IRX5

Summary

IRX5 (iroquois homeobox 5, HGNC:14361) is a protein-coding gene on chromosome 16q12.2, encoding Iroquois-class homeodomain protein IRX-5 (P78411). Establishes the cardiac repolarization gradient by its repressive actions on the KCND2 potassium-channel gene.

This gene encodes a member of the iroquois homeobox gene family, which are involved in several embryonic developmental processes. Knockout mice lacking this gene show that it is required for retinal cone bipolar cell differentiation, and that it negatively regulates potassium channel gene expression in the heart to ensure coordinated cardiac repolarization. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10265 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniofacial dysplasia - osteopenia syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 143 total — 4 pathogenic
• Phenotypes (HPO): 55
• MANE Select transcript: NM_005853

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14361
Approved symbol	IRX5
Name	iroquois homeobox 5
Location	16q12.2
Locus type	gene with protein product
Status	Approved
Aliases	IRX-2a
Ensembl gene	ENSG00000176842
Ensembl biotype	protein_coding
OMIM	606195
Entrez	10265

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000320990, ENST00000394636, ENST00000558597, ENST00000560154, ENST00000967637

RefSeq mRNA: 2 — MANE Select: NM_005853 NM_001252197, NM_005853

CCDS: CCDS10751, CCDS58462

Canonical transcript exons

ENST00000394636 — 3 exons

Exon	Start	End
ENSE00001222605	54932498	54932903
ENSE00001519064	54933077	54934485
ENSE00001892986	54930865	54931447

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 88.52.

FANTOM5 (CAGE): breadth broad, TPM avg 3.1891 / max 66.4794, expressed in 838 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154116	2.4648	740
154117	0.7242	390

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	88.52	gold quality
bronchial epithelial cell	CL:0002328	86.02	gold quality
skin of abdomen	UBERON:0001416	84.74	gold quality
heart right ventricle	UBERON:0002080	84.48	gold quality
mammary duct	UBERON:0001765	83.42	gold quality
zone of skin	UBERON:0000014	82.79	gold quality
skin of leg	UBERON:0001511	82.78	gold quality
skin of hip	UBERON:0001554	82.73	gold quality
epithelium of mammary gland	UBERON:0003244	82.12	gold quality
parotid gland	UBERON:0001831	82.08	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.99	gold quality
epithelium of bronchus	UBERON:0002031	81.70	gold quality
apex of heart	UBERON:0002098	81.64	gold quality
bronchus	UBERON:0002185	80.81	gold quality
mammalian vulva	UBERON:0000997	79.21	gold quality
mammary gland	UBERON:0001911	78.60	gold quality
thoracic mammary gland	UBERON:0005200	78.54	gold quality
saliva-secreting gland	UBERON:0001044	78.37	gold quality
minor salivary gland	UBERON:0001830	78.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.88	silver quality
heart left ventricle	UBERON:0002084	77.41	gold quality
cardiac ventricle	UBERON:0002082	77.31	gold quality
metanephros cortex	UBERON:0010533	77.23	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	76.04	gold quality
esophagus mucosa	UBERON:0002469	75.63	gold quality
mouth mucosa	UBERON:0003729	75.22	gold quality
nipple	UBERON:0002030	75.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.84	gold quality
lower esophagus mucosa	UBERON:0035834	73.14	gold quality
tibia	UBERON:0000979	72.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.67

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
BMP10
IRX4
KCND2	Repression

JASPAR motifs

Motif	Name	Family
MA2680.1	IRX5	TALE-type HD

JASPAR matrix evidence (PMIDs): PMID:16203991

miRNA regulators (miRDB)

48 targeting IRX5, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-3911	99.38	66.95	1087

Literature-anchored findings (GeneRIF, showing 16)

• involved in transcriptional regulation of heart morphogenesis (PMID:16527195)
• Irx5 is involved in the regulation of both the cell cycle and apoptosis in human prostate cancer cells (PMID:18519790)
• Our findings suggest that IRX proteins integrate combinatorial transcriptional inputs to regulate key signaling molecules involved in the ontogeny of multiple organs during embryogenesis and homeostasis. (PMID:22581230)
• Genome editing in primary preadipocytes to create the obesity risk allele of rs1421085 caused increased expression of IRX3 and IRX5 during early adipocyte differentiation by disrupting a binding site for the ARID5B repressor. (PMID:26287746)
• Primary preadipocytes from carriers of the obesity risk allele rs1421085, in which expression of IRX3 and IRX5 is increased, displayed excessive accumulation of triglycerides, reduced mitochondrial oxidative capacity, reduced white adipocyte browning, and reduced thermogenesis relative to primary preadipocytes from nonrisk allele carriers. (PMID:26287746)
• Authors identify a novel association that implicates the IRX5 gene region in obesity and compare our results with previously derived interaction data for the region. (PMID:26642925)
• Promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. (PMID:30246301)
• our findings suggested that IRX5 promoted CRC metastasis by inhibiting the RHOA-ROCK1-LIMK1 axis, which correlates with a poor prognosis (PMID:31432570)
• Transcription factorIRX5 promotes hepatocellular carcinoma proliferation and inhibits apoptosis by regulating the p53 signalling pathway. (PMID:32153043)
• IRX5 prompts genomic instability in colorectal cancer cells. (PMID:32162364)
• Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction. (PMID:32898233)
• A duplication on chromosome 16q12 affecting the IRXB gene cluster is associated with autosomal dominant cone dystrophy with early tritanopic color vision defect. (PMID:33891002)
• Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5. (PMID:34083488)
• Iroquois Homeobox 5 Negatively Regulated by miRNA-147 Promotes the Proliferation, Metastasis, and Invasion by Oral Squamous Cell Carcinoma. (PMID:34167624)
• The Hematopoietic TALE-Code Shows Normal Activity of IRX1 in Myeloid Progenitors and Reveals Ectopic Expression of IRX3 and IRX5 in Acute Myeloid Leukemia. (PMID:35328612)
• IRX5 suppresses osteogenic differentiation of hBMSCs by inhibiting protein synthesis. (PMID:38666481)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	irx5a	ENSDARG00000034043
danio_rerio	irx5b	ENSDARG00000074070
mus_musculus	Irx5	ENSMUSG00000031737
rattus_norvegicus	Irx5	ENSRNOG00000011180

Paralogs (6): IRX4 (ENSG00000113430), MKX (ENSG00000150051), IRX6 (ENSG00000159387), IRX1 (ENSG00000170549), IRX2 (ENSG00000170561), IRX3 (ENSG00000177508)

Protein

Protein identifiers

Iroquois-class homeodomain protein IRX-5 — P78411 (reviewed: P78411)

Alternative names: Homeodomain protein IRX-2A, Homeodomain protein IRXB2, Iroquois homeobox protein 5

All UniProt accessions (2): P78411, H0YML8

UniProt curated annotations — full annotation on UniProt →

Function. Establishes the cardiac repolarization gradient by its repressive actions on the KCND2 potassium-channel gene. Required for retinal cone bipolar cell differentiation. May regulate contrast adaptation in the retina and control specific aspects of visual function in circuits of the mammalian retina. Could be involved in the regulation of both the cell cycle and apoptosis in prostate cancer cells. Involved in craniofacial and gonadal development. Modulates the migration of progenitor cell populations in branchial arches and gonads by repressing CXCL12.

Subcellular location. Nucleus.

Disease relevance. Hamamy syndrome (HMMS) [MIM:611174] A syndrome characterized by severe hypertelorism, upslanting palpebral fissures, brachycephaly, abnormal ears, sloping shoulders, enamel hypoplasia, and osteopenia with repeated fractures. Additional features include myopia, mild to moderate sensorineural hearing loss, gonadal anomalies and borderline intelligence. The disease is caused by variants affecting the gene represented in this entry.

Induction. Down-regulated by 1,25-dihydroxyvitamin D3 in prostate cancer samples from patients assigned to receive weekly high-dose 1,25-dihydroxyvitamin D3 before radical prostatectomy. Also down-regulated by 1,25-dihydroxyvitamin D3 in the human androgen-sensitive prostate cancer cell line LNCaP and in the estrogen-sensitive breast cancer cell line MCF-7.

Similarity. Belongs to the TALE/IRO homeobox family.

