HOXA13

Summary

HOXA13 (homeobox A13, HGNC:5102) is a protein-coding gene on chromosome 7p15.2, encoding Homeobox protein Hox-A13 (P31271). Sequence-specific, AT-rich binding transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.

In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which may regulate gene expression, morphogenesis, and differentiation. Expansion of a polyalanine tract in the encoded protein can cause hand-foot-uterus syndrome, also known as hand-foot-genital syndrome.

Source: NCBI Gene 3209 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hand-foot-genital syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 243 total — 7 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 43
• Transcription factor: yes — 16 downstream targets (CollecTRI)
• MANE Select transcript: NM_000522

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5102
Approved symbol	HOXA13
Name	homeobox A13
Location	7p15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000106031
Ensembl biotype	protein_coding
OMIM	142959
Entrez	3209

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000518136, ENST00000649031

RefSeq mRNA: 1 — MANE Select: NM_000522 NM_000522

CCDS: CCDS5412

Canonical transcript exons

ENST00000649031 — 2 exons

Exon	Start	End
ENSE00001213906	27194364	27198442
ENSE00003836209	27199156	27200091

Expression profiles

Bgee: expression breadth broad, 84 present calls, max score 93.65.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7074 / max 101.4961, expressed in 168 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83335	0.4090	106
83336	0.2984	112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.65	silver quality
endocervix	UBERON:0000458	92.08	gold quality
pancreatic ductal cell	CL:0002079	91.69	gold quality
ectocervix	UBERON:0012249	89.06	gold quality
uterine cervix	UBERON:0000002	86.96	gold quality
prostate gland	UBERON:0002367	86.41	gold quality
seminal vesicle	UBERON:0000998	86.11	gold quality
rectum	UBERON:0001052	85.61	gold quality
vagina	UBERON:0000996	85.60	gold quality
buccal mucosa cell	CL:0002336	85.40	gold quality
colonic mucosa	UBERON:0000317	84.55	gold quality
mucosa of sigmoid colon	UBERON:0004993	84.50	gold quality
urinary bladder	UBERON:0001255	82.69	gold quality
mucosa of transverse colon	UBERON:0004991	82.46	gold quality
transverse colon	UBERON:0001157	81.68	gold quality
muscle layer of sigmoid colon	UBERON:0035805	79.56	gold quality
large intestine	UBERON:0000059	78.71	gold quality
colon	UBERON:0001155	78.67	gold quality
placenta	UBERON:0001987	78.14	gold quality
urethra	UBERON:0000057	77.91	gold quality
tibialis anterior	UBERON:0001385	77.75	gold quality
calcaneal tendon	UBERON:0003701	75.28	gold quality
colonic epithelium	UBERON:0000397	75.17	gold quality
tibia	UBERON:0000979	73.02	gold quality
ileal mucosa	UBERON:0000331	70.30	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.27	gold quality
cardiac muscle of right atrium	UBERON:0003379	68.45	gold quality
kidney epithelium	UBERON:0004819	68.41	gold quality
sperm	CL:0000019	68.21	silver quality
left ventricle myocardium	UBERON:0006566	68.10	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.20

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

16 targets.

Target	Regulation
ALDH1A2
BMP4	Activation
BMP7	Unknown
CDKN2A
CISH
EPHA3	Unknown
EPHA4	Repression
EPHA6
EPHA7	Unknown
FGF8	Unknown
FOXF1	Unknown
HOXA11	Repression
SALL1	Repression
SALL3	Repression
SOSTDC1	Repression
TEK	Unknown

JASPAR motifs

Motif	Name	Family
MA0650.1	HOXA13	HOX
MA0650.2	HOXA13	HOX

JASPAR matrix evidence (PMIDs): PMID:17200107

Upstream regulators (CollecTRI, top): HOXD13, KDM6A, KMT2A

miRNA regulators (miRDB)

94 targeting HOXA13, 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-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917

Literature-anchored findings (GeneRIF, showing 40)

