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)
• GWAS associations: 44 (top 2% of genes corpus-wide)
• Clinical variants (ClinVar): 281 total — 21 pathogenic, 12 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈14% of expected missense variation)
• GTEx eGene: eQTL in 10 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 142
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.99 (loss-of-function intolerant), LOEUF 0.39 (moderately constrained)
• 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: 2 — 2 protein_coding

MANE Select: ENST00000260653

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000260653, ENST00001145412

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.

Highest expression (Bgee): pigmented layer of retina, retina, nasal cavity epithelium, nucleus accumbens, mucosa of paranasal sinus.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SIX3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 10 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

11 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Pancreas	eqtl	1.2e-08	-0.56	2:44964966:G:T
Brain Cerebellum	eqtl	2.5e-04	+0.44	2:44927769:G:A
Cells Cultured fibroblasts	eqtl	2.7e-04	+0.26	2:44943014:G:A
Breast Mammary Tissue	eqtl	6.9e-04	+0.26	2:44947064:GCAGCAC:G
Skin Not Sun Exposed Suprapubic	eqtl	1.4e-03	-0.26	2:44924302:G:A
Brain Frontal Cortex BA9	eqtl	1.2e-02	-0.39	2:45112329:A:G
Cells EBV-transformed lymphocytes	eqtl	2.1e-02	+0.39	2:44951417:G:A
Brain Putamen basal ganglia	eqtl	2.9e-02	+0.11	2:44940747:T:A
Testis	sqtl	3.5e-02	-1.39	2:45799771:A:G
Nerve Tibial	eqtl	3.7e-02	-0.24	2:45182287:C:G
Brain Caudate basal ganglia	eqtl	4.8e-02	-0.26	2:43961707:T:C

FANTOM5 promoters

showing 10 of 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

showing 100 of 264 tissues 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
tongue squamous epithelium	UBERON:0006919	64.79	gold quality
secondary oocyte	CL:0000655	64.56	gold quality
tendon of biceps brachii	UBERON:0008188	63.82	gold quality
olfactory bulb	UBERON:0002264	63.80	gold quality
forebrain	UBERON:0001890	63.65	gold quality
cervix squamous epithelium	UBERON:0006922	63.60	gold quality
temporal lobe	UBERON:0001871	63.23	gold quality
mucosa of urinary bladder	UBERON:0001259	62.75	gold quality
cardiac muscle of right atrium	UBERON:0003379	62.66	gold quality
left ventricle myocardium	UBERON:0006566	62.05	gold quality
oocyte	CL:0000023	62.02	gold quality
brain	UBERON:0000955	60.78	gold quality
telencephalon	UBERON:0001893	60.58	gold quality
jejunal mucosa	UBERON:0000399	60.37	gold quality
vena cava	UBERON:0004087	60.36	gold quality
central nervous system	UBERON:0001017	60.13	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	59.90	gold quality
triceps brachii	UBERON:0001509	59.33	gold quality
synovial joint	UBERON:0002217	59.02	silver quality
gluteal muscle	UBERON:0002000	58.96	gold quality
thymus	UBERON:0002370	58.87	gold quality
CA1 field of hippocampus	UBERON:0003881	58.69	gold quality
germinal epithelium of ovary	UBERON:0001304	58.62	gold quality
substantia nigra	UBERON:0002038	58.41	gold quality
pleura	UBERON:0000977	58.15	gold quality
parietal pleura	UBERON:0002400	58.12	gold quality
midbrain	UBERON:0001891	58.06	gold quality
pancreatic ductal cell	CL:0002079	57.99	silver quality
visceral pleura	UBERON:0002401	57.75	gold quality
ventral tegmental area	UBERON:0002691	57.73	silver quality
eye	UBERON:0000970	57.44	silver quality
decidua	UBERON:0002450	57.43	gold quality
squamous epithelium	UBERON:0006914	57.31	gold quality
tibia	UBERON:0000979	57.26	gold quality
pancreas	UBERON:0001264	56.77	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	56.49	gold quality
cardia of stomach	UBERON:0001162	56.39	gold quality
jejunum	UBERON:0002115	56.25	gold quality
substantia nigra pars reticulata	UBERON:0001966	55.81	silver quality
superficial temporal artery	UBERON:0001614	55.75	gold quality
parotid gland	UBERON:0001831	55.66	gold quality
entorhinal cortex	UBERON:0002728	55.36	silver quality
deltoid	UBERON:0001476	55.22	gold quality
trachea	UBERON:0003126	55.03	gold quality
epithelium of esophagus	UBERON:0001976	55.01	gold quality
substantia nigra pars compacta	UBERON:0001965	54.97	gold quality
esophagus squamous epithelium	UBERON:0006920	54.77	gold quality
lateral nuclear group of thalamus	UBERON:0002736	54.40	gold quality
body of tongue	UBERON:0011876	54.39	gold quality
cerebellar vermis	UBERON:0004720	54.32	gold quality
postcentral gyrus	UBERON:0002581	54.13	gold quality
parietal lobe	UBERON:0001872	54.09	gold quality
tongue	UBERON:0001723	53.98	gold quality
lower lobe of lung	UBERON:0008949	53.92	silver quality
epithelial cell of pancreas	CL:0000083	53.68	gold quality
embryo	UBERON:0000922	53.58	silver quality
pharyngeal mucosa	UBERON:0000355	53.22	gold quality
gingival epithelium	UBERON:0001949	53.12	gold quality
cervix epithelium	UBERON:0004801	53.05	gold quality
colonic epithelium	UBERON:0000397	52.89	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
sural nerve	UBERON:0015488	52.43	gold quality
kidney epithelium	UBERON:0004819	52.36	gold quality
superior surface of tongue	UBERON:0007371	52.19	gold quality
oviduct epithelium	UBERON:0004804	51.96	gold quality
medulla oblongata	UBERON:0001896	51.86	gold quality
corpus epididymis	UBERON:0004359	51.86	gold quality
superior vestibular nucleus	UBERON:0007227	51.82	gold quality
mammalian vulva	UBERON:0000997	51.80	gold quality
cauda epididymis	UBERON:0004360	51.40	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

HPA expression

RNA tissue specificity: Tissue enhanced

45 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Basal ganglia	tissue	50.9
Putamen	tissue	50.2
Nucleus accumbens	tissue	42.4
Ventral forebrain	tissue	36.3
Septum	tissue	32.8
Choroid plexus	tissue	25.8
Hypothalamus	tissue	25.7
Caudate putamen	tissue	25.6
Pituitary gland	tissue	25.1
Retina	tissue	23.5
Superior colliculi	tissue	10.9
Amygdala	tissue	9.4
Midbrain	tissue	9.4
Parathyroid gland	tissue	8.6
Periaqueductal gray	tissue	6.2
Thalamus	tissue	4.1
Substantia nigra	tissue	3.7
Postcentral gyrus	tissue	2.2
Hippocampus	tissue	1.6
Cerebellum	tissue	1.2
Hippocampal formation	tissue	1.0
Cervix	tissue	0.6
Pons	tissue	0.6
Frontal cortex	tissue	0.6
Locus coeruleus	tissue	0.6
Cerebral cortex	tissue	0.5
Skeletal muscle	tissue	0.5
Temporal cortex	tissue	0.5
Pancreas	tissue	0.4
Corpus callosum	tissue	0.4
Testis	tissue	0.3
Medulla oblongata	tissue	0.3
Olfactory bulb	tissue	0.3
Insular cortex	tissue	0.3
Prefrontal cortex	tissue	0.2
Vagina	tissue	0.2
Lymph node	tissue	0.1
Motor cortex	tissue	0.1
Tongue	tissue	0.1
Spinal cord	tissue	0.1
Entorhinal cortex	tissue	0.1
Retrosplenial and cingulate cortex	tissue	0.1
Somatosensory cortex	tissue	0.1
Retrosplenial cortex	tissue	0.1
Occipital cortex	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Caudate nucleus (47.3), Arcuate nucleus (37.5), Supraoptic nucleus (29.5), Nucleus basalis of Meynert (27.6), Paraventricular nucleus (26.1).

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)

Targeting SIX3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 111 miRNAs:

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

gnomAD constraint: pLI 0.993, LOEUF 0.387, missense Z 1.58 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000260653 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈14% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:44,942,105–44,942,335	105 / 116.1	0.90	no
2:44,942,336–44,942,771	117 / 205.9	0.57	no
2:44,942,772–44,942,910	15 / 65.4	0.23	yes (p 4.6e-10)
2:44,944,568–44,944,757	110 / 93.3	1.18	no
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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:102764) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 23 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal forebrain development	2
decreased forebrain size	2
abnormal craniofacial morphology	1
abnormal cranium morphology	1
abnormal lens induction	1
abnormal lens vesicle development	1
anophthalmia	1
abnormal lens morphology	1
cataract	1
small lens	1
abnormal neural tube morphology	1
abnormal lens fiber morphology	1
aphakia	1
abnormal optic vesicle formation	1
holoprosencephaly	1
abnormal rostral-caudal axis patterning	1
abnormal lens development	1
absent nasal placodes	1
absent optic vesicle	1
perinatal lethality, complete penetrance	1
increased midbrain size	1
absent embryonic telencephalon	1
absent optic pit	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gorilla gorilla gorilla	A1YER0	100.0%	Diamond
Schizosaccharomyces pombe	P10842	100.0%	Diamond
Schizosaccharomyces kambucha (nom. inval.)	Q6WRX8	100.0%	Diamond
Lagothrix lagotricha	A2D5H2	99.6%	Diamond
Xenopus tropicalis	B4F6V6	98.8%	Diamond
Xenopus laevis	Q8QGC4	98.8%	Diamond
Drosophila pseudoobscura pseudoobscura	Q29CT2	98.7%	Diamond
Gallus gallus	O93307	93.5%	Diamond
Anopheles gambiae	Q7PMT1	84.6%	Diamond
Oryzias latipes	O73916	81.6%	Diamond
Oryza sativa Japonica Group	Q75LX9	75.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SIX2	protein-coding	10736
LINC01833	ncRNA	107985879
SIX3-AS1	ncRNA	100506108
CAMKMT	protein-coding	79823
LINC01121	ncRNA	400952

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

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Helix-turn-helix domains, Disease related genes, Human disease related genes, Congenital malformations, Congenital malformations of the nervous system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IF approved

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 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

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 (28): eye development (GO:0001654), epithelial cell maturation (GO:0002070), lens development in camera-type eye (GO:0002088), optic vesicle morphogenesis (GO:0003404), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), brain development (GO:0007420), visual perception (GO:0007601), proximal/distal axis specification (GO:0009946), gene expression (GO:0010467), neuroblast differentiation (GO:0014016), telencephalon development (GO:0021537), forebrain dorsal/ventral pattern formation (GO:0021798), cell proliferation in forebrain (GO:0021846), telencephalon regionalization (GO:0021978), pituitary gland development (GO:0021983), regulation of cell population proliferation (GO:0042127), negative regulation of neuron differentiation (GO:0045665), negative regulation of DNA-templated transcription (GO:0045892), 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), 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

59 GO namespaces:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
animal gross anatomical part developmental process	2
regulation of DNA-templated transcription	2
forebrain development	2
forebrain regionalization	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
gene expression	1
RNA biosynthetic process	1
transcription by RNA polymerase II	1
central nervous system development	1
animal organ development	1
head development	1
sensory perception of light stimulus	1
axis specification	1
proximal/distal pattern formation	1
macromolecule biosynthetic process	1
cell differentiation	1
generation of neurons	1
dorsal/ventral pattern formation	1
neural precursor cell proliferation	1
regionalization	1
telencephalon development	1
diencephalon development	1
endocrine system development	1
gland development	1
cell population proliferation	1
regulation of cellular process	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
neural retina development	1
regulation of developmental process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transcription coregulator binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
enzyme binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1
protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 40 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
eye development	BP	direct assay
forebrain dorsal/ventral pattern formation	BP	direct assay
gene expression	BP	mutant phenotype
negative regulation of DNA-templated transcription	BP	direct assay
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay
sequence-specific double-stranded DNA binding	MF	direct assay
transcription corepressor binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,338 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIX3	ZIC2	O95409	929
SIX3	PAX6	P26367	919
SIX3	DISP1	Q96F81	906
SIX3	SHH	Q15465	896
SIX3	VSX2	P58304	857
SIX3	OTX2	P32243	854
SIX3	FOXA2	Q9Y261	780
SIX3	GMNN	O75496	765
SIX3	ENTPD2	Q9Y5L3	757
SIX3	P2RY1	P47900	755
SIX3	CDT1	Q9H211	753
SIX3	GLI2	P10070	751
SIX3	LHX2	P50458	723
SIX3	VAX2	Q9UIW0	632
SIX3	PTCH1	Q13635	629

IntAct

Human interaction partners of SIX3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
NR4A3	physical association	0.510	3
GMNN	direct interaction	0.440	1
IL12B	physical association	0.370	1
PPBP	physical association	0.370	1
TNPO2	association	0.350	1

BioGRID (23 interactions; top human partners by supporting records): NR4A3 (Reconstituted Complex; 6 records), AES (Two-hybrid; 2 records), TLE1 (Two-hybrid; 2 records), TRIM27 (Affinity Capture-Western; 2 records), ACTA2 (Affinity Capture-MS), AHNAK2 (Affinity Capture-MS), CLUH (Affinity Capture-MS), CORO2A (Affinity Capture-MS), MPP5 (Affinity Capture-MS), MTA1 (Affinity Capture-Western), OTUD3 (Biochemical Activity), PAX6 (Reconstituted Complex), SIX6 (Affinity Capture-MS), SMURF2 (Affinity Capture-Western), TNPO2 (Affinity Capture-MS)

SIGNOR signaling

2 signaling interactions:

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

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
★ SIX3-LSD1-NuRD(MTA3) complex	9	HDAC1, HDAC2, KDM1A, MBD2, RBBP7, MBD3, MTA3, RBBP4, SIX3
SIX3-LSD1-MTA3 complex	3	KDM1A, MTA3, SIX3
EYA4-SIX3 complex	2	EYA4, SIX3

Disease & clinical

Genetic variants

Variant evidence for SIX3: 281 ClinVar records (33 pathogenic / likely pathogenic); 44 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	12
Uncertain significance	143
Likely benign	64
Benign	15

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 33 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
449840	NM_005413.4(SIX3):c.406_407del (p.Ala136fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
6095	NM_005413.4(SIX3):c.749T>C (p.Val250Ala)	Pathogenic	criteria provided, single submitter	3
6099	NM_005413.4(SIX3):c.339G>T (p.Trp113Cys)	Pathogenic	criteria provided, single submitter	2
280334	NM_005413.4(SIX3):c.357del (p.Ala121fs)	Pathogenic	criteria provided, single submitter	1
487086	NM_005413.4(SIX3):c.406_407dup (p.Val137fs)	Pathogenic	criteria provided, single submitter	1
489225	NM_005413.4(SIX3):c.288T>A (p.Cys96Ter)	Pathogenic	criteria provided, single submitter	1
545576	NM_005413.4(SIX3):c.441_451del (p.Leu148fs)	Pathogenic	criteria provided, single submitter	1
579427	NM_005413.4(SIX3):c.507G>A (p.Trp169Ter)	Pathogenic	criteria provided, single submitter	1
1299645	NM_005413.4(SIX3):c.402_416del (p.Arg135_Ala139del)	Pathogenic	criteria provided, single submitter	1
1809731	NM_005413.4(SIX3):c.794_806+27delinsAGGCCA	Pathogenic	criteria provided, single submitter	1
1995795	NM_005413.4(SIX3):c.425del (p.Thr142fs)	Pathogenic	criteria provided, single submitter	1
2500510	NM_005413.4(SIX3):c.271C>T (p.Gln91Ter)	Pathogenic	criteria provided, single submitter	1
2734182	NM_005413.4(SIX3):c.275T>G (p.Val92Gly)	Pathogenic	criteria provided, single submitter	1
4074347	NM_005413.4(SIX3):c.729del (p.Gly244fs)	Pathogenic	criteria provided, single submitter	1
4823500	NM_005413.4(SIX3):c.361del (p.Ala121fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore SIX3’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 19 predictions of 179):

Position(s)	Effect	Δscore	Sites
2:44942911–44942912	donor_loss	0.9800	5
2:44944150	acceptor_gain	0.9400
2:44944566–44944567	acceptor_loss	0.9300	6
2:44942851	donor_gain	0.9100
2:44944565	acceptor_loss	0.8800
2:44943844	donor_gain	0.8700
2:44942912	donor_loss	0.7500
2:44945801	acceptor_gain	0.7400
2:44943251	donor_gain	0.6900
2:44943260	donor_gain	0.6900

AlphaMissense

1,226 missense substitutions predicted likely pathogenic (of 2,142 scored), across 222 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F213	8	1.000	1.000
N252	8	1.000	1.000
F254	8	1.000	1.000
N256	8	1.000	1.000
D261	8	1.000	1.000
D205	8	0.999	1.000
H211	8	0.999	1.000
F111	8	0.998	1.000
D189	8	0.998	1.000
D228	8	0.998	1.000
H173	8	0.997	1.000
F87	8	0.995	1.000
H162	8	0.994	1.000
D104	8	0.988	0.999
H141	8	0.984	1.000
D327	8	0.979	0.997
F157	8	0.974	1.000
N268	8	0.966	0.995
S326	8	0.868	0.997
D331	8	0.860	0.961

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Ovary Serous Cystadenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Uterine Corpus Endometrial Carcinoma (TCGA)	unfavorable	4.61e-05

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
holoprosencephaly 2	Definitive	Autosomal dominant	4

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (12 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

12 panels:

Panel	Rating
Cerebral malformation	green
Clefting	green
DDG2P	green
Fetal anomalies	green
Holoprosencephaly	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Early onset or syndromic epilepsy	amber
Paediatric disorders	amber
Structural eye disease	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (2): holoprosencephaly 2 (MONDO:0007999), schizencephaly (MONDO:0010011)

Orphanet (2): Holoprosencephaly (Orphanet:2162), Schizencephaly (Orphanet:799)

HPO phenotypes

showing 60 of 142 phenotypes (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
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000772	Abnormal rib morphology
HP:0000818	Abnormality of the endocrine system
HP:0000821	Hypothyroidism
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000826	Precocious puberty
HP:0000830	Anterior hypopituitarism
HP:0000835	Adrenal hypoplasia
HP:0000863	Central diabetes insipidus
HP:0000871	Panhypopituitarism
HP:0000873	Diabetes insipidus
HP:0000924	Abnormality of the skeletal system
HP:0001028	Hemangioma
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001273	Abnormal corpus callosum morphology
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001328	Specific learning disability
HP:0001344	Absent speech
HP:0001355	Megalencephaly
HP:0001360	Holoprosencephaly
HP:0001371	Flexion contracture

GWAS associations

showing 30 of 44 associations:

Study	Trait	p-value
GCST006002_3	Blood sugar levels	7e-46
GCST010002_43	Refractive error	3e-26
GCST011587_2	Fasting blood glucose	7e-25
GCST010701_6	Cortical surface area (MOSTest)	5e-20
GCST007328_36	Alcohol consumption (drinks per week)	1e-19
GCST010703_68	Brain morphology (MOSTest)	2e-18
GCST007324_47	Adventurousness	3e-18
GCST006001_19	Hemoglobin A1c levels	4e-17
GCST008757_2	Alcohol consumption	7e-17
GCST008811_13	Alcohol consumption (drinks per week)	7e-17
GCST007325_245	General risk tolerance (MTAG)	2e-16
GCST007323_6	Risk-taking tendency (4-domain principal component model)	3e-16
GCST007327_171	Smoking status (ever vs never smokers)	4e-16
GCST010546_4	Problematic alcohol use	2e-15
GCST010118_63	Type 2 diabetes	2e-14
GCST010136_27	Fruit consumption	4e-14
GCST010142_59	Fish- and plant-related diet	6e-14
GCST002586_5	Fasting plasma glucose	3e-13
GCST010699_70	Brain morphology (min-P)	4e-13
GCST008810_43	Smoking initiation (ever regular vs never regular)	7e-13
GCST001233_9	Metabolite levels	1e-12
GCST010697_52	Cortical surface area (min-P)	4e-12
GCST003997_16	Myopia	8e-12
GCST007603_28	Smoking initiation	4e-11
GCST008259_22	Alcohol use disorder	9e-11
GCST010702_19	Subcortical volume (MOSTest)	1e-10
GCST008259_4	Alcohol use disorder	2e-10
GCST006941_53	Irritable mood	9e-10
GCST90000047_32	Age at first sexual intercourse	1e-9
GCST006412_20	Intraocular pressure	3e-9

EFO canonical traits (from GWAS)

14 canonical traits:

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

2 disease descriptors:

Descriptor	Name	Tree numbers
D065707	Schizencephaly	C10.500.507.500.750; C16.131.666.507.500.750
C563579	Holoprosencephaly 2 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	9
trichostatin A	decreases expression, affects cotreatment	3
Tretinoin	decreases expression	3
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
Vorinostat	decreases expression, affects cotreatment	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	decreases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 204 trials:

NCT	Phase	Status	Title
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	Phase 3	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	Phase 2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	Phase 2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	Phase 2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	Phase 2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	Phase 1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	Phase 1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	Phase 1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
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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
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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
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NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders
NCT02862808	Not specified	COMPLETED	Molecular Diagnosis of Syndromic or Isolated Severe Intellectual Disability Using Whole Exome Sequencing : a Pilot Study
NCT02881333	Not specified	UNKNOWN	Various Type of Genetic Events in Patients With Intellectual Disability
NCT02889068	Not specified	COMPLETED	Targeted Next Generation Sequencing and Intellectual Disability
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NCT02919826	Not specified	COMPLETED	Dialectical Behaviour Group Therapy for Adults With Intellectual Disabilities
NCT02934854	Not specified	WITHDRAWN	Biomarker for Creatine Deficiency Syndromes (BioCDS)
NCT03033797	Not specified	UNKNOWN	Augmentative and Alternative Communication in Games With Virtual Reality in Intellectual Disabilities
NCT03135236	Not specified	COMPLETED	Parents as the Primary Sexuality Educators for Their Young Adults With Down Syndrome
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NCT03203226	Not specified	COMPLETED	The Feldenkrais Method for People With Intellectual Disability
NCT03212092	Not specified	COMPLETED	Reducing Aggression Among People With an Intellectual Disability
NCT03218462	Not specified	COMPLETED	Effect of Sensory Adapted Dental Environment on Dental Anxiety of Children With Intellectual and Developmental Disabilities
NCT03234231	Not specified	UNKNOWN	Supervised Brushing Programme for Intellectual Disabled Students
NCT03348124	Not specified	UNKNOWN	Prevention Among Young People With Intellectual Disability
NCT03424772	Not specified	UNKNOWN	Whole Genome Sequencing in the Detection of Rare Undiagnosed Genetic Diseases in Children in China
NCT03426059	Not specified	COMPLETED	Mapping the Phenotype in Adults With Phelan-McDermid Syndrome
NCT03492060	Not specified	RECRUITING	Longitudinal Study of Neurogenetic Disorders
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NCT03522337	Not specified	COMPLETED	Oral Health Promotion Among Preschool Children With Special Needs
NCT03525431	Not specified	COMPLETED	Clinical Utility of Pediatric Whole Exome Sequencing