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GeneE
25 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
SIX1
SIX homeobox 1
Chromosome 14 Β· 14q23.1
NCBI Gene: 6495Ensembl: ENSG00000126778.13HGNC: HGNC:10887UniProt: Q15475
187PubMed Papers
22Diseases
0Drugs
24Pathogenic Variants
FUNCTIONAL ROLE
Transcription Factor
RESEARCH IMPACT
Trending
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
DNA bindingnucleoplasmDNA-binding transcription factor activitynucleusBranchio-otic syndromeautosomal dominant nonsyndromic hearing lossprostate carcinomabranchiootic syndrome
✦AI Summary

SIX1 is a transcription factor that plays critical dual roles in development and cancer progression. During embryonic development, SIX1 regulates organ formation including kidney, muscle, and inner ear development, often functioning through interactions with EYA family proteins 1. Mutations in SIX1 cause branchio-oto-renal syndrome, characterized by hearing loss, auricular malformations, and renal anomalies 1. In cancer contexts, SIX1 exhibits complex, context-dependent functions. It promotes tumorigenesis in breast cancer by enhancing stemness, regulating cancer stem cell markers, and controlling metabolic reprogramming through direct transcriptional activation of glycolytic genes via the Warburg effect 23. SIX1 also coordinates with HIF1A to promote triple-negative breast cancer progression 4. However, in Ewing sarcoma, SIX1 unexpectedly functions as an anti-metastatic factor by co-regulating target genes with EWS/FLI1, including integrins that control cell migration and invasion 5. Additionally, SIX1 participates in inflammatory regulation through a NIK-SIX signaling axis that provides negative feedback control of non-canonical NF-ΞΊB signaling 6. These diverse functions highlight SIX1's importance as both a developmental regulator and potential therapeutic target in cancer.

Sources cited
1
SIX1 mutations cause branchio-oto-renal syndrome and the protein functions in kidney, muscle, and inner ear development through interactions with EYA proteins
PMID: 17238186
2
SIX1 promotes breast cancer stemness, correlates with stem cell markers, and enhances tumorigenesis
PMID: 38031089
3
SIX1 directly regulates glycolytic genes to promote the Warburg effect and tumor growth in cancer
PMID: 29455928
4
SIX1 coordinates with HIF1A to promote triple-negative breast cancer progression
PMID: 38476024
5
SIX1 functions as an anti-metastatic factor in Ewing sarcoma by co-regulating genes with EWS/FLI1, including integrins
PMID: 37468459
6
SIX1 participates in a NIK-SIX signaling axis that provides negative feedback control of non-canonical NF-ΞΊB inflammatory signaling
PMID: 30894749
Disease Associationsβ“˜22
Branchio-otic syndromeOpen Targets
0.81Strong
autosomal dominant nonsyndromic hearing lossOpen Targets
0.72Strong
prostate carcinomaOpen Targets
0.50Moderate
branchiootic syndromeOpen Targets
0.50Moderate
branchio-oto-renal syndromeOpen Targets
0.49Moderate
BOR syndromeOpen Targets
0.47Moderate
isolated craniosynostosisOpen Targets
0.46Moderate
hearing lossOpen Targets
0.42Moderate
deafnessOpen Targets
0.39Weak
craniosynostosisOpen Targets
0.37Weak
colorectal adenocarcinomaOpen Targets
0.37Weak
bile duct carcinomaOpen Targets
0.37Weak
Endometrial Endometrioid AdenocarcinomaOpen Targets
0.37Weak
kidney Wilms tumorOpen Targets
0.37Weak
NephroblastomaOpen Targets
0.37Weak
nonsyndromic deafnessOpen Targets
0.37Weak
Ovarian Endometrioid Adenocarcinoma with Squamous DifferentiationOpen Targets
0.37Weak
Preauricular pitOpen Targets
0.37Weak
branchiootic syndrome 1Open Targets
0.35Weak
genetic disorderOpen Targets
0.34Weak
Branchiootic syndrome 3UniProt
Deafness, autosomal dominant, 23UniProt
Pathogenic Variants24
NM_005982.4(SIX1):c.386A>G (p.Tyr129Cys)Pathogenic
Branchiootic syndrome 3|not provided|Autosomal dominant nonsyndromic hearing loss 23|Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23;Branchiootorenal syndrome 1|Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23|SIX1-related disorder|Branchiootic syndrome|Inborn genetic diseases
β˜…β˜…β˜†β˜†2025β†’ Residue 129
NM_005982.4(SIX1):c.397_399del (p.Glu133del)Pathogenic
Autosomal dominant nonsyndromic hearing loss 23|Branchiootic syndrome 3|not provided|Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23
β˜…β˜…β˜†β˜†2025β†’ Residue 133
NM_005982.4(SIX1):c.373G>A (p.Glu125Lys)Pathogenic
Autosomal dominant nonsyndromic hearing loss 23|Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23|Branchiootic syndrome 3|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 125
NM_005982.4(SIX1):c.329G>T (p.Arg110Leu)Likely pathogenic
Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23|Branchiootic syndrome 3
β˜…β˜…β˜†β˜†2025β†’ Residue 110
NM_005982.4(SIX1):c.328C>T (p.Arg110Trp)Pathogenic
Branchiootic syndrome 3|not provided|Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23
β˜…β˜…β˜†β˜†2024β†’ Residue 110
NM_005982.4(SIX1):c.329G>A (p.Arg110Gln)Pathogenic
not provided|Branchiootic syndrome 3
β˜…β˜…β˜†β˜†2023β†’ Residue 110
NM_005982.4(SIX1):c.340A>G (p.Lys114Glu)Pathogenic
Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23
β˜…β˜†β˜†β˜†2025β†’ Residue 114
NM_005982.4(SIX1):c.522C>G (p.Asn174Lys)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 174
NM_005982.4(SIX1):c.337C>T (p.Arg113Ter)Pathogenic
Autosomal dominant nonsyndromic hearing loss 23;Branchiootic syndrome 3
β˜…β˜†β˜†β˜†2024β†’ Residue 113
NM_005982.4(SIX1):c.353C>T (p.Pro118Leu)Likely pathogenic
Autosomal dominant nonsyndromic hearing loss 23
β˜…β˜†β˜†β˜†2024β†’ Residue 118
NM_005982.4(SIX1):c.733A>G (p.Asn245Asp)Likely pathogenic
Branchiootic syndrome 3
β˜…β˜†β˜†β˜†2024β†’ Residue 245
NM_005982.4(SIX1):c.307dup (p.Leu103fs)Pathogenic
Branchiootic syndrome 3
β˜…β˜†β˜†β˜†2023β†’ Residue 103
NM_005982.4(SIX1):c.386_391del (p.Tyr129_Cys130del)Likely pathogenic
Branchiootic syndrome 3
β˜…β˜†β˜†β˜†2023β†’ Residue 129
NM_005982.4(SIX1):c.500A>G (p.Gln167Arg)Likely pathogenic
Melnick-Fraser syndrome
β˜…β˜†β˜†β˜†2022β†’ Residue 167
NM_005982.4(SIX1):c.316G>T (p.Val106Leu)Likely pathogenic
Autosomal dominant nonsyndromic hearing loss
β˜…β˜†β˜†β˜†2021β†’ Residue 106
NM_005982.4(SIX1):c.421G>T (p.Glu141Ter)Likely pathogenic
Branchiootic syndrome 3
β˜…β˜†β˜†β˜†2021β†’ Residue 141
NM_005982.4(SIX1):c.385T>C (p.Tyr129His)Likely pathogenic
Branchiootic syndrome 3;Autosomal dominant nonsyndromic hearing loss 23
β˜…β˜†β˜†β˜†β†’ Residue 129
NM_005982.4(SIX1):c.416T>G (p.Leu139Arg)Likely pathogenic
Branchiootic syndrome 3
β˜…β˜†β˜†β˜†β†’ Residue 139
NM_005982.4(SIX1):c.316G>A (p.Val106Met)Likely pathogenic
Branchiootic syndrome 3
β˜…β˜†β˜†β˜†β†’ Residue 106
NM_005982.4(SIX1):c.396G>C (p.Lys132Asn)Pathogenic
Autosomal dominant nonsyndromic hearing loss 23
β˜†β˜†β˜†β˜†2024β†’ Residue 132
View on ClinVar β†—
Related Genes
EYA3Protein interaction91%EYA4Protein interaction90%EYA2Protein interaction86%MYH3Protein interaction86%MYOD1Protein interaction86%EYA1Protein interaction81%
Tissue Expression6 tissues
Brain
100%
Lung
2%
Ovary
0%
Heart
0%
Liver
0%
Bone Marrow
0%
Gene Interaction Network
Click a node to explore
SIX1EYA3EYA4EYA2MYH3MYOD1EYA1
PROTEIN STRUCTURE
Preparing viewer…
PDB4EGC Β· 1.99 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.69LoF Tolerant
pLIβ“˜
0.26Tolerant
Observed/Expected LoF0.42 [0.26–0.69]
RankingsWhere SIX1 stands among ~20K protein-coding genes
  • #2,299of 20,598
    Most Researched187 Β· top quartile
  • #2,001of 5,498
    Most Pathogenic Variants24
  • #5,228of 17,882
    Most Constrained (LOEUF)0.69
Genes detectedSIX1
Sources retrieved25 papers
Response timeβ€”
πŸ“„ Sources
25β–Ό
1
SIX1 amplification modulates stemness and tumorigenesis in breast cancer.
PMID: 38031089
J Transl Med Β· 2023
1.00
2
Transcriptional Regulation of the Warburg Effect in Cancer by SIX1.
PMID: 29455928
Cancer Cell Β· 2018
0.90
3
PMID: 20301554
0.84
4
Generation of a humanized mesonephros in pigs from induced pluripotent stem cells via embryo complementation.
PMID: 37683604
Cell Stem Cell Β· 2023
0.80
5
CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A.
PMID: 38476024
Protein Cell Β· 2024
0.70