• a NUP98 primer and a degenerate primer corresponding to the third helix of the NUP98 was fused in-frame to HOXA13 in the patient with MDS(myelodysplastic syndrome). (PMID:11830496)
• A novel 2-bp deletion in the HOXA13 gene’s highly conserved promoter region alters a key residue in the recognition helix of the homeodomain and is likely to perturb HOXA13’s DNA-binding properties, resulting in both a loss and specific gain of function. (PMID:11968094)
• A novel stable polyalanine [poly(A)] expansion in the HOXA13 gene associated with hand-foot-genital syndrome: proper function of poly(A)-harbouring transcription factors depends on a critical repeat length? (PMID:12073020)
• The chromosome translocation t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with HOXA13. (PMID:12112533)
• There seems to be no evidence that isolated hypospadias is commonly caused by mutations in HOXA13. (PMID:14675924)
• analysis of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome (PMID:17935235)
• Maintenance of appropriate HOX transcriptional program in adult fibroblasts may serve as a source of positional memory to differentially pattern the epithelia during homeostasis and regeneration. (PMID:18245445)
• In the absence of HOXA13 function, placental endothelial cell morphology is altered, causing a loss in vessel wall integrity, edema of the embryonic blood vessels, and mid-gestational lethality. (PMID:18483557)
• The expression of HOXA13 can be detected in esophageal squamous cell carcinoma and is a negative independent predictor of disease-free survival. (PMID:19145497)
• Vaginal HOXA13 (homeobox A13) expression is diminished in women with pelvic organ prolapse compared with women with normal support (PMID:19423998)
• results showed that HOXA13 expression enhanced tumor growth in vitro and in vivo, and was a negative independent predictor of disease-free survival of patients with esophageal squamous cell carcinoma (PMID:19491265)
• A novel mutation of HOXA13 in a family with hand-foot-genital syndrome. (PMID:19591980)
• Overexpression of HOXA13 mRNA is associated with hepatocellular carcinoma. (PMID:21626505)
• conclude that the non-conserved residue, V373 is critical for structurally recognizing TAA in the major groove, and that HOXA13 dimerization is required to activate transcription of target genes (PMID:21829694)
• Results provide an additional support to a hypothesis that HOXA13 might participate in the carcinogenesis of esophageal squamous cell carcinoma. (PMID:21893383)
• Hoxa9 and Hoxa13 are involved in the early and organised patterning of ENS development in the zebrafish model. (PMID:21971947)
• A total of 14 DNA sequence variations (10 novel and 4 known) within exonic and untranslated regions were detected in HOXA10 and HOXA13 among our cohorts of female genital malformations. (PMID:23376215)
• two de novo cases of hand-foot-genital syndrome associated with polyalanine expansions in HOXA13 were identified. (PMID:23532960)
• Validated HOXA13 as a novel prognostic marker in gastric cancer based on immunohistochemistry and statistical analysis. HOXA13 expression was significantly up-regulated in cancerous tissues compared with the corresponding non-cancerous mucosa. (PMID:23592225)
• Our study highlights the key role of HOTTIP and HOXA13 in hepatocellular carcinoma development. (PMID:24114970)
• the present study demonstrated that ANXA2 and SOD2 are potential target genes of HOXA13 and their coexpression predicts the poor prognosis of Esophageal squamous cell carcinoma patients. (PMID:24626613)
• serum HOXA13 may serve as a biomarker for early hepatocellular carcinoma diagnosing and predicting outcome. (PMID:25341685)
• HOTTIP/HOXA13 axis is a potential therapeutic target and molecular biomarker for pancreatic ductal adenocarcinoma. (PMID:25889214)
• study demonstrates that aberrant reduction of HOTTIP and HOXA13, which have a bidirectional regulatory loop, may play an important role in the pathogenesis of HSCR (PMID:26043692)
• HOXA13 promotes glioma progression in part via Wnt- and TGF-beta-induced epithelial-mesenchymal transition (PMID:26356815)
• This pregnancy-maintaining regionalization of myometrial function may be mediated by HoxA13 (PMID:26485220)
• Atypical hand-foot-genital syndrome and developmental delay due to de novo mutations in HOXA13 and NRXN1 (PMID:26590955)
• Transfection of HOXA13 in HKCs could inhibit the degree of EMT induced by albumin-overload, possibly by increasing BMP-7 expression. (PMID:26695677)
• HoxA13 increases myometrial cell contractility by enhancing the secretion of IL-1beta, resulting in an up-regulation of CAP and other proinflammatory cytokine expression. (PMID:26982635)
• Down-regulation of HOTTIP and HOXA13 was associated with cell growth and cell cycle, and exerts tumor-suppressive functions in the genesis and progression of prostate cancer, providing a potential attractive therapeutic approach for this malignancy. (PMID:27064878)
• expression levels of HOTTIP and HOXA13 were both higher in gastric cancer which was poorly differentiated, at advanced TNM stages and exhibited lymph node-metastasis. Spearman analyses indicated that HOTTIP and HOXA13 had a highly positive correlation both in non-tumor mucosae and cancer lesions. Collectively, these findings suggest that HOTTIP and HOXA13 play important roles in gastric cancer progression. (PMID:27108607)
• Knockdown of HoxA13 caused the downregulation of long non-coding RNA HOTTIP and insulin growth factor-binding protein 3 (IGFBP-3) genes, indicating that both were targets of HoxA13. (PMID:27144338)
• HOXA13 is involved in HSAinduced EMT in HKC cells and upregulation of HOXA13 exerts a beneficial effect in EMT, which may be associated with the GR signaling pathway. (PMID:27176855)
• The results of our study show that high expression of HOXA13 is associated with the progression of bladder cancer and that HOXA13 might serve as a biomarker for prognosis of bladder cancer. (PMID:27830363)
• using both knockdown and knockout approaches we show that Hottip expression is required for activation of the 5’ Hoxa genes (Hoxa13 and Hoxa10/11) and for retaining Mll1 at the 5’ end of Hoxa. Moreover, we demonstrate that artificially inducing Hottip expression is sufficient to activate the 5’ Hoxa genes and that Hottip RNA binds to the 5’ end of Hoxa (PMID:28384324)
• Findings indicated that HOTTIP modulated HOXA13 at both the transcriptional and posttranscriptional levels in ESCC cells. (PMID:28534516)
• HOXA13 is an unfavorable prognostic factor and a novel oncogene for prostate cancer. (PMID:28766961)
• Findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. (PMID:28782268)
• Our study indicated that alteration of EPHA7 promoter transactivation produced by missensemutations of HOXA13 provided a molecular basis for HFGS. (PMID:28947713)
• Data suggest that patients with HOXA13-positive hepatocellular carcinomas experience worse overall survival than those with HOXA13-negative HCC; HOXA13 and HOTTIP (know regulator of HOXA13 expression) are expressed in the same neoplastic hepatocyte populations. (HOTTIP = long noncoding RNA HOTTIP) (PMID:29035381)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hoxa13	ENSMUSG00000038203
rattus_norvegicus	Hoxa13	ENSRNOG00000057061

Paralogs (42): HOXA11 (ENSG00000005073), HOXC8 (ENSG00000037965), HOXA1 (ENSG00000105991), HOXA2 (ENSG00000105996), HOXA3 (ENSG00000105997), HOXA5 (ENSG00000106004), HOXA6 (ENSG00000106006), TLX1 (ENSG00000107807), HOXB6 (ENSG00000108511), TLX2 (ENSG00000115297), HOXB8 (ENSG00000120068), HOXB5 (ENSG00000120075), HOXB3 (ENSG00000120093), HOXB1 (ENSG00000120094), HOXA7 (ENSG00000122592), HOXC13 (ENSG00000123364), HOXC11 (ENSG00000123388), HOXC12 (ENSG00000123407), HOXD1 (ENSG00000128645), HOXD3 (ENSG00000128652), HOXD9 (ENSG00000128709), HOXD10 (ENSG00000128710), HOXD11 (ENSG00000128713), HOXD13 (ENSG00000128714), PDX1 (ENSG00000139515), HOXB13 (ENSG00000159184), TLX3 (ENSG00000164438), HOXD4 (ENSG00000170166), HOXD12 (ENSG00000170178), HOXB9 (ENSG00000170689), HOXC5 (ENSG00000172789), HOXB2 (ENSG00000173917), HOXD8 (ENSG00000175879), GSX2 (ENSG00000180613), HOXC9 (ENSG00000180806), HOXC10 (ENSG00000180818), HOXB4 (ENSG00000182742), HOXA4 (ENSG00000197576), HOXC6 (ENSG00000197757), HOXC4 (ENSG00000198353)

Protein

Protein identifiers

Homeobox protein Hox-A13 — P31271 (reviewed: P31271)

Alternative names: Homeobox protein Hox-1J

All UniProt accessions (1): P31271

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific, AT-rich binding transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.

Subunit / interactions. Binds DNA as a homodimer. Interacts with MEIS1, MEIS2 and MEIS3.

Subcellular location. Nucleus.

Disease relevance. Hand-foot-genital syndrome (HFG) [MIM:140000] A disorder characterized by limb and genitourinary anomalies. Clinical features include small feet with unusually short great toes and abnormal thumbs. Females with the disorder have duplication of the genital tract. The disease is caused by variants affecting the gene represented in this entry. Guttmacher syndrome (GUTTS) [MIM:176305] Dominantly inherited combination of distal limb and genital tract abnormalities. It has several features in common with hand-foot-genital syndrome, including hypoplastic first digits and hypospadias. Typical features not seen in hand-foot-genital syndrome include postaxial polydactyly of the hands and uniphalangeal second toes with absent nails. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Abd-B homeobox family.

RefSeq proteins (1): NP_000513* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR022067	HoxA13_N	Domain
IPR051003	AP_axis_regulatory_Homeobox	Family

Pfam: PF00046, PF12284

UniProt features (16 total): sequence variant 6, sequence conflict 4, helix 3, chain 1, DNA-binding region 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2L7Z	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31271-F1	56.23	0.18

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 345 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_PROSTATE_GLAND_MORPHOGENESIS, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_MALE_GENITALIA_DEVELOPMENT, GOBP_ARTERY_DEVELOPMENT

GO Biological Process (25): skeletal system development (GO:0001501), vasculogenesis (GO:0001570), endothelial cell morphogenesis (GO:0001886), tissue homeostasis (GO:0001894), ventricular septum development (GO:0003281), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), regulation of BMP signaling pathway (GO:0030510), male genitalia development (GO:0030539), response to testosterone (GO:0033574), embryonic forelimb morphogenesis (GO:0035115), positive regulation of mitotic nuclear division (GO:0045840), embryonic hindgut morphogenesis (GO:0048619), inner ear development (GO:0048839), artery morphogenesis (GO:0048844), branching involved in prostate gland morphogenesis (GO:0060442), endothelial cell fate specification (GO:0060847), mesenchymal cell apoptotic process (GO:0097152), mitotic nuclear division (GO:0140014), positive regulation of mesenchymal cell apoptotic process (GO:2001055), regulation of DNA-templated transcription (GO:0006355), anatomical structure morphogenesis (GO:0009653), animal organ morphogenesis (GO:0009887), prostate gland development (GO:0030850), 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), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), cis-regulatory region sequence-specific DNA binding (GO:0000987), DNA-binding transcription factor activity (GO:0003700)

GO Cellular Component (5): chromatin (GO:0000785), nucleoplasm (GO:0005654), chromosome (GO:0005694), intermediate filament cytoskeleton (GO:0045111), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
blood vessel morphogenesis	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
system development	1
cell differentiation	1
endothelial cell development	1
epithelial cell morphogenesis	1
multicellular organismal-level homeostasis	1
anatomical structure homeostasis	1
cardiac ventricle development	1
cardiac septum development	1
transcription by RNA polymerase II	1
DNA-templated transcription	1
BMP signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to growth factor stimulus	1
male sex differentiation	1
genitalia development	1
reproductive system development	1
response to lipid	1
response to ketone	1
embryonic limb morphogenesis	1
forelimb morphogenesis	1
regulation of mitotic nuclear division	1
positive regulation of nuclear division	1
positive regulation of cell cycle process	1
mitotic nuclear division	1
hindgut morphogenesis	1
embryonic morphogenesis	1
ear development	1
anatomical structure development	1
artery development	1
prostate gland morphogenesis	1
prostate gland epithelium morphogenesis	1
morphogenesis of a branching epithelium	1
cell fate specification	1
endothelial cell fate commitment	1
apoptotic process	1

Protein interactions and networks

STRING

1174 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HOXA13	RPS16	P17008	631
HOXA13	NUP98	P52948	607
HOXA13	FOXL2	P58012	607
HOXA13	HOXA10	P31260	596
HOXA13	ZIC2	O95409	596
HOXA13	SMAD5	Q99717	585
HOXA13	WNT5A	P41221	582
HOXA13	KRT9	P35527	577
HOXA13	EMX2	Q04743	573
HOXA13	RPL13A	P40429	549
HOXA13	MEIS1	O00470	547
HOXA13	RUNX2	Q13950	542
HOXA13	MEIS2	O14770	522
HOXA13	SOX3	P35714	509
HOXA13	HOXA7	P31268	503

IntAct

7 interactions, top by confidence:

A	B	Type	Score
PARP1	KPNA3	psi-mi:“MI:0914”(association)	0.350
PSME4	PSMD1	psi-mi:“MI:0914”(association)	0.350
ATF3	C11orf98	psi-mi:“MI:0914”(association)	0.350
AIM2	DDX39A	psi-mi:“MI:0914”(association)	0.350
PYHIN1	SUPT5H	psi-mi:“MI:0914”(association)	0.350
FHIP1B	MED19	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (19): HOXA13 (Affinity Capture-MS), HOXA13 (Co-localization), HOXA13 (Affinity Capture-MS), HOXA13 (Affinity Capture-MS), HOXA13 (Affinity Capture-MS), HOXA13 (Affinity Capture-MS), HOXA13 (Proximity Label-MS), HOXA13 (Proximity Label-MS), HOXA13 (Affinity Capture-MS), HOXA13 (Affinity Capture-MS), HOXA13 (Affinity Capture-MS), HOXA13 (Affinity Capture-MS), HOXA13 (Positive Genetic), HOXA13 (Protein-peptide), HOXA13 (Affinity Capture-MS)

ESM2 similar proteins: M0R6D8, O09113, O35690, O35762, O93385, P02831, P09026, P14651, P23463, P31271, P31314, P32242, P43241, P56673, P70314, P70390, P78337, P78411, P78426, P80205, P81066, P83949, P83950, Q00939, Q04649, Q06453, Q1A1A3, Q1A1A4, Q28EM7, Q566X8, Q5XKR4, Q60554, Q60987, Q61060, Q62424, Q63410, Q6DGH9, Q8NFW5, Q90267, Q91ZK4

Diamond homologs: A1YFT7, A2D5V0, A2D635, A2T6F8, A2T7D1, A2T7H7, G5EFY5, O14627, O42502, O42506, O43248, P02835, P09013, P09067, P09079, P09087, P09631, P09633, P10038, P10179, P17482, P17919, P20615, P23812, P24061, P24341, P24342, P24343, P24344, P28358, P28359, P31257, P31260, P31263, P31268, P31269, P31271, P31272, P31274, P31275

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
HOXA13	“up-regulates quantity by expression”	EPHA7	“transcriptional regulation”
KDM6A	“up-regulates quantity by expression”	HOXA13	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	4
Uncertain significance	146
Likely benign	61
Benign	12

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
14889	NM_000522.5(HOXA13):c.1107G>A (p.Trp369Ter)	Pathogenic
14890	NM_000522.5(HOXA13):c.407C>A (p.Ser136Ter)	Pathogenic
14891	NM_000522.5(HOXA13):c.366_389dup (p.Ala133_Ser134insAlaAlaAlaAlaAlaAlaAlaAla)	Pathogenic
14892	NM_000522.5(HOXA13):c.1114A>C (p.Asn372His)	Pathogenic
14895	NM_000522.5(HOXA13):c.366_392dup (p.Ala133_Ser134insAlaAlaAlaAlaAlaAlaAlaAlaAla)	Pathogenic
14896	NM_000522.5(HOXA13):c.355_406dup (p.Ser136fs)	Pathogenic
3382721	NM_000522.5(HOXA13):c.730C>T (p.Gln244Ter)	Pathogenic
1801485	NM_000522.5(HOXA13):c.869A>C (p.Tyr290Ser)	Likely pathogenic
1805747	NM_000522.5(HOXA13):c.741dup (p.Gly248fs)	Likely pathogenic
3594500	NM_000522.5(HOXA13):c.837G>A (p.Trp279Ter)	Likely pathogenic
3594514	NM_000522.5(HOXA13):c.423_424delinsA (p.Ala142fs)	Likely pathogenic

SpliceAI

319 predictions. Top by Δscore:

Variant	Effect	Δscore
7:27198440:CGT:C	acceptor_gain	0.9900
7:27199375:AGC:A	donor_gain	0.9900
7:27198238:TTA:T	donor_gain	0.9800
7:27198245:T:A	donor_gain	0.9800
7:27198438:CACGT:C	acceptor_gain	0.9800
7:27198443:C:CC	acceptor_gain	0.9800
7:27199171:T:TA	donor_gain	0.9800
7:27198272:G:A	donor_gain	0.9700
7:27198441:GTCT:G	acceptor_loss	0.9400
7:27198442:TCT:T	acceptor_loss	0.9400
7:27198443:C:T	acceptor_loss	0.9400
7:27198444:T:C	acceptor_loss	0.9400
7:27198524:G:A	donor_gain	0.9300
7:27199075:AC:A	donor_gain	0.9100
7:27199076:CC:C	donor_gain	0.9100
7:27198983:A:C	donor_gain	0.9000
7:27199399:C:CA	donor_gain	0.9000
7:27199404:G:C	donor_gain	0.9000
7:27198439:ACGT:A	acceptor_gain	0.8900
7:27198440:CGTC:C	acceptor_gain	0.8900
7:27198267:G:T	donor_gain	0.8800
7:27199375:AG:A	donor_gain	0.8800
7:27199398:T:TA	donor_gain	0.8800
7:27198264:TGTG:T	donor_gain	0.8700
7:27197917:T:C	donor_gain	0.8600
7:27199257:T:A	donor_gain	0.8600
7:27199070:AACG:A	donor_loss	0.8500
7:27199071:ACG:A	donor_loss	0.8500
7:27199072:CGC:C	donor_loss	0.8500
7:27199073:GCA:G	donor_loss	0.8500

