DUX4

Summary

DUX4 (double homeobox 4, HGNC:50800) is a protein-coding gene on chromosome 4q35.2, encoding Double homeobox protein 4 (Q9UBX2). Transcription factor that is selectively and transiently expressed in cleavage-stage embryos.

This gene is located within a D4Z4 repeat array in the subtelomeric region of chromosome 4q. The D4Z4 repeat is polymorphic in length; a similar D4Z4 repeat array has been identified on chromosome 10. Each D4Z4 repeat unit has an open reading frame (named DUX4) that encodes two homeoboxes; the repeat-array and ORF is conserved in other mammals. The encoded protein has been reported to function as a transcriptional activator of paired-like homeodomain transcription factor 1 (PITX1; GeneID 5307). Contraction of the macrosatellite repeat causes autosomal dominant facioscapulohumeral muscular dystrophy (FSHD). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 100288687 — RefSeq curated summary.

At a glance

• Gene–disease (curated): facioscapulohumeral muscular dystrophy 1 (Limited, GenCC)
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_001306068

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:50800
Approved symbol	DUX4
Name	double homeobox 4
Location	4q35.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000260596
Ensembl biotype	protein_coding
OMIM	606009
Entrez	100288687

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000563716, ENST00000564366, ENST00000565211, ENST00000569241, ENST00000570263, ENST00000616166

RefSeq mRNA: 3 — MANE Select: NM_001306068 NM_001293798, NM_001306068, NM_001363820

CCDS: CCDS77990, CCDS93681

Canonical transcript exons

ENST00000565211 — 2 exons

Exon	Start	End
ENSE00002596957	190173774	190175284
ENSE00002600298	190175647	190175845

Expression profiles

Bgee: expression breadth broad, 82 present calls, max score 78.79.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.79	gold quality
monocyte	CL:0000576	57.80	gold quality
cortical plate	UBERON:0005343	57.32	gold quality
sural nerve	UBERON:0015488	56.74	gold quality
leukocyte	CL:0000738	55.08	gold quality
left testis	UBERON:0004533	50.60	gold quality
testis	UBERON:0000473	49.70	gold quality
hindlimb stylopod muscle	UBERON:0004252	49.50	silver quality
right testis	UBERON:0004534	48.53	gold quality
primary visual cortex	UBERON:0002436	44.62	silver quality
smooth muscle tissue	UBERON:0001135	44.11	gold quality
duodenum	UBERON:0002114	43.42	silver quality
bone marrow cell	CL:0002092	43.27	gold quality
apex of heart	UBERON:0002098	42.79	silver quality
uterine cervix	UBERON:0000002	42.21	gold quality
fundus of stomach	UBERON:0001160	41.74	gold quality
ectocervix	UBERON:0012249	41.71	gold quality
ganglionic eminence	UBERON:0004023	40.80	gold quality
urinary bladder	UBERON:0001255	40.42	gold quality
ventricular zone	UBERON:0003053	40.06	gold quality
left uterine tube	UBERON:0001303	39.75	gold quality
pituitary gland	UBERON:0000007	39.06	gold quality
bone marrow	UBERON:0002371	38.98	gold quality
lower esophagus mucosa	UBERON:0035834	38.88	gold quality
endocervix	UBERON:0000458	38.75	gold quality
superior frontal gyrus	UBERON:0002661	38.31	silver quality
prostate gland	UBERON:0002367	37.92	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
tonsil	UBERON:0002372	37.10	gold quality
right uterine tube	UBERON:0001302	36.84	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.08

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA0468.1	DUX4	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:22209328

miRNA regulators (miRDB)

10 targeting DUX4, 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-4713-3P	100.00	65.92	505
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-4539	98.78	67.18	888
HSA-MIR-618	97.62	67.46	861
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-4661-3P	96.81	66.02	342
HSA-MIR-6805-5P	95.79	64.86	670
HSA-MIR-5587-3P	82.90	60.79	138

Literature-anchored findings (GeneRIF, showing 40)

