RHOXF2

Summary

RHOXF2 (Rhox homeobox family member 2, HGNC:30011) is a protein-coding gene on chromosome Xq24, encoding Rhox homeobox family member 2 (Q9BQY4). Transcription factor maybe involved in reproductive processes.

This gene, which encodes a transcriptional repressor, is one of two paralogous X-linked homeobox-containing genes and is highly expressed in a variety of cancers. In addition, the encoded protein associates with the cell membrane and with microtubules, and is concentrated at the leading edge of migratory cells.

Source: NCBI Gene 84528 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 33 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_032498

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30011
Approved symbol	RHOXF2
Name	Rhox homeobox family member 2
Location	Xq24
Locus type	gene with protein product
Status	Approved
Aliases	THG1, PEPP-2, PEPP2, CT107
Ensembl gene	ENSG00000131721
Ensembl biotype	protein_coding
OMIM	300447
Entrez	84528

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000371388

RefSeq mRNA: 1 — MANE Select: NM_032498 NM_032498

CCDS: CCDS14594

Canonical transcript exons

ENST00000371388 — 4 exons

Exon	Start	End
ENSE00001661159	120158613	120158829
ENSE00001678225	120163458	120165630
ENSE00001694270	120160358	120160403
ENSE00001794725	120159015	120159426

Expression profiles

Bgee: expression breadth broad, 22 present calls, max score 82.76.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6132 / max 59.7410, expressed in 55 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
209796	0.6132	55

Top tissues by expression

90 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	82.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.32	gold quality
testis	UBERON:0000473	66.95	gold quality
right testis	UBERON:0004534	65.55	gold quality
left testis	UBERON:0004533	64.90	gold quality
colonic epithelium	UBERON:0000397	54.41	gold quality
bone marrow cell	CL:0002092	52.85	gold quality
sural nerve	UBERON:0015488	48.91	gold quality
tonsil	UBERON:0002372	44.88	gold quality
bone marrow	UBERON:0002371	42.50	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	41.39	silver quality
skeletal muscle tissue	UBERON:0001134	41.18	gold quality
right uterine tube	UBERON:0001302	40.41	silver quality
corpus callosum	UBERON:0002336	39.52	silver quality
adrenal tissue	UBERON:0018303	39.38	silver quality
lower esophagus mucosa	UBERON:0035834	39.04	gold quality
liver	UBERON:0002107	38.79	gold quality
muscle tissue	UBERON:0002385	38.22	gold quality
blood	UBERON:0000178	38.16	silver quality
primary visual cortex	UBERON:0002436	38.10	gold quality
urinary bladder	UBERON:0001255	37.59	gold quality
right hemisphere of cerebellum	UBERON:0014890	37.08	gold quality
monocyte	CL:0000576	36.61	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
leukocyte	CL:0000738	36.33	gold quality
adult mammalian kidney	UBERON:0000082	36.26	silver quality
granulocyte	CL:0000094	35.96	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
endometrium	UBERON:0001295	35.48	gold quality
hindlimb stylopod muscle	UBERON:0004252	35.40	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	265.87
E-ANND-3	no	0.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting RHOXF2, 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-8485	100.00	77.57	4731
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-606	98.72	67.34	960
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-18B-3P	98.05	65.55	595
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-5588-5P	97.46	65.70	913
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-424-3P	97.20	65.86	385
HSA-MIR-3157-3P	95.86	67.08	454
HSA-MIR-31-3P	95.17	69.82	575
HSA-MIR-371B-3P	94.48	66.59	345

Literature-anchored findings (GeneRIF, showing 4)

• RHOXF2 is highly expressed in some leukemia cell lines and a variety of human cancers. Results indicate that RHOXF2 is involved in carcinogenesis. (PMID:21874235)
• In striking contrast to non-human primates, humans appear to have homogenized their two RHOXF2 copies by the endogenous retrovirus -mediated non-allelic recombination mechanism. (PMID:21988730)
• PEPP2 has a role in regulating function of membrane and microtubules (PMID:23682428)
• Human Thg1, two critical tRNA-interacting residues, His-152 and Lys-187, alanine-substituted variants maintain a similar overall interaction with the anticodon region, arguing against the sufficiency of this interaction for driving catalysis. Instead, conservative mutagenesis revealed a new direct function for these residues in recognition of a non-Watson-Crick G-1:A73 bp (PMID:31000629)

Cross-species orthologs

0 orthologs

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155), SHOX (ENSG00000185960)

Protein

Protein identifiers

Rhox homeobox family member 2 — Q9BQY4 (reviewed: Q9BQY4)

Alternative names: Paired-like homeobox protein PEPP-2, Testis homeobox gene 1

All UniProt accessions (1): Q9BQY4

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor maybe involved in reproductive processes. Modulates expression of target genes encoding proteins involved in processes relevant to spermatogenesis.

Subcellular location. Nucleus.

Tissue specificity. Testis. Not detected in epididymis nor placenta. In testis, mainly expressed in germ cells, but also detected in somatic cells such as Sertoli cells, Leydig cells and peritubular cells.

Similarity. Belongs to the paired-like homeobox family. PEPP subfamily.

RefSeq proteins (1): NP_115887* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site

Pfam: PF00046

UniProt features (10 total): sequence variant 4, compositionally biased region 2, chain 1, DNA-binding region 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQY4-F1	64.38	0.22

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 22 (showing top): GOBP_NEUROGENESIS, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, chrXq24, WARTERS_IR_RESPONSE_5GY, NFE2L2.V2, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, MIR1468_3P, MIR5003_3P, MIR3128, MIR149_5P, MIR31_3P, MIR18B_3P, MIR424_3P, GOBP_POSITIVE_REGULATION_OF_GENE_EXPRESSION, GOBP_GENERATION_OF_NEURONS

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of gene expression (GO:0010628), neuron development (GO:0048666), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), identical protein binding (GO:0042802), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of gene expression	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
neuron differentiation	1
cell development	1
DNA-templated transcription	1
regulation of RNA biosynthetic 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
protein binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHOXF2	TGIF2LX	Q8IUE1	599
RHOXF2	ODF4	Q2M2E3	542
RHOXF2	UNC5C	O95185	479
RHOXF2	SLC71A3P	Q5VZR4	448
RHOXF2	TSGA10	Q9BZW7	424
RHOXF2	TPRX1	Q8N7U7	419
RHOXF2	AKAP4	Q5JQC9	415
RHOXF2	INHA	P05111	394
RHOXF2	DUXB	A0A1W2PPF3	373
RHOXF2	NANOGNB	Q7Z5D8	370
RHOXF2	REXO5	Q96IC2	336
RHOXF2	ARGFX	A6NJG6	327
RHOXF2	TET1	Q8NFU7	324
RHOXF2	PRSS37	A4D1T9	312
RHOXF2	DPRX	A6NFQ7	305

IntAct

297 interactions, top by confidence:

A	B	Type	Score
RHOXF2	DAZAP2	psi-mi:“MI:0915”(physical association)	0.850
DAZAP2	RHOXF2	psi-mi:“MI:0915”(physical association)	0.850
RHOXF2	ZBTB32	psi-mi:“MI:0915”(physical association)	0.810
ZBTB32	RHOXF2	psi-mi:“MI:0915”(physical association)	0.810
RHOXF2	TOLLIP	psi-mi:“MI:0915”(physical association)	0.800
TRIP13	RHOXF2	psi-mi:“MI:0915”(physical association)	0.790
RHOXF2	TRIP13	psi-mi:“MI:0915”(physical association)	0.790
KRTAP19-5	RHOXF2	psi-mi:“MI:0915”(physical association)	0.720
RHOXF2	KRTAP19-7	psi-mi:“MI:0915”(physical association)	0.720
VAC14	RHOXF2	psi-mi:“MI:0915”(physical association)	0.720
RHOXF2	MAGED1	psi-mi:“MI:0915”(physical association)	0.720
RHOXF2	KRTAP19-5	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (139): RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid), RHOXF2 (Two-hybrid)

ESM2 similar proteins: A0A1W2PPF3, A0A3B3IT52, E9Q3T6, O02747, O13161, O42173, O57374, O73622, O95238, P01103, P01104, P09632, P0C7M4, P10242, P14837, P17278, P30561, P31538, P41738, P46200, Q1KKS8, Q28G02, Q32NH9, Q4JM65, Q5REX1, Q5WM45, Q66IG8, Q68EH7, Q6U8D7, Q6ZTZ1, Q7T1K4, Q8BIL2, Q8BKE5, Q8CFH6, Q8IWB6, Q8JIT7, Q8NHV9, Q8R4S2, Q8R4S4, Q8R4S5

Diamond homologs: A1A546, A1YEV8, A1YEY5, A1YFI3, A1YG25, A1YG57, A2T711, A2T733, A2T7P4, A6NNA5, A6YP92, F6YCR7, G5EC89, G5EDS1, O14813, O18400, O35085, O35137, O35160, O35602, O35690, O42115, O42201, O42356, O42357, O42358, O42567, O43186, O54751, O70137, O73917, O75360, O75364, O88436, O93385, O95076, O97039, P06601, P0C7M4, P26367

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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	10	19.2×	7e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	23
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2424705	NC_000023.10:g.(?117629935)(119761021_?)del	Pathogenic

SpliceAI

432 predictions. Top by Δscore:

Variant	Effect	Δscore
X:120159414:G:GG	donor_gain	1.0000
X:120159424:GCG:G	donor_gain	1.0000
X:120159427:GTA:G	donor_loss	1.0000
X:120159428:T:A	donor_loss	1.0000
X:120163449:T:A	acceptor_gain	1.0000
X:120159427:G:GG	donor_gain	0.9900
X:120163453:T:A	acceptor_gain	0.9900
X:120163456:A:AG	acceptor_gain	0.9900
X:120163457:G:GG	acceptor_gain	0.9900
X:120163457:GATTT:G	acceptor_gain	0.9900
X:120160356:A:AG	acceptor_gain	0.9800
X:120160357:G:GG	acceptor_gain	0.9800
X:120163453:TGAA:T	acceptor_loss	0.9800
X:120163454:GAAG:G	acceptor_loss	0.9800
X:120163455:AAG:A	acceptor_loss	0.9800
X:120163456:A:C	acceptor_loss	0.9800
X:120163457:G:A	acceptor_loss	0.9800
X:120158828:GG:G	donor_gain	0.9700
X:120158829:GG:G	donor_gain	0.9700
X:120163457:GAT:G	acceptor_gain	0.9700
X:120160636:A:G	donor_gain	0.9600
X:120160636:A:AG	donor_gain	0.9500
X:120163457:GA:G	acceptor_gain	0.9400
X:120163457:GATT:G	acceptor_gain	0.9400
X:120163454:GAAGA:G	acceptor_gain	0.9300
X:120163453:TGAAG:T	acceptor_gain	0.9200
X:120159272:G:GT	donor_gain	0.9000
X:120160357:GAA:G	acceptor_gain	0.9000
X:120163455:AAGAT:A	acceptor_gain	0.9000
X:120163452:TTGAA:T	acceptor_gain	0.8900

AlphaMissense

1918 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:120163464:T:C	F182L	0.996
X:120163466:T:A	F182L	0.996
X:120163466:T:G	F182L	0.996
X:120159356:T:C	F141L	0.995
X:120159358:C:A	F141L	0.995
X:120159358:C:G	F141L	0.995
X:120159392:T:C	F153L	0.995
X:120159394:C:A	F153L	0.995
X:120159394:C:G	F153L	0.995
X:120159357:T:G	F141C	0.989
X:120159407:T:C	F158L	0.989
X:120159409:C:A	F158L	0.989
X:120159409:C:G	F158L	0.989
X:120163465:T:C	F182S	0.989
X:120163478:A:C	R186S	0.989
X:120163478:A:T	R186S	0.989
X:120159393:T:C	F153S	0.988
X:120159393:T:G	F153C	0.986
X:120163465:T:G	F182C	0.986
X:120159357:T:C	F141S	0.985
X:120159381:T:C	L149P	0.985
X:120163463:G:C	W181C	0.980
X:120163463:G:T	W181C	0.980
X:120163475:A:C	R185S	0.979
X:120163475:A:T	R185S	0.979
X:120163477:G:C	R186T	0.977
X:120163464:T:A	F182I	0.976
X:120159392:T:A	F153I	0.975
X:120159392:T:G	F153V	0.975
X:120159372:T:C	L146P	0.974

dbSNP variants (sampled 300 via entrez): RS1157163197 (X:120165269 C>G,T), RS1158059642 (X:120166088 CAGAA>C), RS1158110171 (X:120162425 G>A,C), RS1158614524 (X:120160871 G>T), RS1158680036 (X:120164471 CAAAAG>C), RS1158722971 (X:120162988 G>C), RS1158809182 (X:120165077 T>C), RS1159039261 (X:120159552 C>G,T), RS1159234947 (X:120161599 GA>G), RS1160181564 (X:120158860 C>T), RS1161658741 (X:120159017 A>G), RS1162210873 (X:120161863 T>C), RS1164660199 (X:120163009 A>T), RS1164742912 (X:120158094 GA>G,GAA), RS1164767328 (X:120165483 G>C)

Disease associations

OMIM: gene MIM:300447 | disease phenotypes: MIM:300354, MIM:300676

GenCC curated gene-disease

Mondo (2): X-linked intellectual disability, Cabezas type (MONDO:0010306), syndromic X-linked intellectual disability 14 (MONDO:0010398)

Orphanet (3): Lujan-Fryns syndrome (Orphanet:776), X-linked intellectual disability, Vitale type (Orphanet:85289), X-linked intellectual disability, Cabezas type (Orphanet:85293)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567063	Mental Retardation, X-Linked, Syndromic 14 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725135 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.60	IC50	250	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178798: Inhibition of RHOXF2 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.2500	uM

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Decitabine	increases expression	2
cobaltous chloride	decreases expression	1
Plant Extracts	decreases expression	1
Valproic Acid	increases methylation	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697528	Binding	Inhibition of RHOXF2 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5W2	SEES3-1V human RHOXF2, clone1	Embryonic stem cell	Male
CVCL_A5W3	SEES3-1V human RHOXF2, clone2	Embryonic stem cell	Male
CVCL_A5W4	SEES3-1V human RHOXF2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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