Isoforms (3)

UniProt ID	Names	Canonical?
P78411-1	1	yes
P78411-2	2
P78411-3	3

RefSeq proteins (2): NP_001239126, NP_005844* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR003893	Iroquois_homeo	Domain
IPR008422	KN_HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site

Pfam: PF05920

UniProt features (17 total): compositionally biased region 5, modified residue 2, splice variant 2, sequence variant 2, sequence conflict 2, region of interest 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78411-F1	55.14	0.11

Functional residue map

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

Post-translational modifications (2): 464, 274

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 343 (showing top): RNGTGGGC_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BENPORATH_ES_WITH_H3K27ME3, FARMER_BREAST_CANCER_CLUSTER_7, HNF3ALPHA_Q6, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, PEREZ_TP63_TARGETS, GCANCTGNY_MYOD_Q6, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_NEURON_MATURATION, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GOZGIT_ESR1_TARGETS_DN, GOBP_NEUROGENESIS, GOBP_NEURAL_RETINA_DEVELOPMENT

GO Biological Process (11): regulation of heart rate (GO:0002027), regulation of transcription by RNA polymerase II (GO:0006357), visual perception (GO:0007601), gonad development (GO:0008406), neuron differentiation (GO:0030182), neuron maturation (GO:0042551), cell development (GO:0048468), embryonic cranial skeleton morphogenesis (GO:0048701), retinal bipolar neuron differentiation (GO:0060040), regulation of DNA-templated transcription (GO:0006355), regulation of gene expression (GO:0010468)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), vitamin D binding (GO:0005499), identical protein binding (GO:0042802), DNA-binding transcription factor binding (GO:0140297), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
regulation of heart contraction	1
regulation of biological quality	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
sensory perception of light stimulus	1
development of primary sexual characteristics	1
animal organ development	1
reproductive structure development	1
generation of neurons	1
cell maturation	1
neuron development	1
anatomical structure development	1
cellular developmental process	1
embryonic skeletal system morphogenesis	1
cranial skeletal system development	1
neural retina development	1
retina morphogenesis in camera-type eye	1
glutamatergic neuron differentiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
gene expression	1
regulation of macromolecule biosynthetic 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
steroid binding	1
vitamin binding	1
protein binding	1
transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1272 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRX5	KCND2	Q9NZV8	884
IRX5	SMYD1	Q8NB12	790
IRX5	HAND2	P61296	729
IRX5	KCNE4	Q8WWG9	688
IRX5	FTO	Q9C0B1	687
IRX5	GPD1L	Q8N335	668
IRX5	ARID5B	Q14865	644
IRX5	IRX3	P78415	634
IRX5	KCNE3	Q9Y6H6	612
IRX5	RPGRIP1L	Q68CZ1	606
IRX5	SCN1B	Q07699	601
IRX5	CACNB2	Q08289	595
IRX5	SCN5A	Q14524	594
IRX5	SCN3B	Q9NY72	559
IRX5	IRX6	P78412	556

IntAct

27 interactions, top by confidence:

A	B	Type	Score
	IRX5	psi-mi:“MI:0915”(physical association)	0.370
CCL1	IRX5	psi-mi:“MI:0915”(physical association)	0.370
CCL22	IRX5	psi-mi:“MI:0915”(physical association)	0.370
CCL5	IRX5	psi-mi:“MI:0915”(physical association)	0.370
CXCL10	IRX5	psi-mi:“MI:0915”(physical association)	0.370
IFNL1	IRX5	psi-mi:“MI:0915”(physical association)	0.370
IFNL4	IRX5	psi-mi:“MI:0915”(physical association)	0.370
IL15	IRX5	psi-mi:“MI:0915”(physical association)	0.370
IL33	IRX5	psi-mi:“MI:0915”(physical association)	0.370
PPBP	IRX5	psi-mi:“MI:0915”(physical association)	0.370
TNFSF10	IRX5	psi-mi:“MI:0915”(physical association)	0.370
TNFSF14	IRX5	psi-mi:“MI:0915”(physical association)	0.370
TNFSF4	IRX5	psi-mi:“MI:0915”(physical association)	0.370
TNFSF9	IRX5	psi-mi:“MI:0915”(physical association)	0.370
XCL2	IRX5	psi-mi:“MI:0915”(physical association)	0.370
TIMM10	DCTN6	psi-mi:“MI:0914”(association)	0.350
CALM1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): IRX5 (Synthetic Lethality), IRX5 (Affinity Capture-RNA), IRX5 (Affinity Capture-MS), IRX5 (Affinity Capture-MS), IRX5 (Affinity Capture-MS), IRX5 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A8V0YY16, A1YER7, A1YFD8, A1YFY3, A1YG01, A2D4R4, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T7J2, A8MTJ6, D3Z120, O08656, O43186, O43248, O54751, O60479, P02831, P09016, P09017, P09022, P09023, P09027, P10628, P14653, P17509, P17919, P18864, P31249, P31259, P31270, P31311, P31313, P49639, P50577, P56178, P78411, Q08624, Q08DG7

Diamond homologs: A1YER0, A2D5H2, A2Y007, A6NDR6, A8WL06, B3DM47, B4F6V6, B7ZRT8, O00470, O14770, O35317, O35984, O46339, O70477, O95343, P40424, P40425, P40426, P40427, P41778, P41779, P41817, P48002, P54269, P55347, P56663, P56668, P56669, P70284, P78411, P78412, P78413, P78415, P79937, P81066, P81067, P97367, P97368, Q15475, Q19503

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IRX5	“down-regulates quantity by repression”	KCND2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chemokine receptors bind chemokines	6	66.1×	4e-08
G alpha (i) signalling events	5	11.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
chemokine-mediated signaling pathway	5	90.0×	4e-07
antimicrobial humoral immune response mediated by antimicrobial peptide	5	45.0×	7e-06
cell-cell signaling	6	23.2×	1e-05
immune response	6	15.7×	5e-05
inflammatory response	7	14.7×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	94
Likely benign	34
Benign	8

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1695336	NM_005853.6(IRX5):c.503G>A (p.Arg168His)	Pathogenic
31910	NM_005853.6(IRX5):c.498C>A (p.Asn166Lys)	Pathogenic
31911	NM_005853.6(IRX5):c.448G>C (p.Ala150Pro)	Pathogenic
374379	NM_005853.6(IRX5):c.1362_1368delinsGT (p.Lys455fs)	Pathogenic

SpliceAI

470 predictions. Top by Δscore:

Variant	Effect	Δscore
16:54931445:GTG:G	donor_gain	1.0000
16:54931449:T:A	donor_loss	1.0000
16:54932901:CAG:C	donor_loss	1.0000
16:54932902:AGG:A	donor_loss	1.0000
16:54932903:GGT:G	donor_loss	1.0000
16:54932904:GTT:G	donor_loss	1.0000
16:54931443:ACGTG:A	donor_gain	0.9900
16:54931446:TG:T	donor_gain	0.9900
16:54931447:GG:G	donor_gain	0.9900
16:54931448:G:GG	donor_gain	0.9900
16:54932103:T:TA	acceptor_gain	0.9900
16:54932105:C:CA	acceptor_gain	0.9900
16:54932492:CCGCA:C	acceptor_loss	0.9900
16:54932493:CGCA:C	acceptor_loss	0.9900
16:54932494:GCA:G	acceptor_loss	0.9900
16:54932495:CA:C	acceptor_loss	0.9900
16:54932496:AG:A	acceptor_gain	0.9900
16:54932497:GG:G	acceptor_gain	0.9900
16:54932900:GCAG:G	donor_gain	0.9900
16:54932905:T:A	donor_loss	0.9900
16:54933071:CCGCA:C	acceptor_loss	0.9900
16:54933072:CGCAG:C	acceptor_loss	0.9900
16:54933073:GCAG:G	acceptor_loss	0.9900
16:54933074:CA:C	acceptor_loss	0.9900
16:54933075:A:AC	acceptor_loss	0.9900
16:54933075:A:AG	acceptor_gain	0.9900
16:54933076:G:GG	acceptor_gain	0.9900
16:54933076:GGA:G	acceptor_gain	0.9900
16:54931444:CGTG:C	donor_gain	0.9800
16:54931445:GTGG:G	donor_gain	0.9800

AlphaMissense

3068 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:54932600:A:G	K118E	1.000
16:54932601:A:T	K118M	1.000
16:54932602:G:C	K118N	1.000
16:54932602:G:T	K118N	1.000
16:54932605:C:A	N119K	1.000
16:54932605:C:G	N119K	1.000
16:54932607:C:A	A120D	1.000
16:54932610:C:T	T121I	1.000
16:54932612:A:T	R122W	1.000
16:54932613:G:C	R122T	1.000
16:54932613:G:T	R122M	1.000
16:54932614:G:C	R122S	1.000
16:54932614:G:T	R122S	1.000
16:54932615:G:C	D123H	1.000
16:54932618:G:C	A124P	1.000
16:54932619:C:A	A124D	1.000
16:54932622:C:A	T125K	1.000
16:54932622:C:G	T125R	1.000
16:54932622:C:T	T125M	1.000
16:54932624:G:C	A126P	1.000
16:54932630:C:T	L128F	1.000
16:54932631:T:A	L128H	1.000
16:54932631:T:C	L128P	1.000
16:54932631:T:G	L128R	1.000
16:54932633:A:G	K129E	1.000
16:54932634:A:C	K129T	1.000
16:54932634:A:T	K129M	1.000
16:54932635:G:C	K129N	1.000
16:54932635:G:T	K129N	1.000
16:54932636:G:C	A130P	1.000

dbSNP variants (sampled 300 via entrez): RS1001195200 (16:54929479 A>C), RS1001625127 (16:54929694 G>A,C), RS1003566953 (16:54930874 G>A), RS1003942349 (16:54930706 A>G), RS1004186647 (16:54934240 C>G), RS1004234257 (16:54934632 T>C), RS1004521316 (16:54932328 G>A), RS1005747422 (16:54929136 G>A), RS1006373517 (16:54929300 C>T), RS1007046704 (16:54932114 T>G), RS1007680401 (16:54930054 C>A,T), RS1010173761 (16:54929105 G>A,C), RS1011179609 (16:54929983 C>A), RS1011483601 (16:54929776 G>C), RS1012203916 (16:54932872 G>A,C)

Disease associations

OMIM: gene MIM:606195 | disease phenotypes: MIM:611174

GenCC curated gene-disease

Disease	Classification	Inheritance
craniofacial dysplasia - osteopenia syndrome	Strong	Autosomal recessive
cone dystrophy	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
craniofacial dysplasia - osteopenia syndrome	Moderate	AR

Mondo (2): craniofacial dysplasia - osteopenia syndrome (MONDO:0012634), cone dystrophy (MONDO:0000455)

Orphanet (1): Facial dysmorphism-ocular anomalies-osteopenia-intellectual disability-dental anomalies syndrome (Orphanet:314555)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000154	Wide mouth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000248	Brachycephaly
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000506	Telecanthus
HP:0000581	Blepharophimosis
HP:0000653	Sparse eyelashes
HP:0000668	Hypodontia
HP:0000689	Dental malocclusion
HP:0000767	Pectus excavatum
HP:0000829	Hypoparathyroidism
HP:0000938	Osteopenia
HP:0001159	Syndactyly
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001363	Craniosynostosis

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001066_13	Dialysis-related mortality	9.000000e-06
GCST002367_7	Social communication problems	2.000000e-06
GCST002563_16	Hypospadias	3.000000e-15
GCST005411_8	Thrombin-activatable fibrinolysis inhibitor activation peptide	4.000000e-07
GCST006288_174	Heel bone mineral density	2.000000e-06
GCST006288_276	Heel bone mineral density	2.000000e-13
GCST006288_344	Heel bone mineral density	1.000000e-08
GCST006979_673	Heel bone mineral density	2.000000e-15
GCST006979_674	Heel bone mineral density	8.000000e-48
GCST010002_112	Refractive error	7.000000e-10
GCST90011899_27	Aspartate aminotransferase levels	2.000000e-36
GCST90086158_18	Brugada syndrome	1.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005427	social communication impairment
EFO:0009270	heel bone mineral density
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
C566988	Hypertelorism, Severe, With Midface Prominence, Myopia, Mental Retardation, And Bone Fragility (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation, affects cotreatment, increases expression	5
trichostatin A	increases expression, affects cotreatment	3
sodium arsenite	affects methylation, decreases expression	3
entinostat	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
urushiol	decreases expression	1
arsenite	increases methylation	1
tobacco tar	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
clothianidin	decreases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Vehicle Emissions	decreases expression	1
Benzo(a)pyrene	increases expression	1
Carbamazepine	affects expression	1
Cytarabine	increases expression	1
Lead	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Plant Oils	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B5QE	ITXi002-A-1	Induced pluripotent stem cell	Male
CVCL_B5QF	ITXi002-A-2	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT03990727	Not specified	UNKNOWN	Phenotype Correlates Genotype of Inherited Retina Dystrophies, Retinitis Pigmentosa, Con>Rod Dystrophies.
NCT04658251	Not specified	TERMINATED	Study of New Mutations in Cone Disorders
NCT05355415	Not specified	RECRUITING	Adaptive Optics Imaging of Outer Retinal Diseases