HOXA1

Summary

HOXA1 (homeobox A1, HGNC:5099) is a protein-coding gene on chromosome 7p15.2, encoding Homeobox protein Hox-A1 (P49639). Sequence-specific transcription factor.

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. The encoded protein may be involved in the placement of hindbrain segments in the proper location along the anterior-posterior axis during development. Two transcript variants encoding two different isoforms have been found for this gene, with only one of the isoforms containing the homeodomain region.

Source: NCBI Gene 3198 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 119 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 8
• Transcription factor: yes — 28 downstream targets (CollecTRI)
• MANE Select transcript: NM_005522

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5099
Approved symbol	HOXA1
Name	homeobox A1
Location	7p15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000105991
Ensembl biotype	protein_coding
OMIM	142955
Entrez	3198

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000355633, ENST00000643460

RefSeq mRNA: 2 — MANE Select: NM_005522 NM_005522, NM_153620

CCDS: CCDS5401, CCDS5402

Canonical transcript exons

ENST00000643460 — 2 exons

Exon	Start	End
ENSE00003814410	27092993	27094795
ENSE00003826478	27095261	27096000

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 82.92.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1100 / max 102.1203, expressed in 875 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83256	1.8529	829
83255	0.1225	44
83254	0.1080	41
83252	0.0135	4
83253	0.0131	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	82.92	gold quality
secondary oocyte	CL:0000655	82.02	gold quality
hair follicle	UBERON:0002073	80.69	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.68	gold quality
epithelium of esophagus	UBERON:0001976	80.45	gold quality
oocyte	CL:0000023	79.06	gold quality
squamous epithelium	UBERON:0006914	71.15	gold quality
lower esophagus mucosa	UBERON:0035834	70.42	gold quality
esophagus mucosa	UBERON:0002469	69.08	gold quality
mucosa of transverse colon	UBERON:0004991	68.48	gold quality
germinal epithelium of ovary	UBERON:0001304	67.29	gold quality
granulocyte	CL:0000094	67.12	gold quality
urinary bladder	UBERON:0001255	66.97	gold quality
endometrium epithelium	UBERON:0004811	66.63	gold quality
mucosa of sigmoid colon	UBERON:0004993	64.20	gold quality
colonic mucosa	UBERON:0000317	63.71	gold quality
adrenal tissue	UBERON:0018303	63.18	gold quality
parietal pleura	UBERON:0002400	62.87	gold quality
metanephros	UBERON:0000081	62.62	gold quality
renal glomerulus	UBERON:0000074	62.61	silver quality
nipple	UBERON:0002030	62.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.78	gold quality
stromal cell of endometrium	CL:0002255	61.74	gold quality
tibia	UBERON:0000979	61.48	gold quality
metanephric glomerulus	UBERON:0004736	61.32	silver quality
rectum	UBERON:0001052	61.30	gold quality
skin of hip	UBERON:0001554	61.13	gold quality
esophagus	UBERON:0001043	60.97	gold quality
pleura	UBERON:0000977	60.93	gold quality
lymph node	UBERON:0000029	60.33	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	147.39
E-MTAB-8060	no	70.86
E-ANND-3	no	2.18

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

28 targets.

Target	Regulation
ABI3
ACTB
ADRA1D
ALDH1A2
BCL2	Activation
CCND1	Activation
CDH6	Unknown
EPAS1	Unknown
GRB2	Activation
HOXA1
HOXA4
HOXB1
IBSP
IER3	Unknown
L1CAM
LAMB1	Unknown
LYL1	Unknown
MAP2	Activation
MITF
MT1A
MYC	Activation
NCAM1
NES
PAX3	Activation
PCNA	Unknown
PRLR	Unknown
RHOB	Activation
SOX17	Repression

JASPAR motifs

Motif	Name	Family
MA1495.1	HOXA1	HOX
MA1495.2	HOXA1	HOX
MA1931.1	ELK1::HOXA1	Ets-related::HOX-related factors

JASPAR matrix evidence (PMIDs): PMID:16341070, PMID:24218641

Upstream regulators (CollecTRI, top): ESR1, HOXA1, HOXB1, KDM6A, KMT2A, MBD2, MITF, RARA, RARG, RXRA, ZNF335

miRNA regulators (miRDB)

100 targeting HOXA1, 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-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-4262	100.00	73.26	3931
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734

Literature-anchored findings (GeneRIF, showing 40)

• the effects of mutations in Hoxa1 and HoxA2 in the development of neural crest-derived structures in mice. (PMID:10529419)
• It is unlikely that HoxA1 plays a significant role in the genetic predisposition to autism. (PMID:11840501)
• No evidence for linkage of liability to autism to HOXA1 in a sample from the CPEA network (PMID:12210285)
• hoxa1 protein plays a role in the development of infantile autism (PMID:12349873)
• HOXA1 is a human mammary epithelial oncogene with aggressive in vivo tumor formation (PMID:12482855)
• The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. (PMID:14960295)
• Mutations in HOXA1 resulting in abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder were identified. (PMID:16155570)
• HOXA1 protein with polyhistidine tract expansions misfold, aggregate, and have a toxic effect on cell. (PMID:16168961)
• HOXA1 is a downstream effector of E-cadherin-directed signaling required for anchorage-independent proliferation of mammary carcinoma cells. (PMID:16373333)
• The HOXA1-related syndrome phenotype is variable; HOXA1 mutations are a rare cause of isolated Duane anomaly. (PMID:16528738)
• Study reveals the preferential expression of HOXA1 by metaphase II oocytes. (PMID:16597639)
• Expanded polyhistidine repeats in HOXA1 enhance aggregation and cell death, resulting in impaired neuronal differentiation and cooperative binding with PBX1. (PMID:17131398)
• Variation not associated with autism in an Indian population. (PMID:17167333)
• HOXA1 A218G alleles significantly influence head growth rates, but not final head size, in normal human development. (PMID:17171652)
• Modulation of the p44/42 MAP kinase pathway is one mechanism by which HOXA1 mediates oncogenic transformation of the human mammary epithelial cell. (PMID:17213808)
• This report extends the Bosley-Salih-Alorainy syndrome phenotype and documents the clinical variability resulting from identical HOXA1 mutations within an isolated ethnic population (PMID:17875913)
• Results identified HOXA1 loci showing significant differential DNA methylation levels between tumor and non-tumor lung and highly significant hypermethylation in adenocarcinoma. (PMID:17967182)
• HOXA1 partially mediates oncogenic transformation of the immortalized human mammary epithelial cell through modulation of the STAT3 and STAT5B pathways. (PMID:18276758)
• study describes nine previously unreported individuals from six families who have homozygous mutations of HOXA1 and either the Bosley-Salih-Alorainy syndrome (BSAS) or the Athabascan brainstem dysgenesis syndrome (ABDS) (PMID:18412118)
• These data suggest that the HOXA1 A218G polymorphism may affect cerebellar development in humans. (PMID:19018953)
• HOXA1 is associated with autistic traits, empathy, and Asperger syndrome. (PMID:19598235)
• HOXA1 mutations are not a common cause of sporadic Mobius syndrome in the general population (PMID:20227628)
• the combination of miR-377 and miR-217 help regulate HO-1 protein expression in the presence of hemin (PMID:21106538)
• the importance of the Hox-Pbx interaction for the oncogenic activity of Hoxa1 (PMID:21957483)
• HOXA1 A218G and HOXB1 nINS/INS variants may not contribute significantly to autism spectrum disorders risk (PMID:21980499)
• study demonstrates KDM3A is overexpressed in various types of cancer and directly activates transcription of HOXA1 through demethylation of histone H3K9 by binding to its promoter region (PMID:22020899)
• Loss of HOXA1 is associated with pancreatic cancer. (PMID:22407312)
• HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with oral squamous cell carcinoma. (PMID:22498108)
• Overexpression of HOXA1 is associated with hepatocellular carcinoma. (PMID:22864671)
• The findings in this patient raise the possibility that PTPRN2 may be active during early development of the human brainstem and that its overexpression may cause bilateral Duane retraction syndrome as occurs in patients with homozygous HOXA1 mutations. (PMID:22950449)
• Data indicate that MiR-10a has a role in megakaryocyte differentiation of stem cells via HOXA1 transcription factor targeting. (PMID:23321646)
• validation data and mechanistic insights suggest that patients whose primary tumors express HOXA1 are among a high-risk metastasis subgroup that should be considered for anti-TGFbeta therapy in adjuvant settings (PMID:23435427)
• MicroRNA-99 family members suppress Homeobox A1 expression in epithelial cells. (PMID:24312487)
• HOXA1-mediated SCLC chemoresistance is under the regulation of miR-100. HOXA1 may be a prognostic predictor and potential therapeutic target in human SCLC (PMID:24559685)
• The results demonstrated that miR-181c transcription is suppressed and HOXA1 expression is enhanced in hepatitis C virus-infected hepatocytes. (PMID:24789793)
• In a Middle Eastern population, HOXA1 is not likely a common cause of non-syndromic deafness. (PMID:24878468)
• Analysis indicates that the genes BIRC5, HOXA1 and RARB are critical targets that play an important regulatory role in cervical cancer pathogenesis. (PMID:25069511)
• ACK1 interacts with KDM3A to regulate the mammary tumor oncogene HOXA1. (PMID:25148682)
• YAP regulates the expression of HOXA1 and HOXC13 in human keratinocytes. (PMID:25691658)
• our findings suggest that HOXA1 is involved in the regulation of prostate cancer progression, including cell growth, migration, invasion and metastasis (PMID:26135141)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hoxa1a	ENSDARG00000104307
mus_musculus	Hoxa1	ENSMUSG00000029844
rattus_norvegicus	Hoxa1	ENSRNOG00000005628

Paralogs (42): HOXA11 (ENSG00000005073), HOXC8 (ENSG00000037965), HOXA2 (ENSG00000105996), HOXA3 (ENSG00000105997), HOXA5 (ENSG00000106004), HOXA6 (ENSG00000106006), HOXA13 (ENSG00000106031), 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-A1 — P49639 (reviewed: P49639)

Alternative names: Homeobox protein Hox-1F

All UniProt accessions (2): P49639, E7ERT8

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific transcription factor. Regulates multiple developmental processes including brainstem, inner and outer ear, abducens nerve and cardiovascular development and morphogenesis as well as cognition and behavior. Also part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis. Acts on the anterior body structures. Seems to act in the maintenance and/or generation of hindbrain segments. Activates transcription in the presence of PBX1A and PKNOX1.

Subunit / interactions. Interacts with OGT (via TPR repeats domain); the interaction takes place mainly in the nucleus. Forms a DNA-binding heterodimer with transcription factor PBX1.

Subcellular location. Nucleus.

Disease relevance. Athabaskan brainstem dysgenesis syndrome (ABDS) [MIM:601536] Characterized by horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Some patients had swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies. The disease is caused by variants affecting the gene represented in this entry. Bosley-Salih-Alorainy syndrome (BSAS) [MIM:601536] A disease characterized by horizontal gaze abnormalities, deafness, facial weakness, vascular malformations of the internal carotid arteries and cardiac outflow trac. Some patients manifest intellectual disability and autism spectrum disorder. Affected individuals do not suffer from central hypoventilation. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Lacks the homeobox domain. Lacks the homeobox domain.

Similarity. Belongs to the Antp homeobox family. Labial subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P49639-1	3, 36 kDa	yes
P49639-2	1, 14 kDa
P49639-3	2, 24 kDa

RefSeq proteins (2): NP_005513, NP_705873 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR046327	HXA1/B1/D1	Family

Pfam: PF00046

UniProt features (15 total): splice variant 4, region of interest 3, compositionally biased region 3, sequence variant 2, chain 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49639-F1	59.15	0.20

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis

MSigDB gene sets: 276 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, ACTACCT_MIR196A_MIR196B, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, PAX4_01, TGCGCANK_UNKNOWN, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, TATTATA_MIR374, GOBP_ARTERY_DEVELOPMENT

GO Biological Process (18): regulation of transcription by RNA polymerase II (GO:0006357), sensory perception of sound (GO:0007605), optokinetic behavior (GO:0007634), anatomical structure morphogenesis (GO:0009653), abducens nerve formation (GO:0021599), outer ear morphogenesis (GO:0042473), positive regulation of transcription by RNA polymerase II (GO:0045944), embryonic neurocranium morphogenesis (GO:0048702), inner ear development (GO:0048839), artery morphogenesis (GO:0048844), regulation of behavior (GO:0050795), cognition (GO:0050890), neuromuscular process (GO:0050905), artery development (GO:0060840), semicircular canal formation (GO:0060876), cochlea development (GO:0090102), cochlea morphogenesis (GO:0090103), regulation of DNA-templated transcription (GO:0006355)

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), identical protein binding (GO:0042802), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Activation of HOX genes during differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
embryonic morphogenesis	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
nervous system process	2
sensory perception of mechanical stimulus	1
visual behavior	1
developmental process	1
abducens nerve morphogenesis	1
cranial nerve formation	1
ear morphogenesis	1
positive regulation of DNA-templated transcription	1
embryonic cranial skeleton morphogenesis	1
ear development	1
blood vessel morphogenesis	1
artery development	1
behavior	1
regulation of multicellular organismal process	1
blood vessel development	1
tube formation	1
semicircular canal morphogenesis	1
inner ear development	1
inner ear morphogenesis	1
cochlea development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	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
protein binding	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1

Protein interactions and networks

STRING

654 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HOXA1	CHN1	P15882	847
HOXA1	ROBO3	Q96MS0	722
HOXA1	SALL4	Q9UJQ4	713
HOXA1	CRABP1	P29762	670
HOXA1	PBX1	P40424	559
HOXA1	SHH	Q15465	429
HOXA1	GDAP1	Q8TB36	420
HOXA1	FGFRL1	Q8N441	348
HOXA1	CDYL2	Q8N8U2	327
HOXA1	CLDN14	O95500	318
HOXA1	TP53I11	O14683	310
HOXA1	CDC42EP2	O14613	306
HOXA1	PBX2	P40425	305
HOXA1	CTDSPL	O15194	301
HOXA1	MEIS3	Q99687	301

IntAct

1299 interactions, top by confidence:

A	B	Type	Score
HOXA1	GRN	psi-mi:“MI:0915”(physical association)	0.950
GRN	HOXA1	psi-mi:“MI:0915”(physical association)	0.950
HOXA1	LCE1B	psi-mi:“MI:0915”(physical association)	0.830
LCE1B	HOXA1	psi-mi:“MI:0915”(physical association)	0.830
HOXA1	HOXA1	psi-mi:“MI:0915”(physical association)	0.800
HOXA1	MDFI	psi-mi:“MI:0915”(physical association)	0.800
HOXA1	KRT31	psi-mi:“MI:0915”(physical association)	0.780
KRTAP4-12	HOXA1	psi-mi:“MI:0915”(physical association)	0.780
HOXA1	KRTAP4-11	psi-mi:“MI:0915”(physical association)	0.780
KRT31	HOXA1	psi-mi:“MI:0915”(physical association)	0.780
HOXA1	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.780
KRTAP4-11	HOXA1	psi-mi:“MI:0915”(physical association)	0.780
HOXA1	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.740
KRTAP5-9	HOXA1	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (420): HOXA1 (Two-hybrid), HOXA1 (Two-hybrid), HOXA1 (Two-hybrid), HOXA1 (Two-hybrid), KRTAP5-9 (Two-hybrid), KRT31 (Two-hybrid), PBX2 (Two-hybrid), SDCBP (Two-hybrid), TRAF1 (Two-hybrid), BLZF1 (Two-hybrid), RGS20 (Two-hybrid), CHRD (Two-hybrid), KRT38 (Two-hybrid), SPRY1 (Two-hybrid), N4BP2L2 (Two-hybrid)

ESM2 similar proteins: A0JC51, A5ABV9, O08656, O09100, O18896, O57311, O60481, O73689, O95409, P09022, P10070, P19544, P22561, P23769, P23770, P23771, P23772, P23824, P25932, P46684, P49639, P49952, P54655, P55878, P70062, P70063, Q08DV0, Q0VGT2, Q15915, Q62520, Q62521, Q6DJQ6, Q6VVD7, Q6XP49, Q7TQ40, Q800Q5, Q8JJC0, Q91689, Q924A0, Q924Y4

Diamond homologs: A1L2P5, A1YER7, A1YFD8, A1YFY3, A1YG01, A2D4P8, A2D4R4, A2D5I1, A2D5K9, A2D5Y4, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T7J2, A8DT10, A9L937, B0VXK3, O08656, O13074, O42365, O42366, O42367, O42368, O42370, O43364, O43365, O93353, P02831, P06798, P07548, P09016, P09017, P09021, P09022, P09027, P09070, P09638, P0C1T1, P10105

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PKNOX1	“up-regulates activity”	HOXA1	binding
KDM6A	“up-regulates quantity by expression”	HOXA1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 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
Keratinization	28	35.5×	4e-37
Formation of the cornified envelope	6	12.0×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
hair cycle	5	120.0×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	75
Likely benign	18
Benign	8

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
14898	NM_005522.5(HOXA1):c.175dup (p.Val59fs)	Pathogenic
14899	NM_005522.5(HOXA1):c.84C>G (p.Tyr28Ter)	Pathogenic
14900	NM_005522.5(HOXA1):c.76C>T (p.Arg26Ter)	Pathogenic
14901	NM_005522.5(HOXA1):c.185del (p.Gly62fs)	Pathogenic
1332723	NM_005522.5(HOXA1):c.669C>A (p.Tyr223Ter)	Likely pathogenic

SpliceAI

242 predictions. Top by Δscore:

Variant	Effect	Δscore
7:27094796:C:CA	acceptor_loss	0.9900
7:27094796:C:CC	acceptor_gain	0.9900
7:27094797:T:A	acceptor_loss	0.9900
7:27094802:C:CT	acceptor_gain	0.9900
7:27094806:G:C	acceptor_gain	0.9900
7:27094806:G:GC	acceptor_gain	0.9900
7:27094814:CCA:C	acceptor_gain	0.9900
7:27094815:CA:C	acceptor_gain	0.9900
7:27094816:A:C	acceptor_gain	0.9900
7:27095256:CTGA:C	donor_loss	0.9900
7:27095257:TGAC:T	donor_loss	0.9900
7:27095258:GACCT:G	donor_loss	0.9900
7:27095259:A:C	donor_loss	0.9900
7:27095260:CCTGT:C	donor_loss	0.9900
7:27095566:T:TA	donor_gain	0.9900
7:27094793:TCC:T	acceptor_gain	0.9800
7:27094794:CC:C	acceptor_gain	0.9800
7:27094794:CCC:C	acceptor_gain	0.9800
7:27094795:CC:C	acceptor_gain	0.9800
7:27094796:C:T	acceptor_gain	0.9800
7:27094803:A:T	acceptor_gain	0.9800
7:27095558:CGT:C	donor_gain	0.9800
7:27094792:TTCC:T	acceptor_gain	0.9700
7:27094815:C:T	acceptor_gain	0.9700
7:27095360:C:CT	acceptor_gain	0.9700
7:27095557:A:AC	donor_gain	0.9700
7:27095558:C:CC	donor_gain	0.9700
7:27094791:TTTCC:T	acceptor_gain	0.9600
7:27094816:A:T	acceptor_gain	0.9500
7:27094816:A:AC	acceptor_gain	0.9300

AlphaMissense

2184 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:27094597:T:G	Q284P	1.000
7:27094599:C:A	K283N	1.000
7:27094599:C:G	K283N	1.000
7:27094601:T:C	K283E	1.000
7:27094603:A:G	M282T	1.000
7:27094606:C:G	R281P	1.000
7:27094607:G:C	R281G	1.000
7:27094609:C:G	R280P	1.000
7:27094610:G:C	R280G	1.000
7:27094610:G:T	R280S	1.000
7:27094611:G:C	N279K	1.000
7:27094611:G:T	N279K	1.000
7:27094612:T:A	N279I	1.000
7:27094612:T:C	N279S	1.000
7:27094612:T:G	N279T	1.000
7:27094613:T:C	N279D	1.000
7:27094613:T:G	N279H	1.000
7:27094614:C:A	Q278H	1.000
7:27094614:C:G	Q278H	1.000
7:27094615:T:G	Q278P	1.000
7:27094617:G:C	F277L	1.000
7:27094617:G:T	F277L	1.000
7:27094618:A:C	F277C	1.000
7:27094618:A:G	F277S	1.000
7:27094619:A:C	F277V	1.000
7:27094619:A:G	F277L	1.000
7:27094619:A:T	F277I	1.000
7:27094620:C:A	W276C	1.000
7:27094620:C:G	W276C	1.000
7:27094621:C:G	W276S	1.000

dbSNP variants (sampled 300 via entrez): RS1000021576 (7:27097217 C>G,T), RS1001179012 (7:27097576 C>A), RS1001631660 (7:27097287 A>G,T), RS1001790756 (7:27093837 C>G,T), RS1003696041 (7:27093108 A>C), RS1004923725 (7:27093278 A>G), RS1005277947 (7:27093610 G>A), RS1005591406 (7:27096204 C>T), RS1005935637 (7:27096434 T>A), RS1006341165 (7:27095024 G>A), RS1007988711 (7:27096869 G>A,C), RS1008225872 (7:27095859 G>A), RS1008819283 (7:27096995 G>C), RS1008939351 (7:27096041 G>A), RS1009119571 (7:27096762 G>A)

Disease associations

OMIM: gene MIM:142955 | disease phenotypes: MIM:601536

GenCC curated gene-disease

Disease	Classification	Inheritance
human HOXA1 syndromes	Definitive	Autosomal recessive
syndromic intellectual disability	Definitive	Autosomal recessive
Bosley-Salih-Alorainy syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AR

Mondo (4): human HOXA1 syndromes (MONDO:0011099), Bosley-Salih-Alorainy syndrome (MONDO:0019075), intellectual disability (MONDO:0001071), syndromic intellectual disability (MONDO:0000508)

Orphanet (3): Bosley-Salih-Alorainy syndrome (Orphanet:69737), Athabaskan brainstem dysgenesis syndrome (Orphanet:69739), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001250	Seizure
HP:0002194	Delayed gross motor development
HP:0005290	Internal carotid artery hypoplasia
HP:0007110	Central hypoventilation
HP:0007817	Horizontal supranuclear gaze palsy
HP:0009921	Duane anomaly

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003995_8	Tonsillectomy	2.000000e-13
GCST004343_3	Chronic venous disease	3.000000e-07
GCST004746_15	Small cell lung carcinoma	7.000000e-06
GCST005014_187	Tonsillectomy	2.000000e-13
GCST006976_51	Macular thickness	2.000000e-10
GCST009597_238	Multiple sclerosis	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
Tretinoin	affects cotreatment, decreases reaction, increases expression, affects reaction, increases reaction	5
bisphenol A	affects cotreatment, decreases reaction, increases expression, increases reaction	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Resveratrol	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
LY2955303	affects cotreatment, decreases reaction, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
nickel sulfate	increases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
octa-2,4,6-trienoic acid	increases expression	1
LE 135	increases reaction, affects cotreatment, decreases reaction, increases expression	1
entinostat	increases expression, affects cotreatment	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
dorsomorphin	affects cotreatment, increases expression	1
LG 100815	increases expression	1
4-(2-(5,6-dihydro-5,5-dimethyl-8-(2-phenylethynyl)naphthalen-2-yl)ethen-1-yl)benzoic acid	affects cotreatment, decreases reaction, increases expression	1
4-(5,6-dihydro-5,5-dimethyl-8-(quinolin-3-yl)naphthalen-2-carboxamido)benzoic acid	affects cotreatment, decreases reaction, increases expression	1
jinfukang	decreases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
NSC 689534	increases expression, affects binding	1
(+)-JQ1 compound	increases expression	1
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	affects reaction, increases expression, affects cotreatment, increases reaction	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases expression, increases reaction	1
Panobinostat	affects cotreatment, increases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_A2W1	SEES3-1V human HOXA1, clone1	Embryonic stem cell	Male
CVCL_A2W2	SEES3-1V human HOXA1, clone2	Embryonic stem cell	Male
CVCL_A2W3	SEES3-1V human HOXA1, clone3	Embryonic stem cell	Male
CVCL_D9GB	Ubigene HEK293 HOXA1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
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