SIX1

Summary

SIX1 (SIX homeobox 1, HGNC:10887) is a protein-coding gene on chromosome 14q23.1, encoding Homeobox protein SIX1 (Q15475). Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development.

The protein encoded by this gene is a homeobox protein that is similar to the Drosophila ‘sine oculis’ gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3).

Source: NCBI Gene 6495 — RefSeq curated summary.

At a glance

• Gene–disease (curated): branchio-oto-renal syndrome (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 258 total — 9 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Transcription factor: yes — 19 downstream targets (CollecTRI)
• MANE Select transcript: NM_005982

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10887
Approved symbol	SIX1
Name	SIX homeobox 1
Location	14q23.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000126778
Ensembl biotype	protein_coding
OMIM	601205
Entrez	6495

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000553535, ENST00000554986, ENST00000555627, ENST00000555955, ENST00000645694, ENST00000949515

RefSeq mRNA: 2 — MANE Select: NM_005982 NM_001425142, NM_005982

CCDS: CCDS9748

Canonical transcript exons

ENST00000645694 — 2 exons

Exon	Start	End
ENSE00003815735	60643421	60646577
ENSE00003825363	60648630	60649477

Expression profiles

Bgee: expression breadth ubiquitous, 188 present calls, max score 98.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.4358 / max 396.1017, expressed in 1195 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143514	16.4141	1181
143513	0.9300	453
143516	0.0491	22
143515	0.0426	12

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.40	gold quality
biceps brachii	UBERON:0001507	98.19	gold quality
parotid gland	UBERON:0001831	98.08	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.06	gold quality
bronchial epithelial cell	CL:0002328	96.44	gold quality
vastus lateralis	UBERON:0001379	95.64	gold quality
body of tongue	UBERON:0011876	95.12	gold quality
quadriceps femoris	UBERON:0001377	94.76	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.65	gold quality
skeletal muscle tissue	UBERON:0001134	94.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.40	gold quality
triceps brachii	UBERON:0001509	94.27	gold quality
palpebral conjunctiva	UBERON:0001812	94.09	gold quality
muscle organ	UBERON:0001630	93.90	gold quality
muscle of leg	UBERON:0001383	93.40	gold quality
epithelium of bronchus	UBERON:0002031	93.12	gold quality
gastrocnemius	UBERON:0001388	93.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.01	gold quality
bronchus	UBERON:0002185	92.85	gold quality
nasal cavity mucosa	UBERON:0001826	92.65	gold quality
deltoid	UBERON:0001476	92.14	gold quality
calcaneal tendon	UBERON:0003701	91.54	gold quality
tendon	UBERON:0000043	91.17	gold quality
synovial joint	UBERON:0002217	91.10	gold quality
buccal mucosa cell	CL:0002336	91.01	gold quality
gluteal muscle	UBERON:0002000	90.76	gold quality
diaphragm	UBERON:0001103	90.13	gold quality
pituitary gland	UBERON:0000007	89.49	gold quality
tendon of biceps brachii	UBERON:0008188	89.03	gold quality
nasal cavity epithelium	UBERON:0005384	88.27	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	439.01
E-GEOD-124472	yes	265.19
E-HCAD-10	yes	46.18
E-ANND-3	yes	10.48
E-MTAB-8060	no	52.98

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

19 targets.

Target	Regulation
ATOH1	Activation
BMP4	Activation
CCNA1	Activation
CCND1	Unknown
CDH1	Repression
EYA1
EYA2
EZR	Activation
FGF10	Activation
MYOD1
MYOG	Activation
PTH2R
SALL1
SIX1
SKI
TGFBR1
TSHB
VEGFC	Activation
ZEB1	Activation

JASPAR motifs

Motif	Name	Family
MA1118.1	SIX1	HD-SINE
MA1118.2	SIX1	HD-SINE

JASPAR matrix evidence (PMIDs): PMID:9826681

Upstream regulators (CollecTRI, top): FOXI1, MYOD1, PAX2, SIX1

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Six1 overexpression reinstates an embryonic pathway of proliferation in breast cancer by up-regulating cyclin A1 (PMID:15123840)
• Identification of SIX1 mutations as causing branchio-oto-renal syndrome offers insights into the molecular basis of otic and renal developmental diseases in humans (PMID:15141091)
• SIX1 mutation may cause the enlargement of the vestibular aqueduct in patients diagnosed with branchio-oto syndrome. (PMID:16652090)
• SALL1 is a likely target gene for SIX1 during kidney development (PMID:16670092)
• Results showed that Six1 is frequently overexpressed in hepatocellular carcinoma (HCC) patients and elevated Six1 protein in HCC patients may be an indication of advanced stage and poor overall survival after hepatectomy. (PMID:17008870)
• Cell cycle regulation of Six1 occurs both transcriptionally and post-translationally via phosphorylation (PMID:17130831)
• CSRP3, MUSTN1, SIX1, and FBXO32 expression changes in response to lengthening and shortening contractions in human muscle (PMID:17519359)
• A novel SIX1 mutation suggests a slightly different clinical profile compared to EYA1-related branchio-oto-renal syndrome. (PMID:17637804)
• screen of 247 branchio-oto-renal syndrome families detected five novel SIX1 mutations (c.50T>A, c.218A>C, c.317T>G, c.329G>A, c.334C>T) and one previously reported mutation (c.328C>T) seen in 5 unrelated families (PMID:18330911)
• Six1 overexpression is sufficient for malignant transformation of immortalized, nontumorigenic mammary epithelial cells, and suggest that the mechanism of this transformation involves inappropriate reexpression of cyclin A1 in the adult mammary gland. (PMID:18381426)
• Microarray studies show that our in vitro model system reflects many cellular and molecular alterations characteristic of cervical cancer, and identified SIX1 and GDF15 as 2 novel potential biomarkers of cervical cancer progression. (PMID:18398830)
• BOR and OAVS features are associated with duplication of SIX1, SIX6 and OTX2 resulting from a complex chromosomal rearrangement. (PMID:18666230)
• Exposure to lithium chloride or sodium valproate elicited an increase in 936 changes in gene expression, with a 31.3-fold increase in the expression of Six1. (PMID:19101580)
• The data suggest that Ezrin, but not CD44 and Six1, could be a prognostic factor and a predictor of potential lung metastasis in osteosarcoma. (PMID:19331807)
• SIX1 Branchio-oto-renal syndrome mutations contribute to the pathology of the disease through at least two different mechanisms that involve: 1) abolishing the formation of the SIX1-EYA complex or 2) diminishing the ability of SIX1 to bind DNA. (PMID:19497856)
• misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner (PMID:19726883)
• Six1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis. (PMID:19726885)
• Findings identify a role of EYA4 and possibly interacting SIX and DACH proteins in MPNSTs and suggest the EYA4 pathway as a rational therapeutic target. (PMID:19901965)
• Over expression of Six1 is associated with hepatocellular carcinoma. (PMID:20013809)
• Altered expression of the novel tumor suppressor miR-185 may be one of the central events that leads to dysregulation of oncogenic protein Six1 in human cancers. (PMID:20603620)
• Study reports a screening of 140 patients from 124 families with Branchio-oto-renal and identified 36 EYA1 mutations in 42 unrelated patients, 2 mutations, and 1 change of unknown significance in SIX1 in 3 unrelated patients, but no mutation in SIX5. (PMID:21280147)
• Six1 was overexpressed in cervical cancer cell lines and in cervical cancer tissues. Alteration of Six1 expression might contribute to the occurrence and development of cervical cancer. (PMID:21370601)
• SIX1 is significantly associated with open-angle glaucoma. (PMID:21427129)
• Identification of a novel mutation in SIX1 (p.E125K) in a Tunisian family with variable hearing impairment and preauricular pits. (PMID:21700001)
• Data implicate Eya2 as a necessary co-factor for many of the metastasis promoting functions of Six1. (PMID:21706047)
• Data show that lesser differentiated tumors had elevated expression of Six1 and Ezrin mRNA and protein. (PMID:21874375)
• An exception is the predominant expression of SIX1 in blastemal cells, hereby identifying this protein as a candidate marker for blastema. (PMID:22180226)
• Paired upregulation of Notch2 and Six1 is a transcriptional aberration that contributes to preinvasive-to-invasive adenocarcinoma progression by inducing epithelial-mesenchymal transition and nuclear atypia. (PMID:22190591)
• SIX1 overexpression contributes to epithelial-mesenchymal transition partly through repression of miR-200-family expression and activation of ZEB1 in colorectal cancer. (PMID:22286765)
• It is required downstream of Six1 to induce these phenotypes. (PMID:22286770)
• In East Asian populations, a SIX1 mutation has been reported in a Japanese family with branchio-oto (BO) syndrome. (PMID:22447252)
• A critical role for SIX1 in lymphatic dissemination of breast cancer cells, providing a direct mechanistic explanation for how VEGF-C expression is upregulated in breast cancer. (PMID:22466647)
• Six1 plays an important role in the TIC population in luminal breast cancers and induces a TIC phenotype by enhancing both TGF-beta and ERK signaling. (PMID:22765220)
• The identification of SIX1 and CDKN2B variant was found to be associated more strongly with advanced open-angle glaucoma. (PMID:22840486)
• Given that SIX1 and EYA are overexpressed in many tumor types, our data indicate that targeting the SIX1-EYA complex may be a potent approach to inhibit tumor progression in multiple cancer types (PMID:23435380)
• Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. (PMID:23527134)
• data suggested that Six1 might be involved in the promotion of growth, proliferation, and migration of osteosarcoma cell lines (PMID:24114014)
• these data suggest that Six1 may function as an important modifier of the paclitaxel response in breast cancer cells, and serve as a potential target for overcoming paclitaxel resistance in breast cancer. (PMID:24184484)
• SIX1 overexpression is associated with pancreatic ductal adenocarcinoma. (PMID:24263054)
• In breast phyllodes tumors, Six1 and Pax3 expression is correlated with tumour grade, unfavourable clinicopathological parameters and poorer clinical outcome, suggesting that both proteins may play a role in malignant progression. (PMID:24438019)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	six1b	ENSDARG00000026473
danio_rerio	six1a	ENSDARG00000039304
mus_musculus	Six1	ENSMUSG00000051367
rattus_norvegicus	Six1	ENSRNOG00000022777
drosophila_melanogaster	so	FBGN0003460