• Results show that both DUX4-FL isoforms are expressed in facioscapulohumeral muscular dystrophy (FSHD) myotubes; DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes (PMID:23966205)
• The distinct gene signature and immunoprofile of CIC-DUX4 sarcomas suggest a distinct pathogenesis from Ewing sarcoma. (PMID:24723486)
• There is a special role of the 4q/10q D4Z4 chromatin and the DUX4 open reading frame in facioscapulohumeral muscular dystrophy. (PMID:24838473)
• These findings demonstrate that the expression of DUX4 accounts for the majority of the gene expression changes in facioscapulohumeral dystrophy skeletal muscle together with an immune cell infiltration. (PMID:24861551)
• Our results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to Facioscapulohumeral muscular dystrophy. (PMID:25326393)
• This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with ‘bursts’ of DUX4 expression in facioscapulohumeral muscular dystrophy muscle. (PMID:25564732)
• Loss of D4Z4 repression in facioscapulohumeral muscular dystrophy is observed as hypomethylation of the array accompanied by loss of repressive chromatin marks. [Review] (PMID:26113644)
• DUX4 mRNAs were induced during the differentiation of hMSCs into osteoblasts and that this process involved DUX4 and new longer protein forms. (PMID:26192274)
• Endogenous DUX4 expression in FSHD myotubes is sufficient to cause cell death and disrupts RNA splicing and cell migration pathways. (PMID:26246499)
• Recent studies indicate that a combination of genetic and epigenetic factors that act on the D4Z4 repeat array determine the probability of DUX4 expression in skeletal muscle and disease penetrance and progression (PMID:26356006)
• CIC-DUX4 gene fusion is associated with Round cell sarcoma. (PMID:26800124)
• Interactions between DUX4 and DUX4c with cytoplasmic proteins play a major role during muscle differentiation. (PMID:26816005)
• Report DNA-binding sequence preferences of DUX4. (PMID:26823969)
• selective loss of H3K9me3 from the DUX4 locus is associated with expression of DUX4 in late-phase squamous differentiation of human keratinocytes in vitro and in vivo. (PMID:26872601)
• We show that a DUX4 minigene, bearing only the homeodomains and C-terminus, is transcriptionally functional and cytotoxic, and that overexpression of a nuclear targeted C-terminus impairs the ability of WT DUX4 to interact with p300 and to regulate target genes. (PMID:26951377)
• data shows that DUX4 can become an oncogenic driver as a result of somatic chromosomal rearrangements and that acute lymphoblastic leukemia in adolescents and young adults may be a clinical entity distinct from ALL at other ages (PMID:27019113)
• The aim of this study was to describe seven cases of CIC-DUX4 fusion-positive sarcomas, including the first reported example arising primarily in bone. Our series confirms that CIC-DUX4 fusion-positive sarcomas are aggressive tumours with an adverse prognosis (PMID:27079694)
• These novel inhibitors of DUX4 transcriptional activity may thus act on pathways or cofactors needed by DUX4 for transcriptional activation in these cells. (PMID:27245141)
• recurrent IGH-DUX4 or ERG-DUX4 fusions, ETV6-RUNX1-like gene-expression profile in B-cell precursor acute lymphoblastic leukaemia, is reported. (PMID:27265895)
• It has been proposed that the induction of DNA damage is a novel function of the DUX4 protein affecting myogenic differentiation of facioscapulohumeral dystrophy myoblasts. (PMID:27519269)
• We propose that DUX4 controls the cellular migration of mesenchymal stem cells through the CXCR4 receptor. (PMID:27556182)
• Targeted next-generation sequencing of CIC-DUX4 soft tissue sarcomas demonstrates low mutational burden and recurrent chromosome 1p loss. (PMID:27664537)
• Transcriptomic analysis showed that DUX4 operates through both target gene activation and repression to orchestrate a transcriptome characteristic of a less-differentiated cell state. (PMID:27744317)
• DUX4 rearrangement and overexpression is associated with acute lymphoblastic leukemia. (PMID:27776115)
• The study describes a model system for inducible DUX4 expression that enables reproducible and synchronized experiments and validates the fidelity and facioscapulohumeral dystrophy (FSHD) relevance of multiple distinct models of DUX4 expression. (PMID:28171552)
• DUX4 and Dux may regulate some common pathways, and despite diverging from a common progenitor under different selective pressures for millions of years, the two genes maintain partial functional homology. (PMID:28173143)
• Estrogens antagonize DUX4 transcriptional activity and its differentiation inhibitory function and support the protective role of these hormones toward facioscapulohumeral muscular dystrophy myoblast in in vitro differentiation. (PMID:28263188)
• MYC, DUX4, and EIF4A3 might contribute to facioscapulohumeral dystrophy pathophysiology (PMID:28273136)
• Findings show CIC-DUX4 sarcomas occur mostly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior survival compared with Ewing sarcoma. Results support classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors. (PMID:28346326)
• Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro (PMID:28404587)
• DUX4 activate genes associated with a cleavage-stage embryos in muscle cells. (PMID:28459454)
• DUX4 role in activating cleavage-stage genes and MERVL/HERVL retrotransposons. (PMID:28459457)
• results underscore the complexity of the region immediately downstream of the D4Z4 and uncover a previously unknown function for the beta-satellite region in Dux4 cleavage and polyadenylation. (PMID:28540412)
• Case Report: t(10;19) CIC-DUX4 undifferentiated small round cell sarcoma of the abdominal wall. (PMID:28645808)
• We discuss the involvement of this rearrangement in Facioscapulohumeral dystrophy (FSHD), since all mutations in SMCHD1 are not associated with D4Z4 hypomethylation and do not always segregate with the disease (PMID:28744936)
• The DUX4 homeodomains mediate inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain. (PMID:28935672)
• Biallelic DUX4 expression lowers the threshold for disease presentation and is a modifier for disease severity in FSHD2. (PMID:29162933)
• The recent identification of aberrant activation of DUX4 transcription in Facioscapulohumeral muscular dystrophy. (PMID:29478599)
• These and other approaches identified the Nucleosome Remodeling Deacetylase (NuRD) and Chromatin Assembly Factor 1 (CAF-1) complexes as necessary for DUX4 repression in human skeletal muscle cells and induced pluripotent stem (iPS) cells.Furthermore, DUX4-induced expression of MBD3L proteins partly relieved this repression in FSHD muscle cells. (PMID:29533181)
• Dux4 regulates the expression of small RNAs in the facioscapulohumeral muscular dystrophy muscle cells. (PMID:29741619)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mxtx2	ENSDARG00000015906
danio_rerio	mxtx1	ENSDARG00000069382
mus_musculus	Duxbl1	ENSMUSG00000048502
rattus_norvegicus	Dux4	ENSRNOG00000025408

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), RHOXF2 (ENSG00000131721), 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)

Protein

Protein identifiers

Double homeobox protein 4 — Q9UBX2 (reviewed: Q9UBX2)

Alternative names: Double homeobox protein 10

All UniProt accessions (2): C3U3A0, Q9UBX2

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that is selectively and transiently expressed in cleavage-stage embryos. Binds to double-stranded DNA elements with the consensus sequence 5’-TAATCTAATCA-3’. Binds to chromatin containing histone H3 acetylated at ‘Lys-27’ (H3K27ac) and promotes deacetylation of H3K27ac. In parallel, binds to chromatin that lacks histone H3 acetylation at ‘Lys-27’ (H3K27ac) and recruits EP300 and CREBBP to promote acetylation of histone H3 at ‘Lys-27’ at new sites. Involved in transcriptional regulation of numerous genes, primarily as transcriptional activator, but also mediates repression of a set of target genes. Promotes expression of ZSCAN4 and KDM4E, two proteins with essential roles during early embryogenesis. Promotes nuclear translocation of CTNNB1/beta-catenin and its subsequent activation of target genes. Heterologous expression in cultured embryonic stem cells mediates transcription of HERVL retrotransposons and transcripts derived from ACRO1 and HSATII satellite repeats. May activate expression of PITX1. May regulate microRNA (miRNA) expression. Inappropriate expression can inhibit myogenesis and promote apoptosis. Probably inactive as a transcriptional activator, due to the absence of the C-terminal region that is important for transcriptional activation. Can inhibit transcriptional activation mediated by isoform 1. Heterologous expression of isoform 2 has no deleterious effect on cell survival.

Subunit / interactions. Binds DNA as a monomer. Interacts (via C-terminus) with EP300 and CREBBP.

Subcellular location. Nucleus. Cytoplasm Nucleus.

Tissue specificity. Isoform 1: Does not seem to be expressed in normal muscle, but is detected in muscle of individuals with FSHD, and also in testis (at protein level). Isoform 1: Does not seem to be expressed in normal muscle, but in muscle of individuals with FSHD, where it may be toxic to cells. Isoform 2: Detected in skeletal muscle, fibroblasts and testis from healthy individuals.

Disease relevance. Facioscapulohumeral muscular dystrophy 1 (FSHD1) [MIM:158900] A degenerative muscle disease characterized by slowly progressive weakness of the muscles of the face, upper-arm, and shoulder girdle. The onset of symptoms usually occurs in the first or second decade of life. Affected individuals usually present with impairment of upper extremity elevation. This tends to be followed by facial weakness, primarily involving the orbicularis oris and orbicularis oculi muscles. The gene represented in this entry is involved in disease pathogenesis. The disease is caused by deletion of an integral number of units of a 3.3-kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome 4q35. In unaffected subjects, the D4Z4 array consists of 11-150 repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats. DUX4 is located in D4Z4 macrosatellite which is epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation in FSHD1 results in inefficient epigenetic repression of DUX4 and a variegated pattern of DUX4 protein expression in a subset of skeletal muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death.

Domain organisation. The two homeobox domains are arranged in a head-to-head orientation when bound to double-stranded DNA, each domain binding to one of the two DNA strands. Together, the homeobox domains can be considered to bind DNA with the consensus sequence 5’-TAATCTAATCA-3’, but due to the head-to-head orientation of the DNA-bound domains, the first homeobox domain binds to the consensus sequence 5’-TAAT-3’, and the second homeobox domain binds DNA on the opposite strand, with the consensus sequence 5’-TGAT-3’. Both homeobox domains confer nuclear targeting. The C-terminal region is required for efficient activation of transcription from target promoters. It mediates interaction with EP300 and CREBBP.

Miscellaneous. DUX genes are present in 3.3-kilobase elements, a tandem repeat family scattered in the genome found on the short arms of all acrocentric chromosomes as well as on several other chromosomes.

Similarity. Belongs to the paired homeobox family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBX2-1	1, DUX4-fl	yes
Q9UBX2-2	2, DUX4-s

RefSeq proteins (3): NP_001280727, NP_001292997, NP_001350749 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR051306	Homeobox_regulator	Family

Pfam: PF00046

UniProt features (43 total): mutagenesis site 22, region of interest 6, helix 6, compositionally biased region 4, DNA-binding region 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
5Z2S	X-RAY DIFFRACTION	1.5
6A8R	X-RAY DIFFRACTION	1.6
5ZFZ	X-RAY DIFFRACTION	1.9
5ZFW	X-RAY DIFFRACTION	2.1
6E8C	X-RAY DIFFRACTION	2.12
5ZFY	X-RAY DIFFRACTION	2.3
5Z6Z	X-RAY DIFFRACTION	2.3
6U81	X-RAY DIFFRACTION	2.34
5Z2T	X-RAY DIFFRACTION	2.62
6DFY	X-RAY DIFFRACTION	2.62
6U82	X-RAY DIFFRACTION	3.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBX2-F1	63.51	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (22):

Position	Phenotype
20	decreased dna binding affinity.
23	mildly decreased dna binding affinity.
26	no effect on dna binding affinity.
69	mildly decreased dna binding affinity.
95	decreased dna binding affinity.
95	no effect on dna binding affinity.
96	decreased dna binding affinity.
97	decreased dna binding affinity.
98	decreased dna binding affinity.
143	decreased dna binding affinity.
144	decreased dna binding affinity.
145	altered sequence specificity, with increased affinity for the dna sequence 5’-taatctaatta-3’.
147	altered sequence specificity, with increased affinity for the dna sequence 5’-taatctaatta-3’.
148	decreased dna binding affinity.
159–371	decreased activity as transcriptional activator.
159–326	no effect on activity as transcriptional activator.
160–342	no effect on activity as transcriptional activator.
327–424	loss of interaction with ep300 and crebbp.
374–424	abolishes activity as transcriptional activator.
405–424	reduced activity as transcriptional activator.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9819196	Zygotic genome activation (ZGA)

MSigDB gene sets: 112 (showing top): GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, chr4q35, GOBP_REGULATION_OF_CELL_CYCLE_PROCESS, GOCC_NUCLEAR_ENVELOPE, GOCC_NUCLEOLUS, GOCC_NUCLEAR_MEMBRANE, GOBP_CELL_CYCLE_PROCESS, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, GOCC_ORGANELLE_ENVELOPE, GOBP_G0_TO_G1_TRANSITION, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOMF_DNA_BINDING_TRANSCRIPTION_ACTIVATOR_ACTIVITY, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY

GO Biological Process (5): regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), negative regulation of cell population proliferation (GO:0008285), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of G0 to G1 transition (GO:0070317)

GO Molecular Function (8): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), 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 activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), nuclear membrane (GO:0031965)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
cytoplasm	2
regulation of DNA-templated transcription	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
positive regulation of DNA-templated transcription	1
negative regulation of cell cycle process	1
G0 to G1 transition	1
regulation of G0 to G1 transition	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
transcription cis-regulatory region binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
endomembrane system	1
nucleus	1
nuclear envelope	1
organelle membrane	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

66 interactions, top by confidence:

A	B	Type	Score
C1QBP	DUX4	psi-mi:“MI:0915”(physical association)	0.540
DUX4	C1QBP	psi-mi:“MI:2364”(proximity)	0.540
DUX4	Des	psi-mi:“MI:0915”(physical association)	0.510
DES	DUX4	psi-mi:“MI:0915”(physical association)	0.470
DUX4	IPO13	psi-mi:“MI:0915”(physical association)	0.470
DUX4	IPO13	psi-mi:“MI:2364”(proximity)	0.470
DUX4	DES	psi-mi:“MI:2364”(proximity)	0.470
AP2B1	DUX4	psi-mi:“MI:0407”(direct interaction)	0.440
RBM3	DUX4	psi-mi:“MI:0915”(physical association)	0.400
SRSF9	DUX4	psi-mi:“MI:0915”(physical association)	0.400
LMCD1	DUX4	psi-mi:“MI:0915”(physical association)	0.400
DUX4	HMGA2	psi-mi:“MI:0915”(physical association)	0.400
FUS	DUX4	psi-mi:“MI:0403”(colocalization)	0.380
SFPQ	DUX4	psi-mi:“MI:0403”(colocalization)	0.380
DUX4	SFPQ	psi-mi:“MI:2364”(proximity)	0.380
DUX4	FUS	psi-mi:“MI:2364”(proximity)	0.380
DUX4	Trip6	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Cap1	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Pi4k2a	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Lmcd1	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Tpt1	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Cenpa	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Tubgcp6	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Rbm3	psi-mi:“MI:0915”(physical association)	0.370
DUX4	C1qbp	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Srsf9	psi-mi:“MI:0915”(physical association)	0.370
Mif4gd	DUX4	psi-mi:“MI:0915”(physical association)	0.370
DUX4	Eid1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (302): CREBBP (Affinity Capture-MS), EP300 (Affinity Capture-MS), CREBBP (Affinity Capture-Western), EP300 (Affinity Capture-Western), EP300 (Reconstituted Complex), DUX4 (Co-localization), Des (Two-hybrid), Trip6 (Two-hybrid), Cap1 (Two-hybrid), Pi4k2a (Two-hybrid), Lmcd1 (Two-hybrid), Tpt1 (Two-hybrid), Cenpa (Two-hybrid), Tubgcp6 (Two-hybrid), Rbm3 (Two-hybrid)

ESM2 similar proteins: A1YEV8, A1YF08, A1YG25, A1YG85, A2T756, A6NJT0, O14813, O15499, O15522, O35602, O70218, O73592, O75360, P0CJ85, P0CJ86, P0CJ87, P0CJ88, P0CJ