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FLASH GENE
Symbol MBNL1 contributors: mct/ - updated : 30-04-2018
HGNC name muscleblind-like (Drosophila)
HGNC id 6923
Location 3q25.2      Physical location : 151.985.828 - 152.183.568
Synonym name
  • triplet repeat (CUG) expansion,RNA binding proteins
  • muscleblind-like 1
  • Synonym symbol(s) KIAA0428, EXP42, EXP, MBNL, EXP35, EXP40, DKFZp686P06174
    DNA
    TYPE functioning gene
    STRUCTURE 197.74 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure
  • MBNL1 can be transcribed from three different promoters and the transcription initiation site determines the mode of e1 regulation
  • MAPPING cloned Y linked N status provisional
    Map cen - D3S1279 - AADAC - MBNL1 - D3S1280 - qter
    Authors Gene Map (98)
    RNA
    TRANSCRIPTS type messenger
    text
  • several alternatively spliced exons (PMID: 20009516)
  • conserved developmental stage- and tissue-specific alternative splicing of MBNL1, MBNL2 transcripts is an important mechanism by which MBNL activity is regulated during embryonic development ( PMID: 20009516)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 splicing 5390 41.8 388 - 2004 14722159
  • also called MBNL1 42 or hEXP42 or variant 3/isoform c
  • transcripts containing exon 5 and the respective protein isoforms (MBNL1 42-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei (PMID: 23949219)
  • 9 splicing 6368 39.8 370 - 2004 14722159
    also called MBNL1 40 or hEXP40 or variant 1/isoform b
    7 splicing 5132 33 302 - 2004 14722159
    also called MBNL1 35 or hEXP35 or variant 4/isoform d
    10 splicing 6404 41 382 - 2004 14722159
    also called MBNL1 41 or variant 1/isoform a
    8 splicing 5168 36 314 - 2004 14722159
    also called MBNL1 36 or variant 5/isoform e
    8 splicing 5277 - 342 - 2004 14722159
    also called MBNL1 41S or variant 7/isoform g
    8 splicing 5246 - 340 - 2004 14722159
    also called MBNL1 40S or variant 6/isoform f
    - splicing - - 68 - 2004 14722159
    also called MBLN1 In
    12 splicing 5266 - 343 - 2004 14722159
  • also called MBLN1 Idn
  • lack the N-terminus region and starts in the secong zinc finger motif
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   highly
     thymus   highly
    Cardiovascularheart   highly
    Digestiveliver   highly
    Endocrinepancreas    
    Nervousbrain    
    Reproductivemale systemprostate  highly
    Respiratorylung   highly
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoietic    
    Epithelialsecretoryglandularendocrine 
    Epithelialsecretoryglandularexocrine 
    Lymphoid    
    Muscularstriatumcardiac  
    Muscularstriatumskeletal  
    cell lineage lymphoblastoid cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • core regulatory regions for both activation and repression of splicing located within an 80-AA segment located downstream of the N-terminal zinc-finger pair
  • four CCCH zinc finger motifs (ZF1-4) of the CX7CX46CX3H-type, that play an important role in RNA target identification , a tandem CCCH zinc-finger (ZnF) domains that target pre-mRNAs containing YGCU(U/G)Y sequence elements (where Y is a pyrimidine)
  • two classes of nuclear localization signal (NLS), a classical bipartite NLS and a novel conformational NLS
  • HOMOLOGY
    interspecies homolog to C.elegans
    ortholog to murine Mbnl
    homolog to Drosophila muscleblind
    intraspecies paralog to MBNL2, MBLN3
    Homologene
    FAMILY
  • muscleblind family
  • CATEGORY RNA associated , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic,granule
    intracellular,nucleus,nucleoplasm
    text
  • accumulating in nuclear foci in dystrophia myotonic
  • in response to stress, MBNL1 moved to cytoplasmic stress granules, where it colocalized with YBX1, which was previously reported to be a component of stress granules
  • MBNL1 cytoplasmic, but not nuclear, isoform promotes neurite morphogenesis and reverses the morphological defects caused by expanded CUG RNA
  • basic FUNCTION
  • may be promoting muscle differentiation
  • playing a role in mRNA metabolism in the cytoplasm
  • having a determinative role for a large subset of splicing transitions that occur during postnatal heart development
  • involved in the differentiation of muscle inclusion by controlling the splicing patterns of several pre-mRNAs
  • plays a crucial role in myotonic dystrophy
  • RNA binding protein that regulate alternative splicing transitions during development
  • implicated in regulating fetal-to-adult transitions in alternative splicing in the heart
  • role for MBNL1 in controlling insulin receptor exon 11 inclusion via binding to a downstream intronic enhancer element
  • promotes exon inclusion, as it does for the INSR gene, by binding to downstream sites
  • CELF1 and MBNL1 regulate alternative splicing
  • exerts robust splicing activity in the absence of RNA binding
  • can act as either a splicing suppressor or enhancer in a transcript-specific manner
  • MBNL1, MBNL2, MBNL3 plays important roles in muscle and eye development and in myotonic dystrophy (DM), in which expanded CUG or CCUG repeats functionally deplete MBNL proteins
  • central and negative regulatory role for MBNL1, MBNL2 proteins in pluripotency
  • MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation
  • RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1
  • key role for MBNL1 loss in the initiation of DM1 cardiac disease
  • plays a conserved role in negatively regulating TGFB1 signaling, and is required for normal valve morphogenesis and homeostasis
  • depletion of MBNL1 and/or MBNL2 reduced localization of hundreds of transcripts, implicating MBLN1, 2, 3 in localization of mRNAs to neurites
  • plays an important role in regulating the transition between differentiation and pluripotency and in the pathogenesis of myotonic dystrophy type 1 (DM1), a CTG expansion disorder
  • K63-linked ubiquitination of MBNL1 is required for its cytoplasmic localization and deubiquitination of cytoplasmic MBNL1 is pathogenic in the DM1 brain
  • CELLULAR PROCESS nucleotide, RNA splicing
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • formed an RNP complex with YBX1 and DDX1
  • INTERACTION
    DNA
    RNA
  • binding to CUG triplet repeat expansion dsRNA
  • . MBNL1, MBNL2, MBNL3 bind to hundreds of pre- and mature mRNAs to regulate their alternative splicing, alternative polyadenylation, stability and subcellular localization
  • small molecule metal binding,
  • Zn2+
  • protein
  • DMPK,(CTG)n expansion
  • binding to repetitive motifs in ZNF9(containing a minimal length of CCUG repeats with non-CCUG insertions)
  • may bind all of its RNA substrates, both normal and pathogenic, as structured stem-loops containing pyrimidine mismatches
  • compete with U2AF2 by binding to mutually exclusive RNA structures (binds a portion of the intron as a stem-loop, whereas U2AF65 binds the same region in a single-strand structure)
  • interact directly with 3 pre-mRNAs that are mis-regulated in DM1, TNNT3, TNNT2, and SERCA1
  • binds specifically to the INSR (insulin receptor gene) RNA, a strong MBNL1 binding to a GGCUUU motif in INSR gene
  • binds the BIN1 pre-mRNA and regulates its alternative splicing
  • recognize and bind to the stem of hairpin structures that form in both toxic expanded CUG RNAs and in normal splicing targets
  • MBNL1 and MBNL2 bind to nascent transcripts to regulate alternative splicing during muscle and brain development
  • directly binds to and regulates a network of differentiation-specific and cytoskeletal/matrix-assembly transcripts to promote myofibroblast differentiation
  • MBNL proteins control steady-state levels of MBNL1 through an interaction with e1 in its precursor mRNA
  • MBNL1, MBNL2, MBNL3 are capable of fine-tuning cellular content of MBNL1, by binding to the first coding exon (e1) of its pre-mRNA
  • cell & other
    REGULATION
    induced by myoblast differentiation
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    during heart development
    constitutional     --low  
    in myotonic dystrophy lead to aberrant alternative splicing of a subset of pre-mRNAs , and can bind short structured CUG and CCUG repeats with high affinity and specificity
    constitutional     --over  
    elevated levels of individual members of MBNL1CUG complexes may alter other key processes and contribute in additional important ways to DM1 pathology
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target therapeutic strategy would employ a drug that binds to CUG repeats, thereby freeing MBNL1 to regulate splicing of its pre-mRNA targets
    SystemTypeDisorderPubmed
    neuromuscular  
    potential therapies against myotonic dystrophy based on manipulation of the transcription initiation site and e1 splicing of MBNL1 mRNA
    ANIMAL & CELL MODELS
  • depletion of Mbnl proteins in mouse embryo fibroblasts leads to misregulation of thousands of alternative polyadenylation events