HMX2

Summary

HMX2 (H6 family homeobox 2, HGNC:5018) is a protein-coding gene on chromosome 10q26.13, encoding Homeobox protein HMX2 (A2RU54). Transcription factor involved in specification of neuronal cell types and which is required for inner ear and hypothalamus development.

The protein encoded by this gene is a member of the NKL homeobox family of transcription factors. Members in this family are of ancient origin and play an important role in organ development during embryogenesis. A related mouse protein plays a role in patterning of inner ear structures. In humans, variations in a region containing this gene have been associated with inner ear malformations, vestibular dysfunction, and hearing loss.

Source: NCBI Gene 3167 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 48 total
• MANE Select transcript: NM_005519

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5018
Approved symbol	HMX2
Name	H6 family homeobox 2
Location	10q26.13
Locus type	gene with protein product
Status	Approved
Aliases	NKX5-2
Ensembl gene	ENSG00000188816
Ensembl biotype	protein_coding
OMIM	600647
Entrez	3167

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000339992

RefSeq mRNA: 1 — MANE Select: NM_005519 NM_005519

CCDS: CCDS31305

Canonical transcript exons

ENST00000339992 — 2 exons

Exon	Start	End
ENSE00001370710	123149570	123150672
ENSE00001448150	123148136	123148646

Expression profiles

Bgee: expression breadth broad, 28 present calls, max score 73.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1482 / max 61.3597, expressed in 22 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107484	0.0952	15
107485	0.0304	8
107486	0.0226	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	73.33	silver quality
buccal mucosa cell	CL:0002336	70.21	gold quality
tibialis anterior	UBERON:0001385	65.97	silver quality
kidney epithelium	UBERON:0004819	65.12	gold quality
adult mammalian kidney	UBERON:0000082	62.19	gold quality
ileal mucosa	UBERON:0000331	60.66	gold quality
vena cava	UBERON:0004087	58.35	gold quality
epithelial cell of pancreas	CL:0000083	56.27	gold quality
mucosa of transverse colon	UBERON:0004991	55.75	gold quality
kidney	UBERON:0002113	55.13	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
upper leg skin	UBERON:0004262	51.25	gold quality
myocardium	UBERON:0002349	50.25	gold quality
lower lobe of lung	UBERON:0008949	50.03	silver quality
hypothalamus	UBERON:0001898	49.63	gold quality
quadriceps femoris	UBERON:0001377	47.52	gold quality
nasal cavity epithelium	UBERON:0005384	47.03	gold quality
vastus lateralis	UBERON:0001379	45.40	gold quality
amniotic fluid	UBERON:0000173	44.97	gold quality
layer of synovial tissue	UBERON:0007616	43.55	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
superior surface of tongue	UBERON:0007371	42.79	gold quality
lower esophagus mucosa	UBERON:0035834	42.78	silver quality
jejunum	UBERON:0002115	42.73	gold quality
cortex of kidney	UBERON:0001225	42.68	gold quality
duodenum	UBERON:0002114	42.63	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
skin of hip	UBERON:0001554	42.50	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.65

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
SLC26A9

Upstream regulators (CollecTRI, top): HMX3, RBPJ

miRNA regulators (miRDB)

45 targeting HMX2, 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-5692A	100.00	74.40	6850
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
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-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-3190-5P	98.87	64.89	1345

Literature-anchored findings (GeneRIF, showing 2)

• propose that hemizygous deletions of HMX2 and HMX3 are responsible for inner ear malformations, vestibular dysfunction, and congenital sensorineural hearing loss (PMID:19253379)
• Aberrant expression of NKL homeobox genes HMX2 and HMX3 interferes with cell differentiation in acute myeloid leukemia. (PMID:33048949)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hmx2	ENSDARG00000070954
mus_musculus	Hmx2	ENSMUSG00000050100
rattus_norvegicus	Hmx2	ENSRNOG00000020638

Paralogs (3): HOXA9 (ENSG00000078399), HMX3 (ENSG00000188620), HMX1 (ENSG00000215612)

Protein

Protein identifiers

Homeobox protein HMX2 — A2RU54 (reviewed: A2RU54)

Alternative names: Homeobox protein H6 family member 2

All UniProt accessions (1): A2RU54

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.

Subcellular location. Nucleus.

Similarity. Belongs to the HMX homeobox family.

RefSeq proteins (1): NP_005510* (*=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 (5 total): compositionally biased region 2, chain 1, DNA-binding region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A2RU54-F1	65.51	0.24

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 80 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_RNA_SPLICING, GOBP_POSITIVE_REGULATION_OF_MRNA_PROCESSING, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, KOYAMA_SEMA3B_TARGETS_UP, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_RNA_SPLICING, GOBP_EAR_MORPHOGENESIS, GOBP_HEAD_DEVELOPMENT, TANAKA_METHYLATED_IN_ESOPHAGEAL_CARCINOMA, GOBP_REGULATION_OF_MRNA_SPLICING_VIA_SPLICEOSOME, GOBP_EMBRYO_DEVELOPMENT, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_SENSORY_ORGAN_MORPHOGENESIS

GO Biological Process (12): regulation of transcription by RNA polymerase II (GO:0006357), brain development (GO:0007420), cell differentiation (GO:0030154), inner ear morphogenesis (GO:0042472), positive regulation of mRNA splicing, via spliceosome (GO:0048026), epithelial cell proliferation (GO:0050673), positive regulation of epithelial cell proliferation (GO:0050679), stem cell proliferation (GO:0072089), positive regulation of stem cell proliferation (GO:2000648), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), cell population proliferation (GO:0008283)

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), 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 population proliferation	2
positive regulation of cell population proliferation	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
cellular developmental process	1
ear morphogenesis	1
embryonic morphogenesis	1
inner ear development	1
mRNA splicing, via spliceosome	1
positive regulation of RNA splicing	1
regulation of mRNA splicing, via spliceosome	1
positive regulation of mRNA processing	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
stem cell division	1
stem cell proliferation	1
regulation of stem cell proliferation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
cellular process	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
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

310 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HMX2	GAL	P22466	687
HMX2	PAX2	Q02962	617
HMX2	GHRH	P01286	550
HMX2	NXPH2	O95156	521
HMX2	GRAMD1B	Q3KR37	480
HMX2	BMP4	P12644	445
HMX2	LRRC3B	Q96PB8	418
HMX2	GJA9	P57773	395
HMX2	ZNF560	Q96MR9	380
HMX2	GJA10	Q969M2	366
HMX2	CTNNB1	P35222	364
HMX2	NALF2	O75949	360
HMX2	CALY	Q9NYX4	332
HMX2	BUB3	O43684	319
HMX2	GZF1	Q9H116	315

IntAct

4 interactions, top by confidence:

A	B	Type	Score
STAMBPL1		psi-mi:“MI:0914”(association)	0.350
USP38		psi-mi:“MI:0914”(association)	0.350
HMX2	CALB2	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): LHPP (Affinity Capture-MS), CALB2 (Affinity Capture-MS), HMX2 (Affinity Capture-MS), HMX2 (Cross-Linking-MS (XL-MS)), HMX2 (Cross-Linking-MS (XL-MS)), HMX2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A1W2PQ73, A1YF16, A1YG93, A2RU54, A5PKG8, O02786, O14813, O15353, O35602, O43638, O57601, P13297, P19419, P28360, P35548, P41969, P42580, P43687, P49640, P50223, P50548, P52946, P52950, P63156, P63157, P70459, P78413, Q03358, Q14549, Q2VL78, Q2VL79, Q2VL82, Q2VL83, Q2VL84, Q2VL85, Q2VL86, Q2VL87, Q2VL88, Q5NSW5, Q61575

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

325 predictions. Top by Δscore:

Variant	Effect	Δscore
10:123148558:G:GT	donor_gain	1.0000
10:123148592:GGCCC:G	donor_gain	1.0000
10:123148593:GCCC:G	donor_gain	1.0000
10:123148559:A:T	donor_gain	0.9900
10:123148600:G:GT	donor_gain	0.9900
10:123148601:G:GT	donor_gain	0.9900
10:123148607:GGCCC:G	donor_gain	0.9900
10:123149560:C:A	acceptor_gain	0.9900
10:123149566:TCA:T	acceptor_loss	0.9900
10:123149567:CA:C	acceptor_loss	0.9900
10:123149568:A:G	acceptor_loss	0.9900
10:123149569:G:GC	acceptor_loss	0.9900
10:123148507:G:GT	donor_gain	0.9800
10:123148645:GG:G	donor_gain	0.9800
10:123148646:GG:G	donor_gain	0.9800
10:123149568:A:AG	acceptor_gain	0.9800
10:123149569:G:GG	acceptor_gain	0.9800
10:123149569:GGT:G	acceptor_gain	0.9800
10:123148596:C:CG	donor_gain	0.9700
10:123148602:A:T	donor_gain	0.9700
10:123148643:CTGGG:C	donor_loss	0.9700
10:123148644:TGGG:T	donor_loss	0.9700
10:123148647:GT:G	donor_loss	0.9700
10:123148648:TAA:T	donor_loss	0.9700
10:123149568:AG:A	acceptor_gain	0.9700
10:123149569:GG:G	acceptor_gain	0.9700
10:123149569:GGTA:G	acceptor_gain	0.9700
10:123148341:G:GT	donor_gain	0.9500
10:123148538:G:GT	donor_gain	0.9500
10:123148596:C:G	donor_gain	0.9500

AlphaMissense

1749 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:123149767:T:A	F156I	1.000
10:123149767:T:C	F156L	1.000
10:123149767:T:G	F156V	1.000
10:123149768:T:C	F156S	1.000
10:123149768:T:G	F156C	1.000
10:123149769:T:A	F156L	1.000
10:123149769:T:G	F156L	1.000
10:123149781:G:C	Q160H	1.000
10:123149781:G:T	Q160H	1.000
10:123149792:T:A	L164H	1.000
10:123149792:T:C	L164P	1.000
10:123149792:T:G	L164R	1.000
10:123149796:G:C	E165D	1.000
10:123149796:G:T	E165D	1.000
10:123149797:T:C	S166P	1.000
10:123149803:T:A	F168I	1.000
10:123149803:T:C	F168L	1.000
10:123149803:T:G	F168V	1.000
10:123149804:T:C	F168S	1.000
10:123149804:T:G	F168C	1.000
10:123149805:C:A	F168L	1.000
10:123149805:C:G	F168L	1.000
10:123149818:T:C	Y173H	1.000
10:123149819:A:G	Y173C	1.000
10:123149822:T:A	L174Q	1.000
10:123149836:C:A	R179S	1.000
10:123149846:T:C	L182P	1.000
10:123149849:C:A	A183D	1.000
10:123149858:T:C	L186P	1.000
10:123149864:T:A	L188H	1.000

dbSNP variants (sampled 300 via entrez): RS1001022112 (10:123150384 G>A), RS1001559774 (10:123150128 C>T), RS1001652693 (10:123148265 G>A,C), RS1001976564 (10:123149290 T>C), RS1002290976 (10:123147922 C>G), RS1002660096 (10:123147282 G>T), RS1002712614 (10:123147048 G>A), RS1004404254 (10:123146368 C>T), RS1004532803 (10:123150640 A>T), RS1004602520 (10:123149665 A>C,T), RS1004975484 (10:123150803 G>T), RS1005073336 (10:123150434 G>A), RS1005200290 (10:123148609 C>A), RS1005408077 (10:123147746 G>C), RS1005644373 (10:123148786 G>A)

Disease associations

OMIM: gene MIM:600647 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_677	Metabolite levels	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010506	kynurenic acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Valproic Acid	increases expression, increases methylation	2
bisphenol F	increases expression	1
bisphenol A	increases expression	1
trichostatin A	decreases expression	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	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
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation, affects cotreatment	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	affects cotreatment, increases expression	1
Panobinostat	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Carbamazepine	affects expression	1
Estradiol	affects expression	1
Methotrexate	increases expression	1
Niclosamide	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2U4	SEES3-1V human HMX2, clone1	Embryonic stem cell	Male
CVCL_A2U5	SEES3-1V human HMX2, clone2	Embryonic stem cell	Male

Clinical trials (associated diseases)

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