HHEX

Summary

HHEX (hematopoietically expressed homeobox, HGNC:4901) is a protein-coding gene on chromosome 10q23.33, encoding Hematopoietically-expressed homeobox protein HHEX (Q03014). Recognizes the DNA sequence 5’-ATTAA-3'.

This gene encodes a member of the homeobox family of transcription factors, many of which are involved in developmental processes. Expression in specific hematopoietic lineages suggests that this protein may play a role in hematopoietic differentiation.

Source: NCBI Gene 3087 — RefSeq curated summary.

At a glance

• GWAS associations: 49
• Clinical variants (ClinVar): 31 total
• Phenotypes (HPO): 1
• Transcription factor: yes — 31 downstream targets (CollecTRI)
• MANE Select transcript: NM_002729

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4901
Approved symbol	HHEX
Name	hematopoietically expressed homeobox
Location	10q23.33
Locus type	gene with protein product
Status	Approved
Aliases	HEX, HOX11L-PEN
Ensembl gene	ENSG00000152804
Ensembl biotype	protein_coding
OMIM	604420
Entrez	3087

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000282728, ENST00000472590, ENST00000492654, ENST00000551454, ENST00000881554

RefSeq mRNA: 1 — MANE Select: NM_002729 NM_002729

CCDS: CCDS7423

Canonical transcript exons

ENST00000282728 — 4 exons

Exon	Start	End
ENSE00001007291	92692702	92692752
ENSE00001162575	92694547	92695647
ENSE00002393381	92689955	92690347
ENSE00003513123	92692368	92692546

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.7966 / max 520.7343, expressed in 1330 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106250	13.1367	1141
106249	4.4382	1055
106248	0.8815	490
106251	0.2296	116
205944	0.1107	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.18	gold quality
right lobe of thyroid gland	UBERON:0001119	97.69	gold quality
oocyte	CL:0000023	97.37	gold quality
thyroid gland	UBERON:0002046	97.27	gold quality
left lobe of thyroid gland	UBERON:0001120	97.19	gold quality
monocyte	CL:0000576	96.60	gold quality
mononuclear cell	CL:0000842	96.30	gold quality
leukocyte	CL:0000738	96.10	gold quality
right lobe of liver	UBERON:0001114	95.65	gold quality
liver	UBERON:0002107	92.42	gold quality
granulocyte	CL:0000094	92.16	gold quality
spleen	UBERON:0002106	92.08	gold quality
body of pancreas	UBERON:0001150	91.86	gold quality
gall bladder	UBERON:0002110	91.24	gold quality
pancreas	UBERON:0001264	90.40	gold quality
blood	UBERON:0000178	90.00	gold quality
bone marrow	UBERON:0002371	89.08	gold quality
islet of Langerhans	UBERON:0000006	88.74	gold quality
lymph node	UBERON:0000029	88.37	gold quality
right adrenal gland cortex	UBERON:0035827	87.18	gold quality
vermiform appendix	UBERON:0001154	87.08	gold quality
left adrenal gland	UBERON:0001234	86.85	gold quality
right adrenal gland	UBERON:0001233	86.83	gold quality
bone marrow cell	CL:0002092	86.12	gold quality
left adrenal gland cortex	UBERON:0035825	85.62	gold quality
adrenal gland	UBERON:0002369	85.57	gold quality
adrenal tissue	UBERON:0018303	85.16	gold quality
adrenal cortex	UBERON:0001235	84.26	gold quality
upper lobe of left lung	UBERON:0008952	84.05	gold quality
upper lobe of lung	UBERON:0008948	83.66	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	299.54
E-ENAD-27	yes	99.38
E-HCAD-11	yes	41.26
E-GEOD-135922	yes	10.51
E-ANND-3	yes	9.91
E-GEOD-81608	yes	8.64
E-CURD-112	yes	5.52
E-GEOD-81547	yes	5.14
E-MTAB-6386	no	597.50

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

31 targets.

Target	Regulation
ABL1
ACTA2	Activation
BCR
CD81
CER1	Repression
CSNK2A1
CSNK2A2
CTSG
ESM1
FGF2
FLT1
GSC
HHEX	Activation
HNF4A	Activation
KDR	Unknown
MYH10	Activation
NOS2	Repression
PKLR	Activation
PPIG
SLC10A1
SLC5A5	Activation
SLU7
SRC
TAGLN	Activation
TG
TLE1	Unknown
TLE4	Repression
TLE5
TRIB3
VEGFA	Repression

Upstream regulators (CollecTRI, top): APEX1, FOXA2, GATA1, GATA2, GATA4, HHEX, LHX1, LMO2, MYB, NKX2-1, OTX2, PAX8, RUNX1, SP1, SP3, SSRP1, TTF1

miRNA regulators (miRDB)

70 targeting HHEX, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-4524A-3P	99.72	66.85	2406

Literature-anchored findings (GeneRIF, showing 40)

• genomic organization and chromosome 10 mapping (PMID:11701950)
• PRH is a negative regulator of eIF4E in myeloid cells, interacting with eIF4E through a conserved binding site typically found in translational regulators (PMID:12554669)
• HEX may not affect the differentiation of endothelial cells but acts as a negative regulator of angiogenesis. (PMID:12588764)
• PRH interacts with the HC8 subunit of the proteasome in the context of both 20 and 26 S proteasomes and is associated with the proteasome in K562 hematopoietic cells; the proline-rich PRH N-terminal domain is responsible for this interaction. (PMID:12826010)
• Hex can act as a T lineage oncogene when misexpressed in hematopoietic precursor cells (PMID:14555989)
• Tgf-beta mediated repression of flk-1/KDR and mediated repression of flk-1/KDR and VEGF signaling involves the inducible formation of inhibitory Hex-GATA signaling Hex-GATA involves the formation of Hex-GATA complexes. (PMID:15016828)
• Pax8 regulates the transcriptional activity of Hex promoter; several Pax8 binding sites in the Hex promoter are present (PMID:15062550)
• Hex, a hematopoietically expressed homeobox protein, induces transcription of the SM22alpha gene by facilitating the interaction between SRF and its cognate binding site in embryonic fibroblasts. (PMID:15242862)
• region of PRH contains a novel proline-rich dimerisation domain that mediates oligomerisation (PMID:16540119)
• HEX may play a role in differentiation of the epithelial breast cell (PMID:16854221)
• Variations are not linked to diabetes mellitus. (PMID:17618412)
• Genetic variation predisposes to type 2 diabetes. (PMID:17632701)
• CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic beta-cell function, including decreased beta-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. (PMID:17804762)
• Variations confer impaired glucose- and tolbutamide-induced insulin release in middle-aged and young healthy subjects. (PMID:17827400)
• HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups. (PMID:17928989)
• Single-nucleotide polymorphisms in the HHEX gene are associated with susceptibility to type 2 diaabetes across the boundary of race. (PMID:17971426)
• Single nucleotid polymorphismallele represents a risk allele for beta-cell dysfunction and, mayconfer increased susceptibility of beta-cells toward adverse environmental factors and type 2 diabetes. (PMID:18039816)
• The association of 6 loci with type 2 diabetes risk in Japanese patients is reported. (PMID:18162508)
• variants near the HHEX gene contribute to the risk of type 2 diabetes in a Dutch population (PMID:18231124)
• translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene found in acute myeloid leukemia (PMID:18388181)
• Data confirmed the associations of single nucleotide polymorphisms in HHEX with risk for type 2 diabetes in Asians. (PMID:18469204)
• Gene variants of CDKAL1, PPARG, IGF2BP2, HHEX, TCF7L2, and FTO predispose to type 2 diabetes in the German KORA 500 K study population. (PMID:18597214)
• Results demonstrate that transcriptional repression by PRH is dependent on TLE availability and suggest that subnuclear localization of TLE plays an important role in transcriptional repression by PRH. (PMID:18713067)
• PRH octamers wrap DNA in order to bring about transcriptional repression (PMID:18755198)
• Single nucleotide polymorphism in HHEX is associated with type 2 diabetes. (PMID:18991055)
• Data show that SNPs in HHEX did not confer a significant risk for type 2 diabetes in Pima Indians. (PMID:19008344)
• Type 2 diabetes susceptibility of HHEX was confirmed in Japanese. (PMID:19033397)
• Located on chromosome 10 and suscptibility of polymorphisms are related to type 2 diabetes. (PMID:19053027)
• HEX/Hex is a novel bile acid-induced FXR/Fxr target gene during adaptation of hepatocytes to chronic bile acid exposure. (PMID:19072826)
• Variations within the HHEX gene conferred the impaired insulin secretion and changes of insulin degradation but no alteration in insulin sensitivity in carriers of risk for gluccose intolerance. (PMID:19117022)
• The association of low birth weight and type 2 diabetes risk alleles of the HHEX-IDE locus is confirmed in children of mothers with type 1 diabetes. (PMID:19622614)
• there is an association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes in the Chinese population (PMID:19862325)
• the same genetic HHEX-IDE variant, which is associated with type 2 diabetes from previous studies, also influences pediatric body mass index (PMID:19933996)
• the interaction between Hhex and SOX13 may contribute to control Wnt/TCF1 signaling in the early embryo. (PMID:20028982)
• There was no association of the genetic polymorhism rs1111875 of HHEX with the occurrence of polycystic ovary syndrome in the Chinese population. (PMID:20041287)
• HHEX has been implicated in pancreas development and the regulation of insulin secretion and risk of type 2 diabetes. (PMID:20080751)
• PRH is a key regulator of the VEGF signaling pathway and describe a mechanism whereby PRH plays an important role in tumorigenesis and leukemogenesis. (PMID:20176809)
• Type 2 diabetes susceptibility alleles at HHEX are associated with low body mass index at 8 years in children who were born large for gestational age. (PMID:20460429)
• Data report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. (PMID:20490451)
• Our data indicate that common genetic variants in two genes previously related to obesity (FTO) and diabetes (HHEX) by genome-wide association scans were not associated with endometrial cancer risk. (PMID:20647405)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Hematopoietically-expressed homeobox protein HHEX — Q03014 (reviewed: Q03014)

Alternative names: Homeobox protein PRH, Proline-rich homeodomain protein

All UniProt accessions (2): Q03014, F8VU08

UniProt curated annotations — full annotation on UniProt →

Function. Recognizes the DNA sequence 5’-ATTAA-3’. Transcriptional repressor. Activator of WNT-mediated transcription in conjunction with CTNNB1. Establishes anterior identity at two levels; acts early to enhance canonical WNT-signaling by repressing expression of TLE4, and acts later to inhibit NODAL-signaling by directly targeting NODAL. Inhibits EIF4E-mediated mRNA nuclear export. May play a role in hematopoietic differentiation.

Subunit / interactions. Interacts with CD81; the interaction prevents nuclear translocation of HHEX. Interacts (via N-terminus) with SOX13; abolishes the SOX13-mediated inhibition of WNT-mediated transcriptional activity via competitive inhibition of the SOX13-TCF7 complex. Interacts with EIF4E; the interaction inhibits EIF4E-mediated mRNA nuclear export.

Subcellular location. Nucleus. Nuclear body. Cytoplasm.

Tissue specificity. Liver and promyelocytic leukemia cell line HL-60.

RefSeq proteins (1): NP_002720* (*=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
IPR051000	Homeobox_DNA-bind_prot	Family

Pfam: PF00046

UniProt features (16 total): mutagenesis site 3, helix 3, region of interest 3, sequence conflict 2, compositionally biased region 2, chain 1, DNA-binding region 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2E1O	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q03014-F1	66.34	0.22

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 (1): 53

Mutagenesis-validated functional residues (3):

Position	Phenotype
189	loss of nuclear localization; when associated with a-188.
23–24	abolishes interaction with eif4e and inhibitory effect on eif4e-mediated mrna nuclear export.
188	loss of nuclear localization; when associated with a-189.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9937080	Developmental Lineage of Multipotent Pancreatic Progenitor Cells
R-HSA-2892245	POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation

MSigDB gene sets: 428 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_CHROMOSOME_ORGANIZATION, ELVIDGE_HYPOXIA_DN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, BENPORATH_ES_WITH_H3K27ME3, GRUETZMANN_PANCREATIC_CANCER_DN, CCAWYNNGAAR_UNKNOWN, GAANYNYGACNY_UNKNOWN, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_B_CELL_ACTIVATION, GCANCTGNY_MYOD_Q6, SP3_Q3, GOZGIT_ESR1_TARGETS_DN

GO Biological Process (21): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), anterior/posterior pattern specification (GO:0009952), regulation of mRNA export from nucleus (GO:0010793), obsolete negative regulation of transcription by competitive promoter binding (GO:0010944), Wnt signaling pathway (GO:0016055), negative regulation of angiogenesis (GO:0016525), cell differentiation (GO:0030154), positive regulation of Wnt signaling pathway (GO:0030177), B cell differentiation (GO:0030183), negative regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030948), protein localization to nucleus (GO:0034504), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of leukocyte proliferation (GO:0070663), DNA conformation change (GO:0071103), positive regulation of canonical Wnt signaling pathway (GO:0090263), negative regulation of cytoplasmic translational initiation (GO:1904689), regulation of DNA-templated transcription (GO:0006355), obsolete negative regulation of transcription by transcription factor localization (GO:0010621)

GO Molecular Function (14): transcription cis-regulatory region binding (GO:0000976), 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 repressor activity, RNA polymerase II-specific (GO:0001227), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), eukaryotic initiation factor 4E binding (GO:0008190), DNA binding, bending (GO:0008301), TBP-class protein binding (GO:0017025), protein homodimerization activity (GO:0042803), sequence-specific DNA binding (GO:0043565), translation regulator activity (GO:0045182), DNA-binding transcription factor binding (GO:0140297), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737), nuclear body (GO:0016604), protein-DNA complex (GO:0032993)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Developmental Cell Lineages of the Exocrine Pancreas	1
Transcriptional regulation of pluripotent stem cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	4
regulation of transcription by RNA polymerase II	3
transcription by RNA polymerase II	3
regulation of DNA-templated transcription	3
DNA-templated transcription	3
DNA-binding transcription factor activity, RNA polymerase II-specific	2
DNA binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
regionalization	1
mRNA export from nucleus	1
regulation of RNA export from nucleus	1
regulation of ribonucleoprotein complex localization	1
cell surface receptor signaling pathway	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
cellular developmental process	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
lymphocyte differentiation	1
B cell activation	1
negative regulation of signal transduction	1
regulation of vascular endothelial growth factor receptor signaling pathway	1
vascular endothelial growth factor receptor signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
protein localization to organelle	1
negative regulation of RNA biosynthetic process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
regulation of cell population proliferation	1
leukocyte proliferation	1
chromosome organization	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
cytoplasmic translational initiation	1
negative regulation of translational initiation	1
regulation of cytoplasmic translational initiation	1

Protein interactions and networks

STRING

1620 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HHEX	SLC30A8	Q8IWU4	934
HHEX	CDKAL1	Q5VV42	925
HHEX	IGF2BP2	Q9Y6M1	908
HHEX	TCF7L2	Q9NQB0	880
HHEX	FTO	Q9C0B1	863
HHEX	KIF11	P52732	824
HHEX	TSPAN8	P19075	817
HHEX	KCNJ11	Q14654	798
HHEX	EXT2	Q93063	784
HHEX	KCNQ1	P51787	755
HHEX	TAL1	P17542	742
HHEX	CDC123	O75794	720
HHEX	ONECUT1	Q9UBC0	718
HHEX	HNF1B	P35680	716
HHEX	MTNR1B	P49286	696

IntAct

124 interactions, top by confidence:

A	B	Type	Score
KRTAP10-8	HHEX	psi-mi:“MI:0915”(physical association)	0.720
HHEX		psi-mi:“MI:0915”(physical association)	0.560
HHEX	KRTAP10-5	psi-mi:“MI:0915”(physical association)	0.560
HHEX	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
	HHEX	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-5	HHEX	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-8	HHEX	psi-mi:“MI:0915”(physical association)	0.560
HHEX	ABI1	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLC	HHEX	psi-mi:“MI:0915”(physical association)	0.560
PSTPIP1	HHEX	psi-mi:“MI:0915”(physical association)	0.560
HHEX	KRTAP5-7	psi-mi:“MI:0915”(physical association)	0.560
HHEX	KRTAP2-4	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	HHEX	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-3	HHEX	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	HHEX	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-6	HHEX	psi-mi:“MI:0915”(physical association)	0.560
HHEX	RBMY1F	psi-mi:“MI:0915”(physical association)	0.560
HHEX	TP53BP2	psi-mi:“MI:0915”(physical association)	0.560
HHEX	KHDRBS2	psi-mi:“MI:0915”(physical association)	0.560
HHEX	MDFI	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	HHEX	psi-mi:“MI:0915”(physical association)	0.560
HHEX	ABI2	psi-mi:“MI:0915”(physical association)	0.560
HHEX	PFDN5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (55): KRTAP10-7 (Two-hybrid), KRTAP10-5 (Two-hybrid), KRTAP10-8 (Two-hybrid), KRTAP10-3 (Two-hybrid), KRTAP4-12 (Two-hybrid), EFEMP2 (Two-hybrid), HHEX (Affinity Capture-Western), HHEX (Affinity Capture-Western), HHEX (Affinity Capture-Western), HHEX (Affinity Capture-Western), HHEX (Affinity Capture-Western), HHEX (Affinity Capture-Western), HHEX (Two-hybrid), HHEX (Two-hybrid), HHEX (Two-hybrid)

ESM2 similar proteins: A1YEY5, A1YFA5, A1YFI3, A1YG57, A2T733, A2T764, A2T7P4, A6NJ46, O42115, O43248, O43711, O55144, O95096, P02830, P09023, P09024, P09629, P09633, P17509, P17919, P18864, P23410, P28362, P29454, P31259, P31311, P31313, P31315, P42586, P43120, P43345, P43697, P48031, P52951, P53544, P53545, P53546, P56915, P97334, Q02591

Diamond homologs: A0JPN1, A1YG85, A5PKG8, A6NJ46, A6NMT0, A7MB54, A9L937, B0VXK3, D2KQB0, E7FDX5, M0R6D8, O08686, O13023, O35762, O42365, O43364, O43711, O55144, O88181, O93366, O93367, O93590, P0C1T1, P10035, P14652, P14837, P20009, P28468, P31245, P31246, P31261, P31314, P42583, P42584, P43120, P43345, P43688, P50219, P52945, P52950

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RUNX1	“up-regulates quantity”	HHEX	“transcriptional regulation”
HHEX	“up-regulates activity”	Proliferation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 46 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chemokine receptors bind chemokines	5	23.4×	8e-05
Keratinization	13	18.1×	1e-11

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cell migration	5	8.8×	8e-03
inflammatory response	7	7.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

644 predictions. Top by Δscore:

Variant	Effect	Δscore
10:92690346:GG:G	donor_gain	1.0000
10:92690347:GG:G	donor_gain	1.0000
10:92690349:T:G	donor_loss	1.0000
10:92691161:G:GT	donor_gain	1.0000
10:92691168:G:GT	donor_gain	1.0000
10:92691201:G:T	donor_gain	1.0000
10:92692542:GACAG:G	donor_gain	1.0000
10:92692543:ACAG:A	donor_gain	1.0000
10:92692543:ACAGG:A	donor_loss	1.0000
10:92692544:CAG:C	donor_gain	1.0000
10:92692545:AG:A	donor_gain	1.0000
10:92692546:GG:G	donor_gain	1.0000
10:92692547:G:GG	donor_gain	1.0000
10:92692699:TAGGT:T	acceptor_loss	1.0000
10:92692751:AGGTA:A	donor_loss	1.0000
10:92690343:CCTGG:C	donor_gain	0.9900
10:92690348:G:GG	donor_gain	0.9900
10:92691161:G:T	donor_gain	0.9900
10:92691192:T:G	donor_gain	0.9900
10:92692399:GA:G	acceptor_gain	0.9900
10:92692697:T:A	acceptor_gain	0.9900
10:92692700:A:AG	acceptor_gain	0.9900
10:92692700:AG:A	acceptor_gain	0.9900
10:92692701:G:GG	acceptor_gain	0.9900
10:92692701:GG:G	acceptor_gain	0.9900
10:92692701:GGTC:G	acceptor_gain	0.9900
10:92692701:GGTCA:G	acceptor_gain	0.9900
10:92692753:G:GG	donor_gain	0.9900
10:92692754:T:A	donor_loss	0.9900
10:92694541:A:AG	acceptor_gain	0.9900

AlphaMissense

1751 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:92690080:T:C	F32L	1.000
10:92690082:T:A	F32L	1.000
10:92690082:T:G	F32L	1.000
10:92690087:T:A	I34N	1.000
10:92692418:A:G	K138E	1.000
10:92692419:A:T	K138I	1.000
10:92692420:A:C	K138N	1.000
10:92692420:A:T	K138N	1.000
10:92692425:G:A	G140D	1.000
10:92692436:T:A	F144I	1.000
10:92692436:T:C	F144L	1.000
10:92692436:T:G	F144V	1.000
10:92692437:T:C	F144S	1.000
10:92692437:T:G	F144C	1.000
10:92692438:C:A	F144L	1.000
10:92692438:C:G	F144L	1.000
10:92692440:C:T	S145F	1.000
10:92692449:A:C	Q148P	1.000
10:92692450:G:C	Q148H	1.000
10:92692450:G:T	Q148H	1.000
10:92692461:T:A	L152Q	1.000
10:92692461:T:C	L152P	1.000
10:92692461:T:G	L152R	1.000
10:92692464:A:T	E153V	1.000
10:92692465:G:C	E153D	1.000
10:92692465:G:T	E153D	1.000
10:92692472:T:A	F156I	1.000
10:92692472:T:C	F156L	1.000
10:92692472:T:G	F156V	1.000
10:92692473:T:C	F156S	1.000

dbSNP variants (sampled 300 via entrez): RS1000267586 (10:92688140 A>G), RS1000305349 (10:92694145 C>T), RS1000326112 (10:92695133 C>A,T), RS1000378559 (10:92694782 T>G), RS1000668024 (10:92693239 A>G,T), RS1001034899 (10:92696042 G>A,C,T), RS1001120570 (10:92689749 T>C,G), RS1001766211 (10:92688493 C>T), RS1001834806 (10:92695416 G>A,T), RS1002477713 (10:92695609 CTA>C), RS1002574073 (10:92693734 A>G,T), RS1002674090 (10:92690232 C>T), RS1002772241 (10:92689664 G>C), RS1003129280 (10:92692181 T>C), RS1003478437 (10:92693722 G>A)

Disease associations

OMIM: gene MIM:604420 | disease phenotypes: MIM:174050

GenCC curated gene-disease

Mondo (1): autosomal dominant polycystic liver disease (MONDO:0000447)

Orphanet (1): Isolated polycystic liver disease (Orphanet:2924)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0006557	Polycystic liver disease

GWAS associations

49 associations (top):

Study	Trait	p-value
GCST000012_2	Type 2 diabetes	3.000000e-06
GCST000024_6	Type 2 diabetes	6.000000e-10
GCST000025_3	Type 2 diabetes	5.000000e-06
GCST000028_4	Type 2 diabetes	6.000000e-10
GCST000167_13	Type 2 diabetes	7.000000e-08
GCST000383_5	Type 2 diabetes	7.000000e-12
GCST000712_21	Type 2 diabetes	1.000000e-15
GCST000796_3	Type 2 diabetes	9.000000e-06
GCST001038_6	Dehydroepiandrosterone sulphate levels	5.000000e-09
GCST001198_22	Multiple sclerosis	5.000000e-09
GCST001550_9	Type 2 diabetes	2.000000e-09
GCST002128_8	Type 2 diabetes	2.000000e-08
GCST002352_7	Type 2 diabetes	3.000000e-19
GCST003400_27	Type 2 diabetes	2.000000e-14
GCST003400_28	Type 2 diabetes	2.000000e-14
GCST003400_50	Type 2 diabetes	6.000000e-20
GCST004131_111	Inflammatory bowel disease	5.000000e-07
GCST004600_93	Eosinophil percentage of white cells	6.000000e-14
GCST004606_194	Eosinophil count	6.000000e-16
GCST004617_184	Eosinophil percentage of granulocytes	9.000000e-11
GCST004624_179	Sum eosinophil basophil counts	1.000000e-13
GCST004894_103	Type 2 diabetes	6.000000e-39
GCST004894_74	Type 2 diabetes	3.000000e-26
GCST004904_161	Body mass index	3.000000e-12
GCST004904_51	Body mass index	2.000000e-09
GCST005047_13	Type 2 diabetes	2.000000e-19
GCST005047_79	Type 2 diabetes	7.000000e-13
GCST005047_95	Type 2 diabetes	5.000000e-12
GCST005146_12	Birth weight	1.000000e-14
GCST005160_2	Insulin levels in response to oral glucose tolerance test (30 minutes)	5.000000e-07

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0005090	basophil count
EFO:0004340	body mass index
EFO:0004344	birth weight
EFO:0004307	glucose tolerance test
EFO:0004467	insulin measurement
EFO:0008473	insulin response measurement
EFO:0004471	insulin sensitivity measurement
EFO:0006832	disposition index measurement
EFO:0004541	HbA1c measurement
EFO:0004695	intraocular pressure measurement
EFO:0006335	systolic blood pressure
EFO:0007710	cognitive decline measurement
EFO:0005000	leptin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	affects expression, decreases expression, affects localization, increases expression	5
Cyclosporine	decreases expression	4
Valproic Acid	affects expression, decreases expression, increases expression	3
trichostatin A	affects localization, increases expression	2
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol A	affects expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
potassium chromate(VI)	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
NSC668394	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2Q2	SEES3-1V human HHEX, clone1	Embryonic stem cell	Male
CVCL_A2Q3	SEES3-1V human HHEX, clone2	Embryonic stem cell	Male
CVCL_A2Q4	SEES3-1V human HHEX, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01157858	PHASE2	COMPLETED	Everolimus and LongActing Octreotide Trial in Polycystic Livers
NCT01670110	PHASE2	COMPLETED	Pasireotide LAR in Severe Polycystic Liver Disease
NCT02021110	PHASE2	COMPLETED	Ursodeoxycholic Acid as Treatment for Polycystic Liver Disease
NCT05478083	PHASE2	RECRUITING	A GnRH Agonist IN Pre-menopausal Women STudy to Treat Severe Polycystic Liver Disease
NCT00426153	PHASE2/PHASE3	COMPLETED	Octreotide in Severe Polycystic Liver Disease
NCT00565097	PHASE2/PHASE3	COMPLETED	Lanreotide as Treatment of Polycystic Livers
NCT00771888	PHASE2/PHASE3	UNKNOWN	Open-Label Extension of LOCKCYST Trial
NCT01315795	PHASE2/PHASE3	COMPLETED	Lanreotide Autogel in the Treatment of Symptomatic Polycystic Liver Disease
NCT05281328	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Assess the Efficacy and Safety of Octreotide Subcutaneous Depot in Patients With PLD
NCT00934791	Not specified	TERMINATED	Polycystic Liver Disease in Kidney Transplant
NCT01354405	Not specified	COMPLETED	Somatostatin Analogues as a Volume Reducing Treatment of Polycystic Livers (RESOLVE)
NCT02173080	Not specified	COMPLETED	Development and Assessment of The Polycystic Liver Disease Questionnaire (PLD-Q).
NCT03960710	Not specified	UNKNOWN	Automatic Segmentation of Polycystic Liver
NCT04111692	Not specified	RECRUITING	A Prospective Observational Study of Foam Sclerotherapy .
NCT04645251	Not specified	RECRUITING	Polycystic Liver Disease Registry (UK)
NCT05215964	Not specified	UNKNOWN	The Association Between Skeletal Muscle Mass and Severity of Polycystic Liver Disease and Polycystic Kidney Disease
NCT05500157	Not specified	UNKNOWN	Assessment of Treatment With Laparoscopic Fenestration or Aspiration Sclerotherapy for Large Symptomatic Hepatic Cysts