75:437–450. - PMC - PubMed
    1. Du H, Cline MS, Osborne RJ, Tuttle DL, Clark TA, Donohue JP, Hall MP, Shiue L, Swanson MS, Thornton CA, et al. Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat Struct Mol Biol. 2010;17:187–193. - PMC - PubMed
    1. Fugier C, Klein AF, Hammer C, Vassilopoulos S, Ivarsson Y, Toussaint A, Tosch V, Vignaud A, Ferry A, Messaddeq N, et al. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat Med. 2011;17:720–725. - PubMed
    1. Gehman LT, Meera P, Stoilov P, Shiue L, O'Brien JE, Meisler MH, Ares M, Jr, Otis TS, Black DL. The splicing regulator Rbfox2 is required for both cerebellar development and mature motor function. Genes Dev. 2012;26:445–460. - PMC - PubMed

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