Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy.
Myotonic dystrophy (DM), the most common adult-onset muscular dystrophy, is caused by CTG or CCTG microsatellite repeat expansions. Expanded DM mRNA microsatellite repeats are thought to accumulate in the nucleus, sequester Muscleblind proteins, and interfere with alternative mRNA splicing. Muscleblind2 (Mbnl2) is a member of the family of Muscleblind RNA binding proteins (that also include Mbnl1 and Mbnl3) that are known to bind CTG/CCTG RNA repeats. Recently, it was demonstrated that Mbnl1-deficient mice have characteristic features of human DM, including myotonia and defective chloride channel expression. Here, we demonstrate that Mbnl2-deficient mice also develop myotonia and have skeletal muscle pathology consistent with human DM. We also find defective expression and mRNA splicing of the chloride channel (Clcn1) in skeletal muscle that likely contributes to the myotonia phenotype. Our results support the hypothesis that Muscleblind proteins and specifically MBNL2 contribute to the pathogenesis of human DM.
Hao
Minqi
M
Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1760, USA.
Akrami
Kevan
K
Wei
Ke
K
De Diego
Carlos
C
Che
Nam
N
Ku
Jeong-Hee
JH
Tidball
James
J
Graves
Michael C
MC
Shieh
Perry B
PB
Chen
Fabian
F
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018118:Chloride Channels / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D042622:DNA Repeat Expansion / Q000235:genetics; D004576:Electromyography; D005697:Galactosides; D007150:Immunohistochemistry; D007211:Indoles; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000473:pathology*; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018118:Chloride Channels; D017931:DNA Primers; D005697:Galactosides; D007211:Indoles; C529512:Mbnl2 protein, mouse; D016601:RNA-Binding Proteins; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside