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FLASH GENE
Symbol FHL1 contributors: mct/npt/pgu - updated : 04-03-2015
HGNC name four and a half LIM domains 1
HGNC id 3702
Corresponding disease
SPM1 scapuloperoneal myopathy 1
XMPMA X-linked myopathy with postural muscle atrophy and generalized hypertrophy
Location Xq26.3      Physical location : 135.228.860 - 135.293.518
Synonym name
  • four-and-a-half LIM domains 1
  • LIM protein SLIMMER
  • skeletal muscle LIM-protein 1
  • four-and-a-half Lin11, Isl-1 and Mec-3 domains 1
  • Synonym symbol(s) SLIM1, FHL1B, KYO-T, KYOT2, bA535K18.1, FLH1A, MGC111107
    DNA
    TYPE functioning gene
    STRUCTURE 64.56 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    text the first two exons are thought to be noncoding, exons 3 to 8 are alternatively spliced and give rise to three major transcribed isoforms: FHL1A, FHL1B, and FHL1C (PMID: 19716112)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    7 splicing 2455 31.5 280 . predominantly expressed in skeletal and cardiac striated muscles . expressed in many cell types, with highest levels in skeletal muscle, intermediate levels in the heart and low expression in placenta, ovary, prostate, testis, small intestine, colon and spleen 2012 22523091
  • also called FHL1A/SLIM1
  • localizing at focal adhesions
  • 4.5 LIM domains
  • 8 splicing 2724 - 323 . nuclear . in striated muscles and also in brain . expressed in brain, skeletal muscle and, to a lesser extent, in heart, colon, prostate and small intestine 2012 22523093
  • FHL1B/SLIM3, slimmer
  • lack exon 4 and contain a C-terminal putative binding domain for J-recombination signal protein (RBP-J)
  • interacts with SIVA1 and delays skeletal myoblast apoptosis (PMID: 19643733)
  • shuttle between nucleus and cytoplasm at different phases of the cell cycle
  • FHL1B/PPP2CA interaction may illustrate a novel cell-cycle regulatory pathway (PMID: 20969868)
  • one of the roles of FHL1B is to act as a specific regulator of PPP2CA in human muscles and brain (PMID: 20969868)
  • contains the LIM domains 13 plus nuclear localization and export signals, as well as an RBP-J binding region
  • 6 - 2906 - 280 - -
    6 - 2331 - 309 - 1999 9929984
    6 - 2337 - 194 - 1999 9929984
    7 - 2524 - 280 - 1999 9929984
    7 splicing 2392 - 280 . specifically expressed in testis, skeletal muscle, and heart at a relatively low level, also seen in aorta, left atrium, left, and right ventricles at low level . expressed at much lower levels in heart, testis and skeletal muscle 2011 22053194
  • also called isoform FHL1C, or KyoT2
  • loss of exon 4
  • contains a single zinc finger and two tandem repeats of LIM domains at the N-terminus followed by a putative RBP-J binding region at the C-terminus
  • homolog of murine Kyot2
  • localized both in the nucleus and cytoplasm
  • 2.5 LIM domains
  • is a binding partner for KCNA5
  • FHL1C could induce TJP1 translocating into nucleus, and could contribute to the epithelial-mesenchymal transition (EMT) (PMID: 24657059)
  • 6 - 2460 - 296 - 1999 9929984
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   predominantly Homo sapiensAdult
    Digestiveliver   moderately
     mouthtongue  highly
    Nervousbrain   moderately
    Reproductivefemale systemplacenta  moderately
    Respiratorylung   moderately
    Urinarykidney   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal highly Homo sapiens
    Muscularstriatumcardiac highly Homo sapiensAdult
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Muscularmyocyte Homo sapiens
    cell lineage myoblasts, myotubes
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • four and a half LIM domains (Lin-11, Isl-1, Mec3), which are highly conserved sequences constituted by two zinc fingers in tandem, implicated in numerous interactions
  • a novel C terminal 96 AAs with three potential nuclear localization signals (NLS)
  • a putative nuclear export sequence and 27AA identical to the RBPJ region of KyoT2
  • HOMOLOGY
    Homologene
    FAMILY
    CATEGORY adhesion
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytoskeleton
    intracellular,nucleus,nucleoplasm
    text
  • with isoforms FHL1A, FHL1B,(SLIM1) localizing at focal adhesions and SLIM3 (slimmer) in the nucleus of myoblasts and cytoplasm of myotubes
  • can be localized to the sarcolemma, sarcomere, and nucleus of muscle cells
  • localized within the cytoskeleton and the nucleus and can shuttle between these compartments
  • mainly localize to the sarcomeric I-band, but also to a lesser extent to the M-band of the sarcomere in skeletal myocytes
  • basic FUNCTION
  • sugesting distinct roles in the cytoskeleton and in nuclear-cytoplasmic communication
  • probably related to neural differentiation
  • playing a role in the development and maintenance of muscle tissue, in sarcomere synthesis and assembly
  • regulator of myosin-binding protein C activity and playinga role in sarcomere assembly
  • LIM domain protein that suppresses the RBPJ-mediated transcriptional activation
  • might inhibit the RBPJ-mediated transactivation through intracellular domain of Notch by recruiting co-suppressors such as CBX4
  • implicated in sarcomere assembly by interacting with myosin binding protein-C
  • suggested to contribute to sarcomere synthesis, assembly and biomechanical stress sensing
  • cooperative regulation of VEGFA signaling by FHL1 and SMAD4 was evidenced, which may provide a novel regulation mechanism underlying cancer development and progression
  • FHL1 and FHL2 are novel cardiac PRKD1 partners, which differentially facilitate PRKD1 activation and HDAC5 phosphorylation by distinct neurohormonal stimuli, but are unlikely to regulate MEF2A-driven transcriptional reprogramming
  • can be an acting molecule mediating both signaling pathways during osteogenesis
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • FHL1 exists as part of a complex that binds with PDLIM1, GSN and ACTN1
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with AKAP1 and FRAP1 for regulating ribosomal protein genes
  • interacting with myosin-binding protein C (MYBPC), and may contribute to muscle cytoarchitecture by interacting
  • interacting with CBX4
  • talin1 is a new interacting partner of FHL1
  • FHL1, FHL2, and FHL3 physically and functionally interact with SMAD2, SMAD3, and SMAD4, important regulators of cancer development and progression, in a TGF-beta-independent manner
  • interaction between ubiquitin-specific protease 15 (USP15) and skeletal muscle LIM protein 1 (FHL1)
  • binds to the EP300/CREBBP co-activators and disrupts binding with HIF1A
  • FHL1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics
  • NFATC1-mediated transcription regulates UTRN expression and FHL1 which promotes muscle hypertrophy, is a transcriptional activator of NFATC1
  • binds RBPJ with high affinity and competes with coactivators, such as NOTCH1, for binding RBPJ
  • cell & other
    REGULATION
    Other regulated by TLX1
    regulation is hypoxia-inducible transcription factor dependent
    ASSOCIATED DISORDERS
    corresponding disease(s) XMPMA , SPM1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    particularly in the pulmonary vasculature, in lungs from patients with idiopathic pulmonary arterial hypertension
    constitutional     --low  
    in hypertrophic cardiomyopathy and failing hearts
    constitutional     --over  
    in hypertrophic cardiomyopathy (HCM)
    constitutional     --over  
    in smooth muscle in Hirschsprung disease (HSCR) might be associated with intestinal wall remodeling in HSCR and might be one of the risk factors for gastrointestinal motor dysfunction
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neuromuscularmyopathy 
    FHL1-NFATC1-UTRN signaling axis that can functionally compensate for dystrophin and treat DMD
    ANIMAL & CELL MODELS
  • W122S mutant mice did not manifest cytoplasmic inclusions (reducing bodies) in muscle, and loss of function is responsible for the late-onset mild myopathy in the Fhl1 W122S knock-in mice