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FLASH GENE
Symbol DUX4 contributors: mct/npt - updated : 22-09-2016
HGNC name double homeobox, 4
HGNC id 3082
Location 4q35.2      Physical location : 72.631 - 191.013.476
Synonym name
  • double homeobox protein 10
  • double homeobox protein 4/10
  • double homeobox protein DUX10
    • Synonym symbol(s) DUX10, DUX4L
    DNA
    TYPE functioning gene
    SPECIAL FEATURE gene in gene
    text
  • maps within the D4Z4 repeat unit
  • is in fact a retrogene, most likely retrotransposed to a DNA gene from the DUXC mRNA
    • STRUCTURE 12.21 kb     1 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    text structure
  • intronless
  • DUX4 promoter activity was dependent on a TACAA and GC box
  • a typical initiator sequence (GCACCTG) overlapping with a putative E box upstream of the ORF start codon
  • two enhancers, DUX4 myogenic enhancer 1 (DME1) and DME2 which activate DUX4-fl expression in skeletal myocytes but not fibroblasts
    • MAPPING cloned Y linked N status provisional
    regionally located in the partially deleted D4Z4 locus (FSHD)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    - splicing - - - in muscles 2012 22798623
  • splice form of DUX4 encoding only the N-terminal portion
    • 3 - 1574 - 424 - 2012 22798623
  • expression of DUX4-fl mRNA or protein, though likely necessary for FSHD pathogenesis, is clearly not a sufficient condition (PMID: 22798623)
    • 2 - 1710 - 424 - 2012 22798623
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Reproductivefemale systemplacenta  specific Homo sapiens
     male systemtestis  highly Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two helix-turn-helix (homeo) domains
    • HOMOLOGY
    Homologene
    FAMILY
  • DUX paired homeobox family
    • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,nucleolus
    intracellular,nuclear envelope
    basic FUNCTION
  • involved in regulation of transcription, DNA-dependent
  • DUX4-mediated cell death contributes to the pathogenic pathway in FSHD (Kowaljow 2007)
  • DUX4 originated from retrotransposition of a processed transcript, most probably DUXC
  • initiates a large transcription deregulation cascade leading to muscle atrophy and oxidative stress, which are FSHMD1A key features
  • role for DUX4 and repetitive elements in mammalian germline evolution and in FSHD muscular dystrophy
  • expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration
  • DUX4, is responsible for driving gene expression signatures known as zygotic gene activation (ZGA) at the cleavage stage of totipotent zygotes
    • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • part of subtelomeric macrosatellite D4Z4 that has 11–150 repeats, each containing a copy of the intronless DUX4 gene
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • transcription activator of PITX1
  • PITX1 protein can further diffuse to additional myonuclei and expand the transcriptional deregulation cascade initiated by DUX4 in FSHMD1A
  • DUX4 might potentially induce proliferation inhibition and G1 phase arrest through upregulation of CDKN1A
  • LMCD1 is a DUX4 partner
    • cell & other
    REGULATION
    repressed by Wnt/CTNNB signaling is important for transcriptional repression of DUX4
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       gain of function
    in patient myoblasts at both mRNA and protein level in FSHMD1A, attributable to the stabilized distal DUX4 transcript (
    constitutional     --over  
    induces cell death, induces caspase 3/7 activity and alters emerin distribution at the nuclear envelope (Kowaljow 2007)
    constitutional     --other  
    in FSHMD1A, the combination of inefficient chromatin silencing of the D4Z4 repeat and inappropriate DUX4 protein expression in muscle cells
    tumoral fusion      
    to CIC as a result of a recurrent chromosomal translocation t(4;19)(q35;q13) in Ewing-like sarcomas
    constitutional     --other  
    expressed in FSHMD1A myotubes
    constitutional     --over  
    over ten-fold in FSHMD1A myoblasts and myotubes with short telomeres, and its expression is inversely proportional to telomere length
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS