SIX3

Summary

SIX3 (SIX homeobox 3, HGNC:10889) is a protein-coding gene on chromosome 2p21, encoding Homeobox protein SIX3 (O95343). Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2.

Source: NCBI Gene 6496 — RefSeq curated summary.

At a glance

• Gene–disease (curated): holoprosencephaly 2 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 44
• Clinical variants (ClinVar): 269 total — 20 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 142
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 12 downstream targets (CollecTRI)
• MANE Select transcript: NM_005413

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10889
Approved symbol	SIX3
Name	SIX homeobox 3
Location	2p21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000138083
Ensembl biotype	protein_coding
OMIM	603714
Entrez	6496

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000260653

RefSeq mRNA: 1 — MANE Select: NM_005413 NM_005413

CCDS: CCDS1821

Canonical transcript exons

ENST00000260653 — 2 exons

Exon	Start	End
ENSE00000809780	44941702	44942910
ENSE00001005777	44944568	44946071

Expression profiles

Bgee: expression breadth broad, 92 present calls, max score 97.37.

FANTOM5 (CAGE): breadth broad, TPM avg 7.0772 / max 301.7540, expressed in 439 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20016	1.4272	261
20014	1.3515	271
20023	0.9014	226
20018	0.8891	269
20020	0.6511	219
20017	0.5476	192
20015	0.2957	162
20022	0.2921	137
20024	0.1350	70
20021	0.1325	85

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	97.37	gold quality
retina	UBERON:0000966	97.35	gold quality
nasal cavity epithelium	UBERON:0005384	92.97	gold quality
nucleus accumbens	UBERON:0001882	91.69	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.75	gold quality
nasal cavity mucosa	UBERON:0001826	90.65	gold quality
cranial nerve II	UBERON:0000941	90.52	gold quality
caudate nucleus	UBERON:0001873	90.45	gold quality
putamen	UBERON:0001874	90.27	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.65	gold quality
adenohypophysis	UBERON:0002196	89.30	gold quality
buccal mucosa cell	CL:0002336	87.27	gold quality
pituitary gland	UBERON:0000007	87.22	gold quality
lateral globus pallidus	UBERON:0002476	84.64	gold quality
choroid plexus epithelium	UBERON:0003911	78.63	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.29	silver quality
hypothalamus	UBERON:0001898	76.32	gold quality
islet of Langerhans	UBERON:0000006	73.87	gold quality
sperm	CL:0000019	73.21	silver quality
globus pallidus	UBERON:0001875	73.15	silver quality
male germ cell	CL:0000015	72.60	silver quality
layer of synovial tissue	UBERON:0007616	72.30	silver quality
medial globus pallidus	UBERON:0002477	71.53	gold quality
middle frontal gyrus	UBERON:0002702	70.24	gold quality
diaphragm	UBERON:0001103	70.16	gold quality
amygdala	UBERON:0001876	69.81	gold quality
vastus lateralis	UBERON:0001379	66.51	gold quality
type B pancreatic cell	CL:0000169	65.34	gold quality
myocardium	UBERON:0002349	65.24	gold quality
quadriceps femoris	UBERON:0001377	64.98	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	789.19
E-MTAB-10018	yes	349.83
E-GEOD-135922	yes	47.40
E-MTAB-7316	yes	19.36
E-HCAD-5	yes	18.04
E-GEOD-93593	yes	10.36
E-ANND-3	no	2.32

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

12 targets.

Target	Regulation
BMP4
EMX1	Repression
GAD1
NODAL	Repression
PAX2	Unknown
PAX6	Activation
RHO
SHH
SIX3
SOX2	Unknown
WNT1	Repression
WNT8B	Repression

Upstream regulators (CollecTRI, top): MSX2, MTA1, PAX6, PROX1, SIX3, SOX2

miRNA regulators (miRDB)

111 targeting SIX3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4779	99.86	66.50	1583

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 30)

• Six3 gene is regulated by Pax6, Prox 1, and Msx2 transcription factors. (PMID:11554737)
• The homeotic protein Six3 is a coactivator of the nuclear receptor NOR-1 and a corepressor of the fusion protein EWS/NOR-1 in human extraskeletal myxoid chondrosarcomas. (PMID:12543801)
• Six3 directly binds to geminin (PMID:14973488)
• Seven novel SIX3 mutations found in a cohort of Holoprosencephaly patinets. (PMID:15221788)
• different SIX3 mutations in HPE2 may affect different signaling pathways, and that one of these pathways may involve the nuclear receptor NOR1 (PMID:15523651)
• Occurrence of aprosencephaly/atelencephaly and holoprosencephaly in a family with a SIX3 gene mutation. (PMID:15635066)
• Upregulation of Six3 expression in single progenitor cells of the embryonic telencephalon keeps them in an undifferentiated state; Six3 overexpression in mammalian brain depends strictly on the integrity of its DNA-binding domain. (PMID:17576749)
• role for the MTA1 as an upstream modifier of Six3 and indicate that Six3 is a direct stimulator of rhodopsin expression. (PMID:17666527)
• 89% of putative deleterious human SIX3 mutations are significant loss-of-function alleles; a systematic comparison of bioactivities of mutant six3 proteins is demonstrated that confirms a role for six3 in causation of holoprosencephaly. (PMID:18791198)
• These data suggest a direct link between Six3 and Shh regulation during normal forebrain development and in the pathogenesis of holoprosencephaly. (PMID:18836447)
• In a cohort of patients (n = 800) with Holoprosencephaly (HPE), SIX3 mutations were found in 4.7% of probands. Suggests mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. (PMID:19346217)
• a novel missense mutation in the SIX3 holoprosencephaly gene was reported. (PMID:19353631)
• A mutational screen was done to identify possible SIX3 mutations in a cohort of 149 (M:F 81:68) patients with hypopituitarism and/or midline abnormalities, falling within the spectrum of septo-optic dysplasia and holoprosencephaly. (PMID:19921650)
• SIX3 acts directly upstream of SHH, and the SHH pathway is a key regulator of ventral forebrain patterning and mutations are associated with schizencephaly. (PMID:20157829)
• screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3 (PMID:20531442)
• There was a positive correlation between the severity of the brain malformation and facial features for SHH, SIX3, and TGIF, but no such correlation was found for ZIC2 mutations. (PMID:21940735)
• Mutations in SIX3 is associated with holoprosencephaly. (PMID:22310223)
• SIX3 may play an important role as a novel suppressor in human lung cancer. (PMID:23977152)
• High SIX3 expression is associated with Head and Neck Squamous Cell Carcinoma. (PMID:27501229)
• SIX2, SIX3, and SIX4 were correlated with higher TNM stages in lung neoplasms (PMID:27821176)
• SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. (PMID:28595628)
• Results demonstrate that Six3 silence or loss in glioma is induced by its promoter hypermethylation and Six3 down-regulation contributes to proliferation and invasion of glioma. And this process is involved in activation of Wnt/beta-catenin pathway. Six3 play a suppressor role in the initiation and progression of human glioma and potentially serve as a target for the diagnosis and treatment of human glioma. (PMID:28643150)
• SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly have been described. (PMID:28670735)
• The authors demonstrate that the SIX3/LSD1/NuRD(MTA3) complex inhibits carcinogenesis in breast cancer cells and suppresses metastasis in breast cancer. (PMID:29463994)
• RNA interference-mediated knockdown of the Drosophila ortholog of SIX3 in insulin-producing cells, a model for mammalian beta cells, conferred reduced insulin output. (PMID:30242153)
• Upregulation of sine oculis homeobox homolog 3 is associated with proliferation, invasion, migration, as well as poor prognosis of esophageal cancer. (PMID:30672777)
• The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically. (PMID:32051553)
• TRIM27 acts as an oncogene and regulates cell proliferation and metastasis in non-small cell lung cancer through SIX3-beta-catenin signaling. (PMID:33264103)
• miR-4306 Suppresses Proliferation of Esophageal Squamous Cell Carcinoma Cell by Targeting SIX3. (PMID:34021861)
• Heterozygous variants in SIX3 and POU1F1 cause pituitary hormone deficiency in mouse and man. (PMID:35951005)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	six3b	ENSDARG00000054879
danio_rerio	six3a	ENSDARG00000058008
mus_musculus	Six3	ENSMUSG00000038805
rattus_norvegicus	Six3	ENSRNOG00000057031
drosophila_melanogaster	Optix	FBGN0025360
caenorhabditis_elegans		WBGENE00000453

Paralogs (6): SIX4 (ENSG00000100625), SIX1 (ENSG00000126778), SIX2 (ENSG00000170577), SIX5 (ENSG00000177045), SIX6 (ENSG00000184302), ANHX (ENSG00000227059)

Protein

Protein identifiers

Homeobox protein SIX3 — O95343 (reviewed: O95343)

Alternative names: Sine oculis homeobox homolog 3

All UniProt accessions (1): O95343

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. During forebrain development represses WNT1 expression allowing zona limitans intrathalamica formation and thereby ensuring proper anterio-posterior patterning of the diencephalon and formation of the rostral diencephalon. Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that in turn SHH maintains its expression. In addition, Six3 activity is required for the formation of the telencephalon. During postnatal stages of brain development is necessary for ependymal cell maturation by promoting the maturation of radial glia into ependymal cells through regulation of neuroblast proliferation and migration. Acts on the proliferation and differentiation of neural progenitor cells through activating transcription of CCND1 and CCND2. During early lens formation plays a role in lens induction and specification by activating directly PAX6 in the presumptive lens ectoderm. In turn PAX6 activates SIX3 resulting in activation of PDGFRA and CCND1 promoting cell proliferation. Also is required for the neuroretina development by directly suppressing WNT8B expression in the anterior neural plate territory. Its action during retina development and lens morphogenesis is TLE5 and TLE4-dependent manner. Furthermore, during eye development regulates several genes expression. Before and during early lens development represses the CRYGF promoter by binding a SIX repressor element. Directly activates RHO transcription, or cooperates with CRX or NRL. Six3 also functions in the formation of the proximodistal axis of the optic cup, and promotes the formation of optic vesicles-like structures. During pituitary development, acts in parallel or alternatively with HESX1 to control cell proliferation through Wnt/beta-catenin pathway. Plays a role in eye development by suppressing WNT1 expression and in dorsal-ventral patterning by repressing BMP signaling pathway.

Subunit / interactions. Interacts with EYA4; translocates EYA4 from the cytoplasm to the nucleus and promotes activation of their target genes. Interacts with MTA1 and HDAC2; represses its own transcription. Interacts with MTA1; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter. Interacts with EYA1; promotes EYA1 translocation to the nucleus. Interacts with TLE1 and TLE5 (via Q domain); can act in combination with either TLE1 and/or TLE5 leading to transcriptional repression or activation, respectively. Interacts (via homeobox) with NR4A3; differentially regulates the transcriptional activities NR4A3. Interacts with GMNN. Interacts with TLE4.

Subcellular location. Nucleus.

Disease relevance. Holoprosencephaly 2 (HPE2) [MIM:157170] A form of holoprosencephaly, a structural anomaly of the brain in which the developing forebrain fails to correctly separate into right and left hemispheres. It is a genetically and clinically heterogeneous disorder with a wide spectrum of severity, ranging from alobar holoprosencephaly with severe facial abnormalities, such as cyclopia and proboscis, to mild forms that include lobar or microform holoprosencephaly, without cerebral malformations and with mild craniofacial defects. HPE2 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Schizencephaly (SCHZC) [MIM:269160] Extremely rare human congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. These clefts are lined with gray matter and most commonly involve the parasylvian regions. Large portions of the cerebral hemispheres may be absent and replaced by cerebro-spinal fluid. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_005404* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR031701	SIX1_SD	Domain

Pfam: PF00046, PF16878

UniProt features (45 total): sequence variant 34, region of interest 4, mutagenesis site 3, compositionally biased region 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95343-F1	70.38	0.37

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (3):

Position	Phenotype
87	decreased interaction with tle5 and loss of interaction with tle1.
95	loss of interaction with tle1 and tle5; when associated with p-99.
99	loss of interaction with tle1 and tle5; when associated with p-95.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 500 (showing top): GOBP_CIRCADIAN_RHYTHM, MORF_RAGE, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, LEE_NEURAL_CREST_STEM_CELL_DN, MORF_FLT1, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_BEHAVIOR, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_GROWTH, GOBP_PITUITARY_GLAND_DEVELOPMENT

GO Biological Process (37): eye development (GO:0001654), epithelial cell maturation (GO:0002070), lens development in camera-type eye (GO:0002088), optic vesicle morphogenesis (GO:0003404), regulation of transcription by RNA polymerase II (GO:0006357), protein import into nucleus (GO:0006606), brain development (GO:0007420), visual perception (GO:0007601), gonad development (GO:0008406), proximal/distal axis specification (GO:0009946), gene expression (GO:0010467), neuroblast differentiation (GO:0014016), telencephalon development (GO:0021537), forebrain anterior/posterior pattern specification (GO:0021797), forebrain dorsal/ventral pattern formation (GO:0021798), cell proliferation in forebrain (GO:0021846), telencephalon regionalization (GO:0021978), pituitary gland development (GO:0021983), negative regulation of Wnt signaling pathway (GO:0030178), thyroid gland development (GO:0030878), multicellular organism growth (GO:0035264), regulation of cell population proliferation (GO:0042127), negative regulation of neuron differentiation (GO:0045665), negative regulation of DNA-templated transcription (GO:0045892), circadian behavior (GO:0048512), lens induction in camera-type eye (GO:0060235), regulation of neural retina development (GO:0061074), lens fiber cell differentiation (GO:0070306), neuroblast migration (GO:0097402), regulation of cell cycle phase transition (GO:1901987), regulation of neuroblast proliferation (GO:1902692), apoptotic process involved in development (GO:1902742), lens fiber cell apoptotic process (GO:1990086), regulation of neural precursor cell proliferation (GO:2000177), diencephalon development (GO:0021536), camera-type eye development (GO:0043010), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription corepressor binding (GO:0001222), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), histone deacetylase binding (GO:0042826), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
forebrain regionalization	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
anatomical structure development	2
animal organ development	2
forebrain development	2
endocrine system development	2
gland development	2
sensory organ development	1
visual system development	1
epithelial cell development	1
cell maturation	1
camera-type eye development	1
embryonic camera-type eye morphogenesis	1
embryonic morphogenesis	1
tissue morphogenesis	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
central nervous system development	1
head development	1
sensory perception of light stimulus	1
development of primary sexual characteristics	1
reproductive structure development	1
axis specification	1
proximal/distal pattern formation	1
macromolecule biosynthetic process	1
cell differentiation	1
generation of neurons	1
anterior/posterior pattern specification	1
dorsal/ventral pattern formation	1
neural precursor cell proliferation	1
regionalization	1
telencephalon development	1
diencephalon development	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1

Protein interactions and networks

STRING

1500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIX3	ZIC2	O95409	934
SIX3	PAX6	P26367	927
SIX3	DISP1	Q96F81	910
SIX3	SHH	Q15465	902
SIX3	OTX2	P32243	866
SIX3	VSX2	P58304	858
SIX3	FOXA2	Q9Y261	780
SIX3	GMNN	O75496	773
SIX3	ENTPD2	Q9Y5L3	773
SIX3	GLI2	P10070	768
SIX3	P2RY1	P47900	762
SIX3	CDT1	Q9H211	756
SIX3	LHX2	P50458	742
SIX3	IRX6	P78412	712
SIX3	IRX3	P78415	696

IntAct

13 interactions, top by confidence:

A	B	Type	Score
SIX3	NR4A3	psi-mi:“MI:0915”(physical association)	0.510
SIX3		psi-mi:“MI:0915”(physical association)	0.510
GMNN	SIX3	psi-mi:“MI:0407”(direct interaction)	0.440
	SIX3	psi-mi:“MI:0915”(physical association)	0.370
IL12B	SIX3	psi-mi:“MI:0915”(physical association)	0.370
PPBP	SIX3	psi-mi:“MI:0915”(physical association)	0.370
SIX3	TNPO2	psi-mi:“MI:0914”(association)	0.350
SIX6	CLUH	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): SIX3 (Reconstituted Complex), SIX3 (Two-hybrid), SIX3 (Reconstituted Complex), TLE1 (Two-hybrid), AES (Two-hybrid), TLE1 (Reconstituted Complex), AES (Reconstituted Complex), SMURF2 (Affinity Capture-Western), TRIM27 (Affinity Capture-Western), SIX3 (Affinity Capture-Western), AHNAK2 (Affinity Capture-MS), SIX3 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), CLUH (Affinity Capture-MS), TNPO2 (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

2 interactions.

A	Effect	B	Mechanism
TLE5	“down-regulates activity”	SIX3	binding
TLE1	“up-regulates activity”	SIX3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	12
Uncertain significance	136
Likely benign	62
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1299645	NM_005413.4(SIX3):c.402_416del (p.Arg135_Ala139del)	Pathogenic
1809731	NM_005413.4(SIX3):c.794_806+27delinsAGGCCA	Pathogenic
1995795	NM_005413.4(SIX3):c.425del (p.Thr142fs)	Pathogenic
2500510	NM_005413.4(SIX3):c.271C>T (p.Gln91Ter)	Pathogenic
2734182	NM_005413.4(SIX3):c.275T>G (p.Val92Gly)	Pathogenic
280334	NM_005413.4(SIX3):c.357del (p.Ala121fs)	Pathogenic
30380	NM_005413.4(SIX3):c.385G>T (p.Glu129Ter)	Pathogenic
4074347	NM_005413.4(SIX3):c.729del (p.Gly244fs)	Pathogenic
449840	NM_005413.4(SIX3):c.406_407del (p.Ala136fs)	Pathogenic
4823500	NM_005413.4(SIX3):c.361del (p.Ala121fs)	Pathogenic
4847295	NM_005413.4(SIX3):c.721C>T (p.Gln241Ter)	Pathogenic
487086	NM_005413.4(SIX3):c.406_407dup (p.Val137fs)	Pathogenic
489225	NM_005413.4(SIX3):c.288T>A (p.Cys96Ter)	Pathogenic
545576	NM_005413.4(SIX3):c.441_451del (p.Leu148fs)	Pathogenic
579427	NM_005413.4(SIX3):c.507G>A (p.Trp169Ter)	Pathogenic
6093	NM_005413.4(SIX3):c.676C>G (p.Leu226Val)	Pathogenic
6095	NM_005413.4(SIX3):c.749T>C (p.Val250Ala)	Pathogenic
6096	NM_005413.4(SIX3):c.556_557dup (p.Pro187fs)	Pathogenic
6099	NM_005413.4(SIX3):c.339G>T (p.Trp113Cys)	Pathogenic
65501	NM_005413.4(SIX3):c.696_705del (p.Asn232fs)	Pathogenic
1318865	NM_005413.4(SIX3):c.27_28del (p.Tyr10fs)	Likely pathogenic
1675777	NM_005413.4(SIX3):c.634_638del (p.Cys212fs)	Likely pathogenic
2577596	NM_005413.4(SIX3):c.820_832delinsCTGGACCT (p.Ala274fs)	Likely pathogenic
2632911	NM_005413.4(SIX3):c.806+2T>C	Likely pathogenic
3359075	NM_005413.4(SIX3):c.401C>A (p.Ala134Glu)	Likely pathogenic
3381887	NM_005413.4(SIX3):c.671G>A (p.Trp224Ter)	Likely pathogenic
426229	NM_005413.4(SIX3):c.777G>T (p.Gln259His)	Likely pathogenic
4532327	NM_005413.4(SIX3):c.221dup (p.Glu75fs)	Likely pathogenic
504413	NM_005413.4(SIX3):c.1A>G (p.Met1Val)	Likely pathogenic
6094	NM_005413.4(SIX3):c.770G>C (p.Arg257Pro)	Likely pathogenic

SpliceAI

319 predictions. Top by Δscore:

Variant	Effect	Δscore
2:44942908:CAGGT:C	donor_loss	0.9900
2:44942909:AGG:A	donor_loss	0.9900
2:44942910:GGTT:G	donor_loss	0.9900
2:44942911:GTT:G	donor_loss	0.9900
2:44944150:C:CA	acceptor_gain	0.9500
2:44942852:G:GG	donor_gain	0.9400
2:44942911:G:GG	donor_gain	0.9400
2:44942851:A:AG	donor_gain	0.9300
2:44944562:CCGCA:C	acceptor_loss	0.9200
2:44944565:CA:C	acceptor_loss	0.9200
2:44944567:G:GT	acceptor_loss	0.9200
2:44942770:G:GT	donor_gain	0.9000
2:44944566:A:AG	acceptor_gain	0.9000
2:44944567:G:GG	acceptor_gain	0.9000
2:44943844:G:A	donor_gain	0.8700
2:44944252:G:GT	donor_gain	0.8100
2:44944566:AG:A	acceptor_gain	0.8100
2:44944567:GG:G	acceptor_gain	0.8100
2:44944464:G:GT	donor_gain	0.7700
2:44944474:G:GT	donor_gain	0.7500
2:44944567:GGCT:G	acceptor_gain	0.7400
2:44945801:G:A	acceptor_gain	0.7400
2:44944753:AT:A	donor_gain	0.7300
2:44945800:T:TA	acceptor_gain	0.7300
2:44944565:CAGG:C	acceptor_gain	0.7100
2:44943250:G:GT	donor_gain	0.7000
2:44943589:C:T	donor_gain	0.7000
2:44942907:ACAG:A	donor_gain	0.6900
2:44943251:G:T	donor_gain	0.6900
2:44943338:A:T	donor_gain	0.6900

AlphaMissense

2142 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:44942363:T:C	F87L	1.000
2:44942364:T:C	F87S	1.000
2:44942364:T:G	F87C	1.000
2:44942365:C:A	F87L	1.000
2:44942365:C:G	F87L	1.000
2:44942381:G:C	A93P	1.000
2:44942388:T:A	V95D	1.000
2:44942390:T:C	C96R	1.000
2:44942391:G:A	C96Y	1.000
2:44942391:G:T	C96F	1.000
2:44942392:T:G	C96W	1.000
2:44942400:T:A	L99Q	1.000
2:44942400:T:C	L99P	1.000
2:44942424:G:C	R107P	1.000
2:44942427:T:A	L108Q	1.000
2:44942427:T:C	L108P	1.000
2:44942433:G:C	R110P	1.000
2:44942435:T:C	F111L	1.000
2:44942435:T:G	F111V	1.000
2:44942436:T:C	F111S	1.000
2:44942436:T:G	F111C	1.000
2:44942437:C:A	F111L	1.000
2:44942437:C:G	F111L	1.000
2:44942439:T:A	L112H	1.000
2:44942439:T:C	L112P	1.000
2:44942441:T:A	W113R	1.000
2:44942441:T:C	W113R	1.000
2:44942444:T:C	S114P	1.000
2:44942448:T:C	L115P	1.000
2:44942499:T:C	L132P	1.000

dbSNP variants (sampled 300 via entrez): RS1002061691 (2:44945239 C>A,T), RS1002167245 (2:44945072 A>G), RS1002529551 (2:44945983 A>G), RS1002732048 (2:44940886 G>A), RS1002941233 (2:44941980 C>A,G,T), RS1002993533 (2:44941650 A>G), RS1003046851 (2:44940669 G>A), RS1003648984 (2:44941801 C>G,T), RS1003784639 (2:44946548 G>A), RS1004010577 (2:44939977 G>T), RS1004066300 (2:44942692 G>A), RS1004145781 (2:44940153 C>A,T), RS1004950351 (2:44946479 T>C), RS1005073807 (2:44940943 G>A), RS1005126167 (2:44940723 C>T)

Disease associations

OMIM: gene MIM:603714 | disease phenotypes: MIM:157170, MIM:269160, MIM:147250

GenCC curated gene-disease

Disease	Classification	Inheritance
holoprosencephaly 2	Definitive	Autosomal dominant
holoprosencephaly	Supportive	Autosomal recessive

Mondo (5): holoprosencephaly 2 (MONDO:0007999), schizencephaly (MONDO:0010011), solitary median maxillary central incisor syndrome (MONDO:0007819), intellectual disability (MONDO:0001071), holoprosencephaly (MONDO:0016296)

Orphanet (4): Holoprosencephaly (Orphanet:2162), Schizencephaly (Orphanet:799), OBSOLETE: Solitary median maxillary central incisor syndrome (Orphanet:2286), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

142 total (30 of 142 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000062	Ambiguous genitalia
HP:0000104	Renal agenesis
HP:0000119	Abnormality of the genitourinary system
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000322	Short philtrum
HP:0000407	Sensorineural hearing impairment
HP:0000446	Narrow nasal bridge
HP:0000453	Choanal atresia
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000520	Proptosis
HP:0000567	Chorioretinal coloboma
HP:0000568	Microphthalmia
HP:0000601	Hypotelorism
HP:0000612	Iris coloboma
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000736	Short attention span

GWAS associations

44 associations (top):

Study	Trait	p-value
GCST001233_18	Metabolite levels	1.000000e-12
GCST001471_1	Alcohol and nicotine co-dependence	5.000000e-06
GCST002586_5	Fasting plasma glucose	3.000000e-13
GCST003997_16	Myopia	8.000000e-12
GCST004748_80	Lung cancer	6.000000e-07
GCST005145_2	Glycated hemoglobin levels	9.000000e-09
GCST005913_1	Fasting blood glucose	2.000000e-08
GCST006001_19	Hemoglobin A1c levels	4.000000e-17
GCST006002_3	Blood sugar levels	7.000000e-46
GCST006291_99	Spherical equivalent or myopia (age of diagnosis)	8.000000e-09
GCST006394_43	Intraocular pressure	3.000000e-08
GCST006412_20	Intraocular pressure	3.000000e-09
GCST006810_22	Self-reported risk-taking behaviour	2.000000e-08
GCST006941_53	Irritable mood	9.000000e-10
GCST007323_56	Risk-taking tendency (4-domain principal component model)	3.000000e-16
GCST007324_56	Adventurousness	3.000000e-18
GCST007325_295	General risk tolerance (MTAG)	2.000000e-16
GCST007327_213	Smoking status (ever vs never smokers)	4.000000e-16
GCST007328_11	Alcohol consumption (drinks per week)	1.000000e-19
GCST007603_28	Smoking initiation	4.000000e-11
GCST008259_22	Alcohol use disorder	9.000000e-11
GCST008259_4	Alcohol use disorder	2.000000e-10
GCST008757_2	Alcohol consumption	7.000000e-17
GCST008803_2	Smoking behaviour (cigarette pack-years)	4.000000e-08
GCST008810_48	Smoking initiation (ever regular vs never regular)	7.000000e-13
GCST008811_33	Alcohol consumption (drinks per week)	7.000000e-17
GCST009462_31	Optic disc size	1.000000e-08
GCST009725_69	Intraocular pressure	2.000000e-08
GCST009817_1	Clozapine-induced myocarditis in schizophrenia	4.000000e-07
GCST010002_389	Refractive error	3.000000e-26

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004541	HbA1c measurement
EFO:0004468	glucose measurement
EFO:0004847	age at onset
EFO:0004695	intraocular pressure measurement
EFO:0008579	risk-taking behaviour
EFO:0009594	irritability measurement
EFO:0004318	smoking behavior
EFO:0005670	smoking initiation
EFO:0009458	alcohol use disorder measurement
EFO:0009115	tobacco smoke exposure measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065707	Schizencephaly	C10.500.507.500.750; C16.131.666.507.500.750
C563579	Holoprosencephaly 2 (supp.)
C537342	Single upper central incisor (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression	9
trichostatin A	affects cotreatment, decreases expression	3
Tretinoin	decreases expression	3
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases methylation	1
butyraldehyde	increases expression	1
manganese chloride	increases expression	1
mercuric bromide	affects cotreatment, decreases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Fulvestrant	decreases methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Dexamethasone	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Hydrogen Peroxide	affects expression	1
Manganese	increases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00005016	Not specified	COMPLETED	Study of the Experiences and Needs of Parents Continuing a Pregnancy Following a Prenatal Diagnosis of Holopresencephaly
NCT00088426	Not specified	COMPLETED	Clinical and Genetic Studies on Holoprosencephaly
NCT00645645	Not specified	COMPLETED	A Study of the Genetic Analysis of Brain Disorders
NCT04691414	Not specified	COMPLETED	Retrospective Study Using Next Generation Sequencing (NGS) on Biological Samples to Improve Genetic Counseling for Patients With Previously Explored Craniofacial Midline Defects.
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders