Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs

Yuan, Yuan; Compton, Sarah A.; Sobczak, Krzysztof; Stenberg, Myrna G.; Thornton, Charles A.; Griffith, Jack D.; Swanson, Maurice S.

doi:10.1093/nar/gkm601

Cited by 191 publications

(273 citation statements)

References 39 publications

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“…The loss of chloride channels in myotonic dystrophy is thought to be due to an accumulation of RNA with CUG or CCUG repeats in the nucleus that disrupt the function of RNA binding proteins, such as muscleblind-like 1 and 2; consequently, aberrantly spliced Clcn1 mRNA that contains exon 7a is degraded via nonsense-mediated decay (27)(28)(29)(30)(31)(32)(33)(34)(35)(36). We tested for this mechanism in HD interosseous muscle (Fig.…”

Section: Resultsmentioning

confidence: 99%

Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction

Waters

Varuzhanyan

Talmadge

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Huntington disease is a progressive and fatal genetic disorder with debilitating motor and cognitive defects. Chorea, rigidity, dystonia, and muscle weakness are characteristic motor defects of the disease that are commonly attributed to central neurodegeneration. However, no previous study has examined the membrane properties that control contraction in Huntington disease muscle. We show primary defects in ex vivo adult skeletal muscle from the R6/2 transgenic mouse model of Huntington disease. Action potentials in diseased fibers are more easily triggered and prolonged than in fibers from WT littermates. Furthermore, some action potentials in the diseased fibers self-trigger. These defects occur because of decreases in the resting chloride and potassium conductances. Consistent with this, the expression of the muscle chloride channel, ClC-1, in Huntington disease muscle was compromised by improper splicing and a corresponding reduction in total Clcn1 (gene for ClC-1) mRNA. Additionally, the total Kcnj2 (gene for the Kir2.1 potassium channel) mRNA was reduced in disease muscle. The resulting muscle hyperexcitability causes involuntary and prolonged contractions that may contribute to the chorea, rigidity, and dystonia that characterize Huntington disease.

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Section: Resultsmentioning

confidence: 99%

Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction

Waters

Varuzhanyan

Talmadge

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In MD patients the sequestration of MBNL1 and other splicing factors by the mutant mRNAs leads to misregulated splicing, which is believed to be the underlying pathogenic mechanism in MD [34][35][36] . Similarly MBNL1 has been shown to bind CAG repeats 37,38 leading to dysregulated alternative splicing of target mRNAs in CAG repeat expansion disorders 39 . Furthermore, in a Drosophila model of MachadoJoseph disease, another CAG repeat expansion disorder, the MBNL1 protein enhanced CAG repeat RNA toxicity 8,[34][35][36][37][38] .…”

Section: Discussionmentioning

confidence: 99%

“…Similarly MBNL1 has been shown to bind CAG repeats 37,38 leading to dysregulated alternative splicing of target mRNAs in CAG repeat expansion disorders 39 . Furthermore, in a Drosophila model of MachadoJoseph disease, another CAG repeat expansion disorder, the MBNL1 protein enhanced CAG repeat RNA toxicity 8,[34][35][36][37][38] . Thus, binding and sequestration of MBNL1 might be one possible mechanism contributing to RNA toxicity in CAG repeat expansion disorders (reviewed in Krzyzosiak et al 40 ).…”

Section: Discussionmentioning

confidence: 99%

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

et al. 2013

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Expansion of CAG repeats is a common feature of various neurodegenerative disorders, including Huntington's disease. Here we show that expanded CAG repeats bind to a translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. Binding of the MID1-protein phosphatase 2A protein complex increases with CAG repeat size and stimulates translation of the CAG repeat expansion containing messenger RNA in a MID1-, protein phosphatase 2A-and mammalian target of rapamycindependent manner. Our data indicate that pathological CAG repeat expansions upregulate protein translation leading to an overproduction of aberrant protein and suggest that the MID1-complex may serve as a therapeutic target for the treatment of CAG repeat expansion disorders.

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“…It was shown that MBNL1 forms dimers and self-interactions are mediated by the C-terminal region (AA positions 239-382). 37 This region contains the described variant and it is possible that in this case dimerization and therefore gene function is impaired.…”

Section: Discussionmentioning

confidence: 99%

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

et al. 2016

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The myotonic dystrophies (DMs) are the most common inherited muscular disorders in adults. In most of the cases, the disease is caused by (CTG) n /(CCTG) n repeat expansions (EXPs) in non-coding regions of the genes DMPK (dystrophia myotonica-protein kinase) and CNBP (CCHC-type zinc-finger nucleic acid-binding protein). The EXP is transcribed into mutant RNAs, which provoke a common pathomechanism that is characterized by misexpression and mis-splicing. In this study, we screened 138 patients with typical clinical features of DM being negative for EXP in the known genes. We sequenced DMPK and CNBPassociated with DM, as well as CELF1 (CUGBP, Elav-like family member 1) and MBNL1 (muscleblind-like splicing regulator 1) -associated with the pathomechanism of DM, for pathogenic variants, addressing the question whether defects in other genes could cause a DM-like phenotype. We identified variants in three unrelated patients in the MBNL1 gene, two of them were heterozygous missense mutations and one an in-frame deletion of three amino acids. The variants were located in different conserved regions of the protein. The missense mutations were classified as potentially pathogenic by prediction tools. Analysis of MBNL1 splice target genes was carried out for one of the patients using RNA from peripheral blood leukocytes (PBL). Analysis of six genes known to show mis-splicing in the skeletal muscle gave no informative results on the effect of this variant when tested in PBL. The association of these variants with the DM phenotype therefore remains unconfirmed, but we hope that in view of the key role of MBNL1 in DM pathogenesis our observations may foster further studies in this direction.

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Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs

Cited by 191 publications

References 39 publications

Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction

Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction

Translation of HTT mRNA with expanded CAG repeats is regulated by the MID1–PP2A protein complex

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

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