RHEX

Summary

RHEX (regulator of hemoglobinization and erythroid cell expansion, HGNC:25341) is a protein-coding gene on chromosome 1q32.1, encoding Regulator of hemoglobinization and erythroid cell expansion protein (Q6ZWK4). Acts as a signaling transduction factor of the EPO-EPOR signaling pathway promoting erythroid cell differentiation.

Enables erythropoietin receptor binding activity. Involved in erythropoietin-mediated signaling pathway and positive regulation of erythrocyte differentiation. Located in plasma membrane.

Source: NCBI Gene 440712 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 17 total
• MANE Select transcript: NM_001007544

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25341
Approved symbol	RHEX
Name	regulator of hemoglobinization and erythroid cell expansion
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ16052
Ensembl gene	ENSG00000263961
Ensembl biotype	protein_coding
OMIM	616088
Entrez	440712

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 retained_intron

ENST00000331555, ENST00000582070, ENST00000603378, ENST00000603488, ENST00000604112, ENST00000871768, ENST00000871769, ENST00000871770, ENST00000871771, ENST00000871772, ENST00000871773, ENST00000959924

RefSeq mRNA: 2 — MANE Select: NM_001007544 NM_001007544, NM_001369490

CCDS: CCDS73014

Canonical transcript exons

ENST00000331555 — 6 exons

Exon	Start	End
ENSE00001301514	206101752	206102449
ENSE00001443588	206097733	206097839
ENSE00001443589	206053173	206053265
ENSE00003724257	206098081	206098181
ENSE00003727936	206099655	206099798
ENSE00003750840	206101136	206101197

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 92.32.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 6.2268 / max 1616.8783, expressed in 170 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8078	4.5156	113
8077	1.0967	53
8079	0.4565	28
8075	0.1125	44
8076	0.0455	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	92.32	silver quality
epithelial cell of pancreas	CL:0000083	92.24	silver quality
seminal vesicle	UBERON:0000998	90.95	gold quality
endometrium	UBERON:0001295	90.93	gold quality
pancreatic ductal cell	CL:0002079	90.43	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.40	gold quality
right uterine tube	UBERON:0001302	88.09	gold quality
metanephros cortex	UBERON:0010533	87.40	gold quality
gall bladder	UBERON:0002110	86.66	gold quality
upper arm skin	UBERON:0004263	85.99	silver quality
skin of hip	UBERON:0001554	85.32	gold quality
oviduct epithelium	UBERON:0004804	84.13	gold quality
trabecular bone tissue	UBERON:0002483	83.63	gold quality
metanephros	UBERON:0000081	82.29	gold quality
decidua	UBERON:0002450	82.17	gold quality
upper leg skin	UBERON:0004262	80.64	gold quality
left ventricle myocardium	UBERON:0006566	80.62	gold quality
uterus	UBERON:0000995	80.59	gold quality
cardiac muscle of right atrium	UBERON:0003379	80.56	gold quality
nasal cavity epithelium	UBERON:0005384	80.56	gold quality
adult mammalian kidney	UBERON:0000082	78.26	gold quality
rectum	UBERON:0001052	78.11	gold quality
endocervix	UBERON:0000458	78.00	gold quality
smooth muscle tissue	UBERON:0001135	77.64	gold quality
mucosa of stomach	UBERON:0001199	77.58	gold quality
lower esophagus muscularis layer	UBERON:0035833	77.52	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	77.52	gold quality
visceral pleura	UBERON:0002401	77.50	gold quality
lower esophagus	UBERON:0013473	77.43	gold quality
urinary bladder	UBERON:0001255	77.29	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	2081.82
E-MTAB-10042	yes	1698.82
E-CURD-119	yes	1483.69
E-CURD-112	yes	1193.90
E-MTAB-7407	yes	1141.50
E-GEOD-131882	yes	1063.74
E-ANND-5	yes	527.04
E-HCAD-1	yes	43.75
E-CURD-88	yes	41.48
E-MTAB-8410	yes	18.09
E-GEOD-130148	yes	13.07
E-CURD-122	yes	12.68
E-HCAD-10	yes	12.21
E-MTAB-6701	yes	10.22
E-MTAB-9801	yes	9.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting RHEX, 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-552-5P	99.93	68.56	1583
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4312	99.34	67.30	511
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-4751	98.80	64.95	525
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-6883-3P	97.97	67.35	643
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-3936	97.64	64.47	732
HSA-MIR-3928-3P	97.61	66.53	1096
HSA-MIR-192-3P	97.52	67.66	1001
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-1289	97.46	65.37	655
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-1225-5P	96.76	66.85	417
HSA-MIR-382-5P	96.71	65.90	762
HSA-MIR-6735-3P	96.10	63.81	600
HSA-MIR-5186	94.63	66.76	627

Literature-anchored findings (GeneRIF, showing 2)

• RHEX(C1orf186) comprises a new EPO/EPOR target and regulator of erythroid cell expansion that additionally acts to support late-stage erythroblast development (PMID:25092874)
• Clorfl86/RHEX Is a Negative Regulator of SCF/KIT Signaling in Human Skin Mast Cells. (PMID:37174705)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Regulator of hemoglobinization and erythroid cell expansion protein — Q6ZWK4 (reviewed: Q6ZWK4)

Alternative names: Regulator of human erythroid cell expansion protein

All UniProt accessions (2): A0A075B7E7, Q6ZWK4

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a signaling transduction factor of the EPO-EPOR signaling pathway promoting erythroid cell differentiation.

Subunit / interactions. Interacts with EPOR; this interaction occurs in a erythropoietin (EPO)-dependent manner. Interacts with JAK2; this interaction occurs in a erythropoietin (EPO)-dependent manner. Interacts (via tyrosine-phosphorylated form) with GRB2.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in the proerythroblasts (at protein level). Expressed strongly in the kidney. Expressed weakly in the pancreas, liver and lung. Expressed strongly in erythroid progenitor cells (EPCs). Expressed weakly in T-cells and neutrophils.

Post-translational modifications. Phosphorylated. Phosphorylation on Tyr-132 and Tyr-141 occurs in a erythropoietin (EPO)-dependent manner.

Induction. Up-regulated during erythroid differentiation.

RefSeq proteins (2): NP_001007545, NP_001356419 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031517	RHEX-like	Family

Pfam: PF15763

UniProt features (7 total): compositionally biased region 2, modified residue 2, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZWK4-F1	65.95	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): 132, 141

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 88 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_POSITIVE_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_RESPONSE_TO_PEPTIDE, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_CELL_MATURATION, GOBP_ERYTHROCYTE_MATURATION, GOBP_POSITIVE_REGULATION_OF_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS

GO Biological Process (5): cellular response to erythropoietin (GO:0036018), erythropoietin-mediated signaling pathway (GO:0038162), erythrocyte maturation (GO:0043249), positive regulation of erythrocyte differentiation (GO:0045648), cell differentiation (GO:0030154)

GO Molecular Function (2): erythropoietin receptor binding (GO:0005128), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to erythropoietin	1
cellular response to cytokine stimulus	1
cytokine-mediated signaling pathway	1
cellular response to erythropoietin	1
cell maturation	1
erythrocyte development	1
erythrocyte differentiation	1
positive regulation of myeloid cell differentiation	1
regulation of erythrocyte differentiation	1
cellular developmental process	1
cytokine receptor binding	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

228 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHEX	STX18	Q9P2W9	525
RHEX	NUGGC	Q68CJ6	459
RHEX	C1orf74	Q96LT6	446
RHEX	EFR3B	Q9Y2G0	431
RHEX	EFNA5	P52803	400
RHEX	RLIG1	Q8N999	391
RHEX	SAGE1	Q9NXZ1	382
RHEX	TOR4A	Q9NXH8	359
RHEX	ASRGL1	Q7L266	348
RHEX	SOX17	Q9H6I2	335
RHEX	GCSAML	Q5JQS6	325
RHEX	EPOR	P19235	324
RHEX	SCGB2A1	O75556	324
RHEX	RTP4	Q96DX8	316
RHEX	SACK1D	Q9H4H8	307

IntAct

24 interactions, top by confidence:

A	B	Type	Score
GET3	RHEX	psi-mi:“MI:0915”(physical association)	0.560
RHEX	SH3GLB1	psi-mi:“MI:0915”(physical association)	0.560
RHEX	PBX3	psi-mi:“MI:0915”(physical association)	0.560
GAD2	RHEX	psi-mi:“MI:0915”(physical association)	0.560
SNX1	RHEX	psi-mi:“MI:0915”(physical association)	0.560
RHEX	RBFA	psi-mi:“MI:0915”(physical association)	0.560
RHEX	SH3GL1	psi-mi:“MI:0915”(physical association)	0.560
RHEX	NOS1AP	psi-mi:“MI:0914”(association)	0.530
PBX3	RHEX	psi-mi:“MI:0915”(physical association)	0.000
GAD2	RHEX	psi-mi:“MI:0915”(physical association)	0.000
SNX1	RHEX	psi-mi:“MI:0915”(physical association)	0.000
RBFA	RHEX	psi-mi:“MI:0915”(physical association)	0.000
SH3GL1	RHEX	psi-mi:“MI:0915”(physical association)	0.000
GET3	RHEX	psi-mi:“MI:0915”(physical association)	0.000
SH3GLB1	RHEX	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (46): SNX17 (Affinity Capture-MS), WDR47 (Affinity Capture-MS), JPH1 (Affinity Capture-MS), TMTC4 (Affinity Capture-MS), SBF1 (Affinity Capture-MS), DYNLL1 (Affinity Capture-MS), PLXDC2 (Affinity Capture-MS), SENP5 (Affinity Capture-MS), DIP2A (Affinity Capture-MS), PLD1 (Affinity Capture-MS), PKN1 (Affinity Capture-MS), ZBTB9 (Affinity Capture-MS), FIGNL1 (Affinity Capture-MS), WDR47 (Affinity Capture-MS), SNX17 (Affinity Capture-MS)

ESM2 similar proteins: A4F4L0, D7PDD4, O00453, O08843, O43914, O46631, O54885, P0CAN6, P11911, P11912, P40259, P40293, P40931, P78324, P86176, P97710, P97797, Q07763, Q13113, Q2KIP5, Q2YFS3, Q3U4N7, Q3UU41, Q3UU67, Q495A1, Q5M869, Q5RA41, Q60837, Q6MG59, Q6SJQ7, Q6UX27, Q6X9T7, Q6ZWK4, Q86YW5, Q8CJ26, Q8IW00, Q8K1T1, Q8MII8, Q8N386, Q8NET5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	2
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

1744 predictions. Top by Δscore:

Variant	Effect	Δscore
1:206061795:ATT:A	donor_gain	1.0000
1:206097838:C:CC	donor_gain	1.0000
1:206097838:CT:C	donor_gain	1.0000
1:206097839:A:AC	donor_gain	1.0000
1:206098077:T:A	acceptor_loss	1.0000
1:206098078:C:CC	acceptor_gain	1.0000
1:206098078:CT:C	acceptor_loss	1.0000
1:206098079:TCTG:T	acceptor_loss	1.0000
1:206098080:CT:C	acceptor_gain	1.0000
1:206098083:TGACT:T	acceptor_gain	1.0000
1:206098177:ATGTG:A	donor_gain	1.0000
1:206101748:T:C	acceptor_gain	1.0000
1:206061771:T:TA	donor_gain	0.9900
1:206061822:C:A	donor_gain	0.9900
1:206061823:T:TA	donor_gain	0.9900
1:206061826:G:C	donor_gain	0.9900
1:206097729:T:A	acceptor_loss	0.9900
1:206097730:CT:C	acceptor_loss	0.9900
1:206097731:TC:T	acceptor_loss	0.9900
1:206097732:ATC:A	acceptor_loss	0.9900
1:206097733:GATC:G	acceptor_loss	0.9900
1:206098082:GACT:G	acceptor_gain	0.9900
1:206098173:G:A	donor_gain	0.9900
1:206099797:C:CC	donor_gain	0.9900
1:206099797:CG:C	donor_gain	0.9900
1:206099798:A:AC	donor_gain	0.9900
1:206101748:T:TC	acceptor_gain	0.9900
1:206053264:C:CC	donor_gain	0.9800
1:206053264:C:T	donor_loss	0.9800
1:206053265:A:AC	donor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000508854 (1:206070790 T>C), RS1000669265 (1:206096525 T>A), RS1000756074 (1:206054191 G>C,T), RS1000796093 (1:206090339 G>A), RS1000892498 (1:206090124 A>G), RS1000946707 (1:206059250 A>C,G,T), RS1001087237 (1:206083699 A>G), RS1001145314 (1:206096848 C>T), RS1001317424 (1:206058225 G>C), RS1001323051 (1:206071487 A>G), RS1001327539 (1:206058572 T>A,G), RS1001501217 (1:206095636 G>A), RS1001539955 (1:206084109 C>T), RS1001574920 (1:206095959 C>T), RS1001715693 (1:206089559 G>A)

Disease associations

OMIM: gene MIM:616088 | 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
GCST010396_49	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases mutagenesis	3
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Zoledronic Acid	increases expression	1
Leflunomide	decreases expression	1
Estradiol	increases expression	1
Nickel	decreases expression	1
Urethane	decreases expression	1

Clinical trials (associated diseases)

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