Paralogs (6): SIX4 (ENSG00000100625), SIX3 (ENSG00000138083), SIX2 (ENSG00000170577), SIX5 (ENSG00000177045), SIX6 (ENSG00000184302), ANHX (ENSG00000227059)

Protein

Protein identifiers

Homeobox protein SIX1 — Q15475 (reviewed: Q15475)

Alternative names: Sine oculis homeobox homolog 1

All UniProt accessions (2): Q15475, H0YK85

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development. Plays an important role in the development of several organs, including kidney, muscle and inner ear. Depending on context, functions as a transcriptional repressor or activator. Lacks an activation domain, and requires interaction with EYA family members for transcription activation. Mediates nuclear translocation of EYA1 and EYA2. Binds the 5’-TCA[AG][AG]TTNC-3’ motif present in the MEF3 element in the MYOG promoter and CIDEA enhancer. Regulates the expression of numerous genes, including MYC, CCND1 and EZR. Acts as an activator of the IGFBP5 promoter, probably coactivated by EYA2. Repression of precursor cell proliferation in myoblasts is switched to activation through recruitment of EYA3 to the SIX1-DACH1 complex. During myogenesis, seems to act together with EYA2 and DACH2. Regulates the expression of CCNA1. Promotes brown adipocyte differentiation.

Subunit / interactions. Interacts with DACH1. Interacts with EYA1. Interacts with EYA2. Interacts with CDH1. Interacts with TBX18. Interacts with CEBPA. Interacts with CEBPB. Interacts with EBF2.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Specifically expressed in skeletal muscle.