AlphaMissense

2495 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:27198228:T:A	K379N	1.000
7:27198228:T:G	K379N	1.000
7:27198230:T:C	K379E	1.000
7:27198231:T:A	K378N	1.000
7:27198231:T:G	K378N	1.000
7:27198232:T:A	K378I	1.000
7:27198233:T:C	K378E	1.000
7:27198235:T:A	E377V	1.000
7:27198236:C:T	E377K	1.000
7:27198237:T:A	K376N	1.000
7:27198237:T:G	K376N	1.000
7:27198238:T:A	K376I	1.000
7:27198239:T:C	K376E	1.000
7:27198239:T:G	K376Q	1.000
7:27198241:A:G	V375A	1.000
7:27198241:A:T	V375D	1.000
7:27198243:C:A	R374S	1.000
7:27198243:C:G	R374S	1.000
7:27198244:C:A	R374M	1.000
7:27198244:C:G	R374T	1.000
7:27198245:T:A	R374W	1.000
7:27198245:T:C	R374G	1.000
7:27198246:C:A	R373S	1.000
7:27198246:C:G	R373S	1.000
7:27198247:C:A	R373M	1.000
7:27198247:C:G	R373T	1.000
7:27198248:T:A	R373W	1.000
7:27198248:T:C	R373G	1.000
7:27198249:G:C	N372K	1.000
7:27198249:G:T	N372K	1.000

dbSNP variants (sampled 300 via entrez): RS1000111576 (7:27200792 G>A), RS1000450095 (7:27198768 T>G), RS1000480322 (7:27196494 A>G), RS1000849097 (7:27196141 C>A,G), RS1000965196 (7:27200553 T>A,C,G), RS1001459584 (7:27194436 C>T), RS1002121673 (7:27197663 A>T), RS1002335913 (7:27199076 C>G), RS1002465599 (7:27195646 A>G), RS1002570235 (7:27194522 T>C), RS1002791214 (7:27200156 C>A,G,T), RS1003061000 (7:27195399 C>T), RS1003215212 (7:27200236 C>A,T), RS1004279498 (7:27196114 C>T), RS1004481864 (7:27201377 A>G)

Disease associations

OMIM: gene MIM:142959 | disease phenotypes: MIM:140000, MIM:176305

GenCC curated gene-disease

Disease	Classification	Inheritance
hand-foot-genital syndrome	Definitive	Autosomal dominant
Guttmacher syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hand-foot-genital syndrome	Definitive	AD

Mondo (3): hand-foot-genital syndrome (MONDO:0007698), Guttmacher syndrome (MONDO:0008301), congenital heart disease (MONDO:0005453)

Orphanet (2): Hand-foot-genital syndrome (Orphanet:2438), Guttmacher syndrome (Orphanet:2957)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000041	Chordee
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000074	Ureteropelvic junction obstruction
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000130	Abnormality of the uterus
HP:0000486	Strabismus
HP:0000795	Abnormality of the urethra
HP:0000807	Glanular hypospadias
HP:0000813	Bicornuate uterus
HP:0000960	Sacral dimple
HP:0001156	Brachydactyly
HP:0001162	Postaxial hand polydactyly
HP:0001216	Delayed ossification of carpal bones
HP:0001245	Small thenar eminence
HP:0001629	Ventricular septal defect
HP:0001792	Small nail
HP:0001885	Short 2nd toe
HP:0003762	Uterus didelphys
HP:0004209	Clinodactyly of the 5th finger
HP:0005048	Synostosis of carpal bones
HP:0005268	Miscarriage
HP:0006110	Shortening of all middle phalanges of the fingers
HP:0007477	Abnormal dermatoglyphics
HP:0008080	Hallux varus
HP:0008103	Delayed tarsal ossification

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006364_3	Hepatitis B surface antigen seroclearance in chronic hepatitis B infection	3.000000e-06
GCST009391_630	Metabolite levels	5.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009345	Hepatitis B virus surface antigen seropositivity
EFO:0010503	inosine measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
C535627	Hand foot uterus syndrome (supp.)
C538278	Preaxial deficiency, postaxial polydactyly and hypospadias (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3807598	HOTTIP, HOXA13		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Copper	affects cotreatment, increases expression, affects binding, decreases expression	2
aristolochic acid I	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
terbufos	increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
NSC 689534	affects binding, decreases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Diazinon	increases methylation	1
Drugs, Chinese Herbal	decreases expression	1
Fonofos	increases methylation	1
Hydrogen Peroxide	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Tunicamycin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
Thapsigargin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE