| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| Q9NR56-1 | 0.988 | 115 | 1.036 | 332.71 | 0.661 | 0.628 | 0.891 | 0.747 | 0.861 | 0.868 | 0.777 | 8,9,10,11,12,13,14,15,44,46,47,49,50,51,52,53,54,5
5,57,58,61,62,63,66,67,68,80,83,84,86,87,90
|
| Q9NR56-2 | 0.986 | 102 | 1.033 | 253.82 | 0.621 | 0.627 | 0.869 | 0.771 | 0.87 | 0.886 | 0.325 | 9,10,11,13,14,51,52,53,54,55,57,58,61,63,65,66,67,
68,76,80,83,84,86,87,90
|
| Q9NR56-3 | 1.045 | 141 | 1.125 | 389.305 | 0.569 | 0.642 | 0.816 | 1.145 | 0.615 | 1.862 | 1.712 | 96,99,100,103,104,107,108,109,110,111,112,113,114,
115,133,134,135,175,178,179,182,185,186,188,189,19
2,193
|
| Q9NR56-4 | 1.037 | 113 | 1.098 | 324.821 | 0.559 | 0.668 | 0.887 | 0.884 | 0.743 | 1.189 | 1.009 | 100,103,104,107,109,110,111,112,113,114,115,133,13
4,175,178,179,182,185,186,188,189
|
| Q9NR56-5 | 0.93 | 75 | 0.963 | 243.53 | 0.639 | 0.658 | 0.888 | 1.018 | 0.753 | 1.351 | 0.552 | 9,10,11,13,14,51,52,53,54,55,57,58,68,80,83,84,86,
87,90
|
| Q9NR56-6 | 0.954 | 86 | 0.976 | 248.332 | 0.576 | 0.673 | 0.956 | 0.996 | 0.92 | 1.083 | 0.59 | 9,10,11,13,14,51,52,53,54,55,57,58,68,80,83,84,86,
87,90
|
| Q9NR56-7 | 0.956 | 95 | 0.977 | 276.801 | 0.597 | 0.652 | 0.913 | 0.742 | 1.014 | 0.732 | 0.512 | 9,10,11,13,14,51,52,53,54,55,57,58,61,62,63,66,67,
68,76,80,83,84,86,87,90
|
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| MBNL1 | 11929853 | Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. | Myotonic dystrophy is a complex neuromuscular disorder associated with DNA expansion mutations in two different genes. In DM1 a CTG repeat in the 3'-untranslated region of DMPK is expanded, whereas in DM2 an intronic CCTG expansion occurs in the gene ZNF9. Transcripts containing expanded repeats form foci in the nuclei of DM1 and DM2 cells. Recent work using antibodies has shown that proteins related to Drosophila muscleblind co-localize with repeat foci in DM1 and DM2 cells. We show that rather than there being a single human muscleblind gene producing multiple proteins through alternative splicing, there are in fact three different muscleblind genes, MBNL, MBLL and MBXL, which map to chromosomes 3, 13 and X, respectively, and which show extensive alternative splicing. Two of the genes, MBNL and MBLL, are expressed in many adult tissues whereas MBXL is expressed predominantly in the placenta. Green fluorescent protein-tagged versions of MBNL, MBLL and MBXL co-localize with nuclear foci in DM1 and DM2 cells, suggesting that all three proteins may play a role in DM pathophysiology. | D009223 | Myotonic Dystrophy |
| MBNL1 | 15546872 | MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1. | In myotonic dystrophy 1 (DM1), aggregation of the mutant DMPK RNA into RNA-protein complexes containing MBNL1 and MBNL2 has been linked to aberrant splicing of the insulin receptor (IR) RNA. In a parallel line of investigation, elevated levels of CUG-binding protein (CUG-BP) have been shown to result in altered IR splicing in DM1. The relative importance of MBNL1, MBNL2, and CUG-BP in DM1 pathogenesis is, however, unclear. Here we have demonstrated that either small interfering RNA-mediated down-regulation of MBNL1 and MBNL2 or the overexpression of CUG-BP in normal myoblasts results in abnormal IR splicing. Our results suggest that CUG-BP regulates the equilibrium of splice site selection by antagonizing the facilitatory activity of MBNL1 and MBNL2 on IR exon 11 splicing in a dose-dependent manner. We have shown that CUG-BP levels are elevated in DM1 cells by mechanisms that are independent of MBNL1 and MBNL2 loss. Importantly, rescue experiments in DM1 myoblasts demonstrated that loss of MBNL1 function is the key event, whereas the overexpression of CUG-BP plays a secondary role in the aberrant alternative splicing of IR RNA in DM1. Small interfering RNA-mediated down-regulation of MBNL1, MBNL2, and CUG-BP in DM1 myoblasts demonstrated that MBNL1 plays a critical role in the maintenance of DM1 focus integrity. Thus, these experiments demonstrate that sequestration of MBNL1 by the expanded CUG repeats is the primary determinant of both DM1 focus formation and the abnormal splicing of the IR RNA in DM1 myoblasts. The data therefore support MBNL1-mediated therapy for DM1. | D009223 | Myotonic Dystrophy |