Post-translational modifications. Phosphorylated during interphase; becomes hyperphosphorylated during mitosis. Hyperphosphorylation impairs binding to promoter elements. Ubiquitinated by the anaphase promoting complex (APC), leading to its proteasomal degradation.

Disease relevance. Deafness, autosomal dominant, 23 (DFNA23) [MIM:605192] A form of non-syndromic deafness characterized by prelingual, bilateral, symmetric hearing loss with a conductive component present in some but not all patients. The disease is caused by variants affecting the gene represented in this entry. Branchiootic syndrome 3 (BOS3) [MIM:608389] A syndrome characterized by usually bilateral branchial cleft fistulas or cysts, sensorineural and/or conductive hearing loss, pre-auricular pits, and structural defects of the outer, middle or inner ear. Otic defects include malformed and hypoplastic pinnae, a narrowed external ear canal, bulbous internal auditory canal, stapes fixation, malformed and hypoplastic cochlea. Branchial and otic anomalies overlap with those seen in individuals with the branchiootorenal syndrome. However renal anomalies are absent in branchiootic syndrome patients. The disease is caused by variants affecting the gene represented in this entry. Defects in SIX1 could be a cause of branchiootorenal syndrome (BOR). BOR is an autosomal dominant disorder manifested by various combinations of preauricular pits, branchial fistulae or cysts, lacrimal duct stenosis, hearing loss, structural defects of the outer, middle, or inner ear, and renal dysplasia. Associated defects include asthenic habitus, long narrow facies, constricted palate, deep overbite, and myopia. Hearing loss may be due to mondini type cochlear defect and stapes fixation. Penetrance of BOR syndrome is high, although expressivity can be extremely variable.

Similarity. Belongs to the SIX/Sine oculis homeobox family.

RefSeq proteins (2): NP_001412071, NP_005973* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR008422	KN_HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR031701	SIX1_SD	Domain

Pfam: PF05920, PF16878

UniProt features (26 total): sequence variant 11, helix 10, compositionally biased region 2, chain 1, DNA-binding region 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4EGC	X-RAY DIFFRACTION	1.99

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15475-F1	76.87	0.54

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9830674	Formation of the ureteric bud
R-HSA-1266738	Developmental Biology
R-HSA-9830369	Kidney development

MSigDB gene sets: 558 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_URETER_DEVELOPMENT, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, WWTAAGGC_UNKNOWN, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, GOBP_METANEPHROS_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT

GO Biological Process (66): negative regulation of transcription by RNA polymerase II (GO:0000122), ureteric bud development (GO:0001657), branching involved in ureteric bud morphogenesis (GO:0001658), organ induction (GO:0001759), kidney development (GO:0001822), outflow tract morphogenesis (GO:0003151), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), Notch signaling pathway (GO:0007219), pattern specification process (GO:0007389), skeletal muscle tissue development (GO:0007519), sensory perception of sound (GO:0007605), regulation of synaptic assembly at neuromuscular junction (GO:0008582), gene expression (GO:0010467), neural crest cell differentiation (GO:0014033), regulation of skeletal muscle satellite cell proliferation (GO:0014842), regulation of skeletal muscle cell proliferation (GO:0014857), facial nerve morphogenesis (GO:0021610), epithelial cell differentiation (GO:0030855), thyroid gland development (GO:0030878), olfactory placode formation (GO:0030910), regulation of protein localization (GO:0032880), protein localization to nucleus (GO:0034504), aorta morphogenesis (GO:0035909), inner ear morphogenesis (GO:0042472), middle ear morphogenesis (GO:0042474), negative regulation of neuron apoptotic process (GO:0043524), regulation of neuron differentiation (GO:0045664), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), thymus development (GO:0048538), neuron fate specification (GO:0048665), generation of neurons (GO:0048699), embryonic cranial skeleton morphogenesis (GO:0048701), embryonic skeletal system morphogenesis (GO:0048704), skeletal muscle fiber development (GO:0048741), inner ear development (GO:0048839), regulation of epithelial cell proliferation (GO:0050678), myoblast proliferation (GO:0051450)

GO Molecular Function (11): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Kidney development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
binding	2
nuclear lumen	2
negative regulation of DNA-templated transcription	1
mesonephric tubule development	1
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
regulation of animal organ formation	1
specification of animal organ identity	1
developmental induction	1
positive regulation of animal organ morphogenesis	1
animal organ development	1
renal system development	1
heart morphogenesis	1
anatomical structure morphogenesis	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell surface receptor signaling pathway	1
multicellular organism development	1
multicellular organismal process	1
striated muscle tissue development	1
skeletal muscle organ development	1
sensory perception of mechanical stimulus	1
regulation of developmental growth	1
synaptic assembly at neuromuscular junction	1
regulation of synapse assembly	1
regulation of neuromuscular junction development	1
macromolecule biosynthetic process	1
mesenchymal cell differentiation	1
stem cell differentiation	1
skeletal muscle satellite cell proliferation	1
regulation of skeletal muscle cell proliferation	1

Protein interactions and networks

STRING

1852 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIX1	EYA1	Q99502	986
SIX1	EYA2	O00167	964
SIX1	DACH1	Q9UI36	937
SIX1	PAX3	P23760	920
SIX1	MYOG	P15173	851
SIX1	EYA3	Q99504	848
SIX1	MYOD1	P15172	846
SIX1	PAX2	Q02962	832
SIX1	SALL1	Q9NSC2	807
SIX1	MYF5	P13349	803
SIX1	PAX7	P23759	744
SIX1	KAT7	O95251	729
SIX1	NCOA3	Q9Y6Q9	719
SIX1	MEOX1	P50221	707
SIX1	LBX1	P52954	704
SIX1	MSX1	P28360	704

IntAct

58 interactions, top by confidence:

A	B	Type	Score
SIX1	EYA1	psi-mi:“MI:0915”(physical association)	0.740
SIX1	TLE5	psi-mi:“MI:0915”(physical association)	0.720
TLE5	SIX1	psi-mi:“MI:0915”(physical association)	0.720
SIX1	EYA2	psi-mi:“MI:0407”(direct interaction)	0.690
EYA2	SIX1	psi-mi:“MI:0915”(physical association)	0.690
H2AP	SIX1	psi-mi:“MI:0915”(physical association)	0.670
P4HA3	FAM171A2	psi-mi:“MI:0914”(association)	0.640
SIX1	TLE5	psi-mi:“MI:0915”(physical association)	0.560
TLE5	SIX1	psi-mi:“MI:0915”(physical association)	0.560
EYA2	SIX1	psi-mi:“MI:0407”(direct interaction)	0.560
POU6F2	SIX1	psi-mi:“MI:0915”(physical association)	0.560
REL	SIX1	psi-mi:“MI:0915”(physical association)	0.560
TLE3	SIX1	psi-mi:“MI:0915”(physical association)	0.560
SIX1	PLEKHG4	psi-mi:“MI:0915”(physical association)	0.560
EYA2	SIX1	psi-mi:“MI:0915”(physical association)	0.560
ERCC6L	CHEK1	psi-mi:“MI:0914”(association)	0.530
SMC1A	PDS5B	psi-mi:“MI:0914”(association)	0.530
MDFI	SIX1	psi-mi:“MI:0915”(physical association)	0.510
SIX1	MDFI	psi-mi:“MI:0915”(physical association)	0.510
SIX1	TTC9C	psi-mi:“MI:0915”(physical association)	0.400
SIX1	VTN	psi-mi:“MI:0915”(physical association)	0.370
SIX1	CCDC85B	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (67): SIX1 (Two-hybrid), EYA4 (Affinity Capture-MS), EYA1 (Affinity Capture-MS), MYH3 (Affinity Capture-MS), MYH7 (Affinity Capture-MS), MYH4 (Affinity Capture-MS), SIX1 (Two-hybrid), CCDC85B (Two-hybrid), SIX1 (Affinity Capture-Western), SIX1 (Two-hybrid), SIX1 (Affinity Capture-MS), SIX1 (Affinity Capture-MS), AES (Two-hybrid), EYA1 (Affinity Capture-MS), EYA4 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M9QN10, A1YER0, A2ARM1, A2D5H2, E9Q0S6, O35260, O42406, O43147, O54943, O73916, O93307, O95343, O95475, P12813, P20263, P49335, P59729, Q13009, Q15475, Q1LVK9, Q5PQS0, Q5PRF9, Q5SXA9, Q5U464, Q62231, Q62232, Q62233, Q64249, Q6DHF9, Q6NXJ0, Q6NZ04, Q6TNU3, Q6ZUJ8, Q7TSI1, Q7TSZ8, Q80TC6, Q80XS6, Q8K3T2, Q8WYP3, Q91474

Diamond homologs: A1YER0, A2D5H2, A6NDR6, A8K0S8, A8WL06, B3DM47, B4F6V6, O00470, O04134, O04135, O14770, O17894, O22299, O35317, O35984, O42406, O46339, O65034, O73916, O80416, O93307, O95343, O95475, P10842, P24345, P40424, P40425, P40426, P40427, P41778, P41779, P41817, P46608, P46609, P46639, P46640, P48731, P53147, P56661, P56662

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
SIX1	“up-regulates quantity”	EZR	“transcriptional regulation”
SIX1	“up-regulates quantity by expression”	MYOG	“transcriptional regulation”
SIX1	“form complex”	Six1/Dach	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
DNA repair	5	10.6×	3e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — WT.

Clinical variants and AI predictions

ClinVar

258 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	12
Uncertain significance	146
Likely benign	46
Benign	11

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1327579	NM_005982.4(SIX1):c.396G>C (p.Lys132Asn)	Pathogenic
2503043	NM_005982.4(SIX1):c.307dup (p.Leu103fs)	Pathogenic
2953157	NM_005982.4(SIX1):c.340A>G (p.Lys114Glu)	Pathogenic
3757320	NM_005982.4(SIX1):c.337C>T (p.Arg113Ter)	Pathogenic
420132	NM_005982.4(SIX1):c.329G>A (p.Arg110Gln)	Pathogenic
4830138	NM_005982.4(SIX1):c.227C>A (p.Ser76Ter)	Pathogenic
8308	NM_005982.4(SIX1):c.386A>G (p.Tyr129Cys)	Pathogenic
8309	NM_005982.4(SIX1):c.328C>T (p.Arg110Trp)	Pathogenic
8311	NM_005982.4(SIX1):c.364T>A (p.Trp122Arg)	Pathogenic
1202646	NM_005982.4(SIX1):c.316G>A (p.Val106Met)	Likely pathogenic
1327912	NM_005982.4(SIX1):c.316G>T (p.Val106Leu)	Likely pathogenic
1517704	NM_005982.4(SIX1):c.329G>T (p.Arg110Leu)	Likely pathogenic
189222	NM_005982.4(SIX1):c.560+1G>C	Likely pathogenic
2503044	NM_005982.4(SIX1):c.386_391del (p.Tyr129_Cys130del)	Likely pathogenic
3066285	NM_005982.4(SIX1):c.421G>T (p.Glu141Ter)	Likely pathogenic
3068253	NM_005982.4(SIX1):c.733A>G (p.Asn245Asp)	Likely pathogenic
3250399	NM_005982.4(SIX1):c.353C>T (p.Pro118Leu)	Likely pathogenic
3356413	NM_005982.4(SIX1):c.301del (p.Arg101fs)	Likely pathogenic
3382037	NM_005982.4(SIX1):c.385T>C (p.Tyr129His)	Likely pathogenic
417916	NM_005982.4(SIX1):c.460A>T (p.Lys154Ter)	Likely pathogenic
974692	NM_005982.4(SIX1):c.416T>G (p.Leu139Arg)	Likely pathogenic

SpliceAI

392 predictions. Top by Δscore:

Variant	Effect	Δscore
14:60648591:T:TA	donor_gain	0.9900
14:60648624:GCGTA:G	donor_loss	0.9900
14:60648625:CGTA:C	donor_loss	0.9900
14:60648626:GTA:G	donor_loss	0.9900
14:60648627:TA:T	donor_loss	0.9900
14:60648628:A:AT	donor_loss	0.9900
14:60648629:C:CT	donor_loss	0.9900
14:60648633:T:A	donor_gain	0.9900
14:60646574:CTCC:C	acceptor_gain	0.9800
14:60646578:C:CC	acceptor_gain	0.9800
14:60646576:CCCTA:C	acceptor_loss	0.9700
14:60646577:CCTAA:C	acceptor_loss	0.9700
14:60646578:CTA:C	acceptor_loss	0.9700
14:60646579:T:A	acceptor_loss	0.9700
14:60646576:CC:C	acceptor_gain	0.9600
14:60646577:CC:C	acceptor_gain	0.9600
14:60648447:G:C	donor_gain	0.9400
14:60648441:T:TA	donor_gain	0.9200
14:60643622:C:CT	acceptor_gain	0.9000
14:60646585:A:C	acceptor_gain	0.9000
14:60648673:TAA:T	donor_gain	0.9000
14:60648674:AAA:A	donor_gain	0.9000
14:60648474:T:A	donor_gain	0.8800
14:60646573:TCTCC:T	acceptor_gain	0.8700
14:60646574:CTCCC:C	acceptor_gain	0.8700
14:60646575:TCC:T	acceptor_gain	0.8700
14:60646575:TCCCT:T	acceptor_gain	0.8700
14:60646576:CCC:C	acceptor_gain	0.8700
14:60643623:G:T	acceptor_gain	0.8600
14:60647472:C:A	donor_gain	0.8600

AlphaMissense

1839 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:60648648:G:T	A181D	1.000
14:60648651:C:A	R180L	1.000
14:60648651:C:G	R180P	1.000
14:60648651:C:T	R180Q	1.000
14:60648652:G:A	R180W	1.000
14:60648652:G:C	R180G	1.000
14:60648655:C:G	D179H	1.000
14:60648656:T:A	R178S	1.000
14:60648656:T:G	R178S	1.000
14:60648657:C:A	R178I	1.000
14:60648657:C:G	R178T	1.000
14:60648658:T:C	R178G	1.000
14:60648659:T:A	Q177H	1.000
14:60648659:T:G	Q177H	1.000
14:60648660:T:G	Q177P	1.000
14:60648662:C:A	R176S	1.000
14:60648662:C:G	R176S	1.000
14:60648663:C:A	R176M	1.000
14:60648663:C:G	R176T	1.000
14:60648663:C:T	R176K	1.000
14:60648664:T:A	R176W	1.000
14:60648664:T:C	R176G	1.000
14:60648666:C:G	R175P	1.000
14:60648667:G:C	R175G	1.000
14:60648668:G:C	N174K	1.000
14:60648668:G:T	N174K	1.000
14:60648669:T:A	N174I	1.000
14:60648669:T:C	N174S	1.000
14:60648669:T:G	N174T	1.000
14:60648670:T:C	N174D	1.000

dbSNP variants (sampled 300 via entrez): RS1001409064 (14:60649081 G>A,C), RS1001857703 (14:60649917 C>A,G,T), RS1002175223 (14:60649365 C>A,T), RS1002436790 (14:60649509 C>T), RS1002672851 (14:60644414 G>A), RS1002743933 (14:60642966 A>C,G), RS1003151328 (14:60644110 A>G), RS1003166994 (14:60649725 G>A), RS1003590047 (14:60645618 T>C), RS1003844969 (14:60644891 C>A,T), RS1003902643 (14:60651144 A>G), RS1003972129 (14:60645203 TA>T,TAA), RS1005556303 (14:60644939 C>T), RS1005667776 (14:60645179 TTAAG>T), RS1005818788 (14:60647107 G>A,C)

Disease associations

OMIM: gene MIM:601205 | disease phenotypes: MIM:605192, MIM:608389, MIM:124900, MIM:113650, MIM:602588

GenCC curated gene-disease

Disease	Classification	Inheritance
branchio-oto-renal syndrome	Definitive	Autosomal dominant
branchiootic syndrome 3	Definitive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss 23	Definitive	Autosomal dominant
branchiootic syndrome	Supportive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
branchio-oto-renal syndrome	Definitive	AD

