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Symbol SIX1 contributors: mct/npt/pgu - updated : 22-01-2014
HGNC name SIX homeobox 1
HGNC id 10887
Corresponding disease
BOR3 branchio-oto-renal syndrome 3
BOS3 branchio-otic syndrome 3
DFNA23 neurosensory deafness 23
Location 14q23.1      Physical location : 61.111.417 - 61.116.155
Synonym name sine oculis homeobox homolog 1 (Drosophila)
Synonym symbol(s) TIP39
TYPE functioning gene
STRUCTURE 4.74 kb     2 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status confirmed
Physical map
DACT1 14q22.3 dapper homolog 1, antagonist of beta-catenin (xenopus) LOC387991 14 similar to ribosomal protein L31 LOC390482 14 similar to Aldo-keto reductase family 1, member B1 PPIAP5 14 peptidylprolyl isomerase A (cyclophilin A) pseudogene 5 DAAM1 14q22.3 dishevelled associated activator of morphogenesis 1 GPR135 14q23.1 G protein-coupled receptor 135 FLJ25436 14q23.1 hypothetical protein FLJ25436 C14orf100 14q22.3 chromosome 14 open reading frame 100 RTN1 14q21-q22 reticulon 1 FLJ46156 14q23.1 FLJ46156 protein C14orf135 14q23.1 chromosome 14 open reading frame 135 DHRS7 14q23.1 dehydrogenase/reductase (SDR family) member 7 PSMA3P 14 proteasome (prosome, macropain) subunit, alpha type, 3 pseudogene PPM1A 14q22.3-q23.1 protein phosphatase 1A (formerly 2C), magnesium-dependent, alpha isoform RBM8B 14q22.1-q22.3 RNA binding motif protein 8B pseudogene C14orf39 14q23.1 chromosome 14 open reading frame 39 LOC390483 14 similar to sal-like 4 SIX6 14q22.3-q23 sine oculis homeobox homolog 6 (Drosophila) LOC387992 14 LOC387992 SIX1 14q22-q23 sine oculis homeobox homolog 1 (Drosophila) SIX4 14q23 sine oculis homeobox homolog 4 (Drosophila) MNAT1 14q23 menage a trois 1 (CAK assembly factor) MAD2L1P 14 MAD2 mitotic arrest deficient-like 1 (yeast) pseudogene SRMP2 14 spermidine synthase pseudogene 2 SLC38A6 14q23.1 solute carrier family 38, member 6 LOC161291 14q23.1 hypothetical protein LOC161291 PRKCH 14q22-q23 protein kinase C, eta HIF1A 14q21-q24 hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) SNAPC1 14q22 small nuclear RNA activating complex, polypeptide 1, 43kDa LOC122867 14q23.1 similar to cytochrome c oxidase subunit IV (COXIV) pseudogene (E.C. MOCS3P 14 molybdenum cofactor synthesis 3 pseudogene SYT14L 14q23.2 synaptotagmin XIV-like LOC390484 14 similar to ATP synthase alpha subunit KCNH5 14q23.1 potassium voltage-gated channel, subfamily H (eag-related), member 5
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
2 - 2687 - 284 - 2000 10801845
Type restricted
   expressed in (based on citations)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Muscularstriatumskeletal   Mus musculus
cell lineage
cell lines
physiological period fetal, pregnancy
Text during development in limb tendons
  • six domains and a helix-turn-helix DNA (homeo) binding domain
  • conjugated PhosphoP
    interspecies homolog to Drosophila sine oculis homeobox SIX1
  • six/sine oculis homeobox family
  • CATEGORY motor/contractile
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • may be involved in limb tendon and ligament development
  • required for the primary myogenesis
  • nuclear phosphoprotein, hyperphosphorylated by CK2 and implicated in cancer and in cell cycle control
  • SIX1 and SIX4 may act synergistically to mediate olfactory placode specification and patterning through FGF and BMP signaling pathways
  • essential function in the MM (metanephric mesenchyme) as an upstream regulator of GREM1 in initiating branching morphogenesis
  • plays important roles in proliferation, differentiation and survival of precursor cells of different organs
  • critical coordinator of SHH-FGF10 signaling during embryonic lung development, and critical for coordination of proper lung epithelial, mesenchymal and vascular development
  • critical regulator of embryonic development that requires interaction with the EYA family of proteins
  • SIX1 and SIX4 are essential global regulators of muscle gene expression, as well as a central switch to drive the skeletal muscle fast phenotype during fetal development
  • SIX1 and SIX4 function synergistically to form gustatory papillae during development of the tongue
  • upon loss of EZH2, SIX1 might activate transcription of a subset of skeletal muscle genes in cardiomyocytes, contributing to instability of cardiac gene expression
  • EZH2 modulates a feed-forward pathway that represses fetal gene expression and is reinforced by repression of SIX1
  • EYA1 and SIX1 are key transcription factors in initiating the neuronal developmental program, probably by recruiting and interacting with the SWI/SNF chromatin-remodeling complex to specifically mediate NEUROG1 and NEUROD1 transcription
  • SIX1 homeoproteins act as a rheostat system to ensure proper regeneration of the tissue and replenishment of the stem cell pool during the events that follow skeletal muscle trauma
  • may play an important role in adult myogenesis, in addition to its role in embryonic muscle formation
  • SIX1 and SIX4 are required for male gonadal differentiation
  • combinatorial expression of SIX1, SIX2, and SIX4 is required for the molecular programs governing craniofacial and cerebral development
  • EYA1 and SIX1 as key components of the SHH transcriptional network in normal development and in oncogenesis
    a component
  • EYA2-SIX1 complex binds to and enhances the expression of MTOR in a synergistic manner
    DNA DNA binding
    small molecule
  • EYA1 and DACH1, mediated by CREBBP(regulating precursor cell proliferation and survival during oganogenesis)
  • target of CK2 in G(2)/M checkpoint control and both molecules participate in the same pathway whose dysregulation leads to cancer
  • SIX1 and SIX4 regulate SLC12A2
  • SIX4 cooperates with SIX1 in the metanephric mesenchyme to regulate the level of GDNF expression
  • SKI is necessary for muscle terminal differentiation and it exerts this role, at least in part, through its association with SIX1 and EYA3 to regulate the MYOG transcription
  • neural crest specifier activity of GBX2 is dependent on the interaction with ZIC1 and the inhibition of preplacodal genes such as SIX1
  • EYA3 and its partner SIX1 synergistically activate TSHB expression (TSHB plays a key role in the pathway that regulates vertebrate photoperiodism)
  • SIX1 and TBX18 genetically interact to synergistically regulate smooth muscle cells development and ureter function
  • is dependent on EYA2 to mediate numerous pro-metastatic characteristics
  • EYA2 in a physical complex with SIX1 plays a critical role in physiological hypertrophy of heart
  • EZH2-mediated repression of SIX1 in differentiating cardiac progenitors is essential for stable gene expression and homeostasis in the postnatal heart
  • transcription factor essential for embryonic myogenesis, also regulating MYOD1 expression in muscle progenitor cells
  • HDAC5 promoted hepatocellular carcinoma cell proliferation through up-regulation of SIX1 expression
  • catalytically active phosphatase EYA1 cooperates with the DNA-binding protein SIX1 to promote gene induction in response to SHH and EYA1/SIX1 together regulate GLI transcriptional activators
  • cell & other
    corresponding disease(s) BOS3 , DFNA23 , BOR3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in metastatic rhabdomyosarcoma
    constitutional     --over  
    can attenuate a DNA damage-induced G(2) cell cycle checkpoint
    tumoral     --low  
    in 44 p100 of primary breast cancers and 90 p100 of metastatic lesions
    tumoral     --over  
    in osteosarcoma cell lines compared to human osteoblastic cell line
    Variant & Polymorphism
    Candidate gene
    Therapy target
    inhibition of SIX1 promotes apoptosis, suppresses proliferation, and migration of osteosarcoma cells
  • Six1-deficient mice lack kidneys, but form ureters
  • Six1(-/-) embryos and newborn mice exhibit mesenchymal overproliferation, decreased Fgf10 expression and severe defects in the smooth muscle component of the bronchi and major pulmonary vessels