| MBNL1 | 15961406 | Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy. | Myotonic dystrophy type I (DM1), which is caused by a non-coding CTG-repeat expansion in the dystrophia myotonica-protein kinase (DMPK) gene, is an RNA-mediated disease. Expanded CUG repeats in transcripts of mutant DMPK form nuclear foci that recruit muscleblind-like (MBNL) proteins, a family of alternative splicing factors. Although transcripts of mutant DMPK and MBNL proteins accumulate in nuclear RNA foci, it is not clear whether foci formation is required for splicing mis-regulation. Here, we use a co-transfection strategy to show that both CUG and CAG repeats form RNA foci that colocalize with green fluorescent protein (GFP)-MBNL1 and endogenous MBNL1. However, only CUG repeats alter splicing of the two tested pre-mRNAs, cardiac troponin T (cTNT) and insulin receptor (IR). Using FRAP, we demonstrate that GFP-MBNL1 in CUG and CAG foci have similar half-times of recovery and fractions of immobile molecules, suggesting that GFP-MBNL1 is bound by both CUG and CAG repeats. We also find an immobile fraction of GFP-MBNL1 in DM1 fibroblasts and a similar rapid exchange in endogenous CUG RNA foci. Therefore, formation of RNA foci and disruption of MBNL1-regulated splicing are separable events. | D009223 | Myotonic Dystrophy |
| MBNL1 | 16717059 | Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. | In myotonic dystrophy (DM), expression of RNA containing expanded CUG or CCUG repeats leads to misregulated alternative splicing of pre-mRNA. The repeat-bearing transcripts accumulate in nuclear foci, together with proteins in the muscleblind family, MBNL1 and MBNL2. In transgenic mice that express expanded CUG repeats, we show that the splicing defect selectively targets a group of exons that share a common temporal pattern of developmental regulation. These exons undergo a synchronized splicing switch between post-natal day 2 and 20 in wild-type mice. During this post-natal interval, MBNL1 protein translocates from a predominantly cytoplasmic to nuclear distribution. In the absence of MBNL1, these physiological splicing transitions do not occur. The splicing defect induced by expanded CUG repeats in mature muscle fibers is closely reproduced by deficiency of MBNL1 but not by deficiency of MBNL2. A parallel situation exists in human DM type 1 and type 2. MBNL1 is depleted from the muscle nucleoplasm because of sequestration in nuclear foci, and the associated splicing defects are remarkably similar to those observed in MBNL1 knockout mice. These results indicate that MBNL1 participates in the post-natal remodeling of skeletal muscle by controlling a key set of developmentally regulated splicing switches. Sequestration of MBNL1, and failure to maintain these splicing transitions, has a pivotal role in the pathogenesis of muscle disease in DM. | D009223 | Myotonic Dystrophy |
| MBNL1 | 17846170 | Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains. | In myotonic dystrophy type 1 (DM1), triplet repeat expansion in the 3' untranslated region of dystrophia myotonica protein kinase (DMPK) causes the nuclear retention of mutant messenger RNA (mRNA). Although the DMPK gene locus positions precisely at the outer edge of a factor-rich SC-35 domain, the normal mRNA consistently accumulates within the domain, and this RNA is depleted upon transcriptional inhibition. In DM1, mutant transcripts detach from the gene but accumulate in granules that abut but do not enter SC-35 domains, suggesting that RNA entry into the domain is blocked. Despite their exclusion from these compartments, mutant transcripts are spliced. MBNL1 (muscleblind-like protein 1) is an alternative splicing factor that becomes highly concentrated with mutant RNA foci. Small interfering RNA-mediated knockdown of MBNL1 promotes the accumulation or entry of newly synthesized mutant transcripts in the SC-35 domain. Collectively, these data suggest that an initial step in the intranuclear path of some mRNAs is passage from the gene into an SC-35 domain and implicate these structures in postsplicing steps before export. | D009223 | Myotonic Dystrophy |
| MBNL1 | 19095965 | Muscleblind-like proteins: similarities and differences in normal and myotonic dystrophy muscle. | In myotonic dystrophy, muscleblind-like protein 1 (MBNL1) protein binds specifically to expanded CUG or CCUG repeats, which accumulate as discrete nuclear foci, and this is thought to prevent its function in the regulation of alternative splicing of pre-mRNAs. There is strong evidence for the role of the MBNL1 gene in disease pathology, but the roles of two related genes, MBNL2 and MBNL3, are less clear. Using new monoclonal antibodies specific for each of the three gene products, we found that MBNL2 decreased during human fetal development and myoblast culture, while MBNL1 was unchanged. In Duchenne muscular dystrophy muscle, MBNL2 was elevated in immature, regenerating fibres compared with mature fibres, supporting some developmental role for MBNL2. MBNL3 was found only in C2C12 mouse myoblasts. Both MBNL1 and MBNL2 were partially sequestered by nuclear foci of expanded repeats in adult muscle and cultured cells from myotonic dystrophy patients. In adult muscle nucleoplasm, both proteins were reduced in myotonic dystrophy type 1 compared with an age-matched control. In normal human myoblast cultures, MBNL1 and MBNL2 always co-distributed but their distribution could change rapidly from nucleoplasmic to cytoplasmic. Functional differences between MBNL1 and MBNL2 have not yet been found and may prove quite subtle. The dominance of MBNL1 in mature, striated muscle would explain why ablation of the mouse mbnl1 gene alone is sufficient to cause a myotonic dystrophy. | D009223 | Myotonic Dystrophy |
| MBNL1 | 19345584 | Ribonuclear inclusions and MBNL1 nuclear sequestration do not affect myoblast differentiation but alter gene splicing in myotonic dystrophy type 2. | Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystemic disorder caused by a CCTG expansion in intron 1 of the zinc finger protein 9 gene on chromosome 3. Mutant transcripts are retained in muscle nuclei producing ribonuclear inclusions, which can bind specific RNA-binding proteins leading to a reduction in their activity. The nuclear sequestration of muscleblind-like proteins appears to be involved in splicing defects of genes directly related to the myotonic dystrophy phenotypes. Experimental evidence suggests that ribonuclear inclusions and muscleblind-like protein 1 (MBNL1) sequestration are strongly involved in DM2 pathogenesis. By using fluorescence in situ hybridization in combination with MBNL1-immunofluorescence, we have observed the presence of ribonuclear inclusions and MBNL1 nuclear sequestration at different time points of in vitro myoblast differentiation in each DM2 patient examined. Immunofluorescence and Western blot analysis of several markers of skeletal muscle differentiation reveal that the degree of differentiation of DM2 myoblasts is comparable to that observed in controls. Nevertheless the splicing pattern of the insulin receptor and MBNL1 transcripts, directly related to the DM2 phenotype, appears to be altered in in vitro differentiated DM2 myotubes. Our data seem indicate that the presence of ribonuclear inclusions and MBNL1 nuclear foci are involved in alteration of alternative splicing but do not impair DM2 myogenic differentiation. | D009223 | Myotonic Dystrophy |
| MBNL1 | 21454535 | Analysis of exonic regions involved in nuclear localization, splicing activity, and dimerization of Muscleblind-like-1 isoforms. | Muscleblind-like-1 (MBNL1) is a splicing regulatory factor controlling the fetal-to-adult alternative splicing transitions during vertebrate muscle development. Its capture by nuclear CUG expansions is one major cause for type 1 myotonic dystrophy (DM1). Alternative splicing produces MBNL1 isoforms that differ by the presence or absence of the exonic regions 3, 5, and 7. To understand better their respective roles and the consequences of the deregulation of their expression in DM1, here we studied the respective roles of MBNL1 alternative and constitutive exons. By combining genetics, molecular and cellular approaches, we found that (i) the exon 5 and 6 regions are both needed to control the nuclear localization of MBNL1; (ii) the exon 3 region strongly enhances the affinity of MBNL1 for its pre-mRNA target sites; (iii) the exon 3 and 6 regions are both required for the splicing regulatory activity, and this function is not enhanced by an exclusive nuclear localization of MBNL1; and finally (iv) the exon 7 region enhances MBNL1-MBNL1 dimerization properties. Consequently, the abnormally high inclusion of the exon 5 and 7 regions in DM1 is expected to enhance the potential of MBNL1 of being sequestered with nuclear CUG expansions, which provides new insight into DM1 pathophysiology. | D009223 | Myotonic Dystrophy |
| MBNL1 | 21623381 | Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. | Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy. | D018908 | Muscle Weakness |
| MBNL1 | 21623381 | Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. | Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy. | D009223 | Myotonic Dystrophy |
| MBNL1 | 23949219 | MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases. | Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142-43, succeeded in reducing the nuclear localization of both Lyn and MBNL142-43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway. | D009223 | Myotonic Dystrophy |
| MBNL1 | 24354850 | Transcriptionally correlated subcellular dynamics of MBNL1 during lens development and their implication for the molecular pathology of myotonic dystrophy type 1. | DM1 (myotonic dystrophy type 1) is caused by elongation of a CTG repeat in the DMPK (dystrophia myotonica-protein kinase) gene. mRNA transcripts containing these CUGexp (CUG expansion) repeats form accumulations, or foci, in the nucleus of the cell. The pathogenesis of DM1 is proposed to result from inappropriate patterns of alternative splicing caused by sequestration of the developmentally regulated alternative splicing factor MBNL1 (muscleblind-like 1) by these foci. Since eye lens cataract is a common feature of DM1 we have examined the distribution and dynamics of MBNL1 in lens epithelial cell lines derived from patients with DM1. The results of the present study demonstrate that only a small proportion of nuclear MBNL1 accumulates in CUGexp pre-mRNA foci. MBNL1 is, however, highly mobile and changes localization in response to altered transcription and splicing activity. Moreover, immunolocalization studies in lens sections suggest that a change in MBNL1 distribution is important during lens growth and differentiation. Although these data suggest that the loss of MBNL1 function due to accumulation in foci is an unlikely explanation for DM1 symptoms in the lens, they do demonstrate a strong relationship between the subcellular MBNL1 localization and pathways of cellular differentiation, providing an insight into the sensitivity of the lens to changes in MBNL1 distribution. | D009223 | Myotonic Dystrophy |
| MBNL1 | 26018658 | Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. | Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1. | D009223 | Myotonic Dystrophy |
Gene summary
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