Mondo (8): autosomal dominant nonsyndromic hearing loss 23 (MONDO:0011519), branchiootic syndrome 3 (MONDO:0012025), hearing loss disorder (MONDO:0005365), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), branchiootorenal syndrome 1 (MONDO:0007236), branchiootic syndrome 1 (MONDO:0011258), branchiootic syndrome (MONDO:0018878), branchio-oto-renal syndrome (MONDO:0007029)

Orphanet (3): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), BOR syndrome (Orphanet:107), Branchiootic syndrome (Orphanet:52429)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000074	Ureteropelvic junction obstruction
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000110	Renal dysplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000324	Facial asymmetry
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000359	Abnormality of the inner ear
HP:0000365	Hearing impairment
HP:0000370	Abnormality of the middle ear
HP:0000376	Incomplete partition of the cochlea type II
HP:0000377	Abnormal pinna morphology
HP:0000378	Cupped ear
HP:0000384	Preauricular skin tag
HP:0000394	Lop ear
HP:0000402	Stenosis of the external auditory canal
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000658_2	Optic nerve measurement (rim area)	9.000000e-06
GCST000700_1	Vertical cup-disc ratio	1.000000e-11
GCST001451_3	Glaucoma (primary open-angle)	9.000000e-08
GCST001493_4	Glaucoma (primary open-angle)	4.000000e-11
GCST002606_3	Prostate cancer	2.000000e-09
GCST002626_12	Vertical cup-disc ratio	2.000000e-16
GCST003875_13	Gut microbiota (bacterial taxa)	3.000000e-09
GCST005919_2	Exhaled carbon monoxide levels in smokers with chronic obstructive pulmonary disease	6.000000e-08
GCST006065_44	Glaucoma (primary open-angle)	8.000000e-24
GCST006066_6	Glaucoma (primary open-angle)	6.000000e-13
GCST006067_7	Glaucoma (primary open-angle)	4.000000e-13
GCST008839_119	Height	2.000000e-25
GCST009462_66	Optic disc size	3.000000e-21
GCST009722_9	Glaucoma (multi-trait analysis)	6.000000e-17
GCST009726_19	Glaucoma	6.000000e-12
GCST010002_153	Refractive error	2.000000e-40
GCST90020028_1865	Hip circumference adjusted for BMI	6.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0007883	taxonomic microbiome measurement
EFO:0006520	carbon monoxide exhalation measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D019280	Branchio-Oto-Renal Syndrome	C16.131.077.208; C16.131.260.090; C16.320.180.090
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C564248	Branchiootic Syndrome 3 (supp.)
C537104	Branchiootic syndrome (supp.)
C565357	Deafness, Autosomal Dominant 23 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630826 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, increases expression, increases response to substance, affects expression	9
trichostatin A	affects cotreatment, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
mercuric bromide	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
A-485 compound	decreases reaction, increases expression	1
methylmercuric chloride	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
arsenite	increases reaction, affects binding	1
sodium arsenite	affects methylation	1
vanadyl sulfate	decreases expression	1
diallyl trisulfide	decreases expression	1
15-acetyldeoxynivalenol	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	decreases expression, affects binding	1
Temozolomide	increases expression	1
Amiodarone	increases expression	1
Antimycin A	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Copper	affects binding, decreases expression	1
Demecolcine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4604658	Binding	Inhibition of SIX1 in human C33A cells at 2 to 4 uM after 48 hrs by Western blot analysis	The Marine Natural Product Manzamine A Inhibits Cervical Cancer by Targeting the SIX1 Protein. — J Nat Prod

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6E5	SEES3-1V human SIX1, clone1	Embryonic stem cell	Male
CVCL_A6E6	SEES3-1V human SIX1, clone2	Embryonic stem cell	Male
CVCL_A6E7	SEES3-1V human SIX1, clone3	Embryonic stem cell	Male
CVCL_E0V0	Ubigene Hep G2 SIX1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss