HMX3

Summary

HMX3 (H6 family homeobox 3, HGNC:5019) is a protein-coding gene on chromosome 10q26.13, encoding Homeobox protein HMX3 (A6NHT5). Transcription factor involved in specification of neuronal cell types and which is required for inner ear and hypothalamus development.

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including embryo implantation; maternal process involved in female pregnancy; and neuromuscular process controlling balance. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 340784 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 45 total
• MANE Select transcript: NM_001105574

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5019
Approved symbol	HMX3
Name	H6 family homeobox 3
Location	10q26.13
Locus type	gene with protein product
Status	Approved
Aliases	NKX5-1
Ensembl gene	ENSG00000188620
Ensembl biotype	protein_coding
OMIM	613380
Entrez	340784

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000357878

RefSeq mRNA: 1 — MANE Select: NM_001105574 NM_001105574

CCDS: CCDS41575

Canonical transcript exons

ENST00000357878 — 2 exons

Exon	Start	End
ENSE00001374360	123135970	123136450
ENSE00001664032	123137058	123139423

Expression profiles

Bgee: expression breadth broad, 52 present calls, max score 72.28.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.3097 / max 54.1666, expressed in 157 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107479	0.6085	121
107481	0.3959	106
107480	0.1710	90
107478	0.1343	69

Top tissues by expression

117 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	72.28	silver quality
mucosa of transverse colon	UBERON:0004991	63.23	gold quality
hypothalamus	UBERON:0001898	59.87	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	56.26	gold quality
colonic epithelium	UBERON:0000397	54.51	gold quality
duodenum	UBERON:0002114	52.31	gold quality
transverse colon	UBERON:0001157	49.74	gold quality
colon	UBERON:0001155	49.48	gold quality
muscle layer of sigmoid colon	UBERON:0035805	49.23	gold quality
intestine	UBERON:0000160	48.47	gold quality
islet of Langerhans	UBERON:0000006	46.12	gold quality
small intestine	UBERON:0002108	45.93	gold quality
vermiform appendix	UBERON:0001154	45.83	gold quality
pituitary gland	UBERON:0000007	45.52	gold quality
omental fat pad	UBERON:0010414	45.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	44.79	gold quality
cortical plate	UBERON:0005343	43.76	gold quality
adult mammalian kidney	UBERON:0000082	43.61	gold quality
kidney	UBERON:0002113	41.95	gold quality
adenohypophysis	UBERON:0002196	41.64	gold quality
sural nerve	UBERON:0015488	41.00	gold quality
rectum	UBERON:0001052	40.63	gold quality
smooth muscle tissue	UBERON:0001135	40.23	silver quality
stromal cell of endometrium	CL:0002255	40.06	gold quality
ventricular zone	UBERON:0003053	39.94	gold quality
pancreas	UBERON:0001264	39.88	gold quality
bone marrow	UBERON:0002371	39.27	gold quality
hindlimb stylopod muscle	UBERON:0004252	38.75	gold quality
cortex of kidney	UBERON:0001225	38.15	silver quality
bone marrow cell	CL:0002092	38.01	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-83139	no	3.60
E-ANND-3	no	1.96

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
HMX1	Activation
HMX2	Activation

Literature-anchored findings (GeneRIF, showing 4)

• propose that hemizygous deletions of HMX2 and HMX3 are responsible for inner ear malformations, vestibular dysfunction, and congenital sensorineural hearing loss (PMID:19253379)
• One sequence alteration, heterozygous c.114C->T (conservative change without alteration of amino acid) in exon 1 of HMX3, was detected in 2 of 15 patients with superior semicircular dehiscence syndrome. (PMID:22779713)
• Aberrant expression of NKL homeobox genes HMX2 and HMX3 interferes with cell differentiation in acute myeloid leukemia. (PMID:33048949)
• USP38 inhibits colorectal cancer cell proliferation and migration via downregulating HMX3 ubiquitylation. (PMID:36204976)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmx3a	ENSDARG00000070955
mus_musculus	Hmx3	ENSMUSG00000040148
rattus_norvegicus	Hmx3	ENSRNOG00000020637

Paralogs (3): HOXA9 (ENSG00000078399), HMX2 (ENSG00000188816), HMX1 (ENSG00000215612)

Protein

Protein identifiers

Homeobox protein HMX3 — A6NHT5 (reviewed: A6NHT5)

Alternative names: Homeobox protein H6 family member 3, Homeobox protein Nkx-5.1

All UniProt accessions (1): A6NHT5

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor involved in specification of neuronal cell types and which is required for inner ear and hypothalamus development. Binds to the 5’-CAAGTG-3’ core sequence. Controls semicircular canal formation in the inner ear. Also required for hypothalamic/pituitary axis of the CNS.

Subcellular location. Nucleus.

Similarity. Belongs to the HMX homeobox family.

RefSeq proteins (1): NP_001099044* (*=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
IPR051300	HMX_Homeobox_TF	Family

Pfam: PF00046

UniProt features (11 total): compositionally biased region 5, modified residue 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-A6NHT5-F1	62.30	0.19

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): 180, 153

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 63 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_EAR_MORPHOGENESIS, GOBP_MULTI_MULTICELLULAR_ORGANISM_PROCESS, GOBP_HEAD_DEVELOPMENT, GOBP_MATERNAL_PROCESS_INVOLVED_IN_FEMALE_PREGNANCY, GOBP_EMBRYO_DEVELOPMENT, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_SENSORY_ORGAN_MORPHOGENESIS, GOBP_NEUROMUSCULAR_PROCESS, GOBP_EMBRYONIC_ORGAN_DEVELOPMENT, GOBP_INNER_EAR_MORPHOGENESIS

GO Biological Process (10): regulation of transcription by RNA polymerase II (GO:0006357), brain development (GO:0007420), embryo implantation (GO:0007566), cell differentiation (GO:0030154), inner ear morphogenesis (GO:0042472), neuromuscular process controlling balance (GO:0050885), maternal process involved in female pregnancy (GO:0060135), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), ear development (GO:0043583)

GO Molecular Function (4): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), sequence-specific DNA binding (GO:0043565)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
female pregnancy	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
central nervous system development	1
animal organ development	1
head development	1
multicellular organism development	1
reproductive process	1
cellular developmental process	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
musculoskeletal movement	1
neuromuscular process	1
multicellular organismal reproductive process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
sensory organ development	1
transcription cis-regulatory region binding	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMX3	WNT7A	O00755	750
HMX3	GAL	P22466	668
HMX3	LHX6	Q9UPM6	649
HMX3	WNT5A	P41221	549
HMX3	WNT4	P56705	549
HMX3	GHRH	P01286	548
HMX3	LIF	P15018	542
HMX3	PAX2	Q02962	477
HMX3	LHX8	Q68G74	449
HMX3	GRAMD1B	Q3KR37	440
HMX3	NPAS1	Q99742	394
HMX3	NR2F1	P10589	392
HMX3	CALB2	P22676	374
HMX3	NPY	P01303	370
HMX3	HTR3A	P46098	357

IntAct

0 interactions, top by confidence:

BioGRID (9): HMX3 (Affinity Capture-MS), HMX3 (Affinity Capture-MS), HMX3 (Affinity Capture-MS), HMX3 (Affinity Capture-MS), USP38 (Affinity Capture-Western), HMX3 (Affinity Capture-MS), HMX3 (Affinity Capture-MS), HMX3 (Affinity Capture-MS), HMX3 (Affinity Capture-MS)

ESM2 similar proteins: A0JPN1, A6NHT5, A6YP92, A7MB54, M0R6D8, O02786, O35085, O35762, O42230, O57601, O88181, O95096, P09065, P13297, P28360, P42581, P43697, P50219, P52955, P70390, P78414, P78415, P79772, P81067, P81068, Q05925, Q0P4W6, Q14549, Q14774, Q1XID0, Q2VL76, Q2VL77, Q2VL78, Q2VL79, Q2VL80, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86

Diamond homologs: A1YF16, A1YG93, A2RU54, A2T764, A6NCS4, A6NHT5, G5EE18, M0R6D8, O02786, O35767, O42230, O57601, O60479, O70218, P10181, P13297, P15857, P19601, P20009, P23410, P28360, P28361, P28362, P35548, P35993, P40764, P42580, P42581, P43687, P43688, P48031, P50219, P50223, P50574, P50575, P50576, P50577, P52953, P53547, P53770

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

192 predictions. Top by Δscore:

Variant	Effect	Δscore
10:123137056:A:AG	acceptor_gain	0.9800
10:123137057:G:GG	acceptor_gain	0.9800
10:123137057:GCCTC:G	acceptor_gain	0.9600
10:123137098:C:CA	acceptor_gain	0.9600
10:123137052:CCCCA:C	acceptor_loss	0.9300
10:123137053:CCCA:C	acceptor_loss	0.9300
10:123137055:CAGCC:C	acceptor_loss	0.9300
10:123137056:AGCCT:A	acceptor_loss	0.9300
10:123137057:G:A	acceptor_loss	0.9300
10:123137057:GC:G	acceptor_gain	0.9300
10:123136446:TGAAG:T	donor_loss	0.9100
10:123136448:AAG:A	donor_loss	0.9100
10:123136449:AG:A	donor_loss	0.9100
10:123136450:GG:G	donor_loss	0.9100
10:123136451:GTAC:G	donor_loss	0.9100
10:123136452:T:G	donor_loss	0.9100
10:123137047:T:A	acceptor_loss	0.9100
10:123136400:G:GA	donor_gain	0.9000
10:123136915:G:GT	donor_gain	0.8900
10:123136824:G:GT	donor_gain	0.8700
10:123137057:GCC:G	acceptor_gain	0.8600
10:123137043:T:A	acceptor_loss	0.8200
10:123136704:G:GT	donor_gain	0.8000
10:123137057:GCCT:G	acceptor_gain	0.8000
10:123137104:A:AG	acceptor_gain	0.7800
10:123137105:G:GG	acceptor_gain	0.7800
10:123136399:T:TA	donor_gain	0.7700
10:123136805:G:GT	donor_gain	0.7500
10:123136705:G:T	donor_gain	0.7400
10:123137099:G:A	acceptor_gain	0.7300

AlphaMissense

2278 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:123137342:A:G	K229E	1.000
10:123137348:C:A	R231S	1.000
10:123137348:C:G	R231G	1.000
10:123137348:C:T	R231C	1.000
10:123137349:G:A	R231H	1.000
10:123137352:C:A	T232K	1.000
10:123137352:C:T	T232I	1.000
10:123137355:T:A	V233D	1.000
10:123137357:T:A	F234I	1.000
10:123137357:T:C	F234L	1.000
10:123137357:T:G	F234V	1.000
10:123137358:T:C	F234S	1.000
10:123137358:T:G	F234C	1.000
10:123137359:C:A	F234L	1.000
10:123137359:C:G	F234L	1.000
10:123137371:G:C	Q238H	1.000
10:123137371:G:T	Q238H	1.000
10:123137372:G:T	V239F	1.000
10:123137373:T:A	V239D	1.000
10:123137373:T:C	V239A	1.000
10:123137375:T:C	F240L	1.000
10:123137377:C:A	F240L	1.000
10:123137377:C:G	F240L	1.000
10:123137381:C:T	L242F	1.000
10:123137382:T:A	L242H	1.000
10:123137382:T:C	L242P	1.000
10:123137382:T:G	L242R	1.000
10:123137384:G:A	E243K	1.000
10:123137385:A:C	E243A	1.000
10:123137385:A:G	E243G	1.000

dbSNP variants (sampled 300 via entrez): RS1000026674 (10:123134107 G>A,C,T), RS1000170194 (10:123136191 G>A), RS1000341464 (10:123134294 G>T), RS1000430903 (10:123136033 C>G,T), RS1001898777 (10:123138299 G>A), RS1002194533 (10:123136587 C>T), RS1002430527 (10:123138623 C>T), RS1002576028 (10:123135647 C>A), RS1003573163 (10:123134316 C>T), RS1003689712 (10:123139207 A>G), RS1004028984 (10:123135976 C>T), RS1004113157 (10:123134670 C>G), RS1004144056 (10:123134882 A>G), RS1004248478 (10:123135760 C>A), RS1005978566 (10:123138357 C>A)

Disease associations

OMIM: gene MIM:613380 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002127_27	Periodontitis (Mean PAL)	9.000000e-06
GCST007355_1	Antidepressant treatment resistance (> 2 drugs prescribed)	3.000000e-07
GCST007356_2	Antidepressant treatment resistance (number of drugs prescribed)	4.000000e-07
GCST007356_3	Antidepressant treatment resistance (number of drugs prescribed)	5.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
TAK-243	increases sumoylation	1
potassium chromate(VI)	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
epigallocatechin gallate	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	decreases methylation, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Metals, Heavy	decreases methylation, increases abundance	1

Clinical trials (associated diseases)

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