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FLASH GENE
Symbol TBX4 contributors: mct - updated : 28-01-2020
HGNC name T-box 4
HGNC id 11603
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a T-box domain, DNA-binding domain
  • a C-terminal transactivation/repression domain
    • HOMOLOGY
    interspecies homolog to murine Tbx4
    intraspecies homolog to TBX5,highly
    Homologene
    FAMILY
  • T box family
    • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • involved in the transcriptional regulation of genes required for mesoderm differentiation and the initiation of hindlimb outgrow
  • TBX4 and TBX5 play similar roles in the initiation of hindlimb and forelimb outgrowth, respectively
  • TBX5 and TBX4, two genes expressed in forelimb and hindlimb-forming regions respectively, play crucial roles in the initiation of limb outgrowth
  • is a mesenchymal transcription factor that drives accumulation of myofibroblasts and the development of lung fibrosis
  • TBX2, TBX3, TBX4, TBX5 and three members of TBX1 (TBX1, TBX15, TBX18), Brachyury (T) and Eomes (TBR2) are expressed in the developing limb
  • importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis
  • TBX4, TBX5 are thus crucial in the specification of hindlimbs and forelimbs, respectively
  • role of a TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in lung organogenesis
  • is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs
    • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS development
    text anteroposterior axis; developing hindlimb
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA binding through T-box
    RNA
    small molecule
    protein
  • ELAVL1 bind and control the FGF10 and TBX4 mRNAs
  • TBX4 and TBX5 interact with FGF10 during the process of lung growth and branching but not during tracheal/bronchial cartilage development
  • activates SHOX2 expression in fore- and hindlimbs, suggesting SHOX2 as a feedback modulator of TBX4
  • TBX4, TBX5 are both upstream regulators of FGF10 and RSPO2, which drive the outgrowth of all four limb buds
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) PTLAH , DEL17Q23 , DUP17QO , PAPPAS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional   amplification    
    familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4 (Alvarado 2010)
    constitutional germinal mutation      
    associated with childhood-onset pulmonary arterial hypertension
    constitutional germinal mutation      
    in developmental lung disease manifesting with severe, often biphasic pulmonary hypertension (PH) at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies
    Susceptibility
  • to lethal lung maldevelopment, including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD) spectrum
  • to pulmonary arterial hypertension (PAH)
    • Variant & Polymorphism other
  • SNVs or CNVs involving TBX4 in our subjects with lethal lung maldevelopment, including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD)spectrum
  • common genetic variants underlying PAH susceptibility
    • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • in mice, a homozygous Tbx4-null allele entirely abrogates hindlimb development while forelimbs remain unaffected (pMID: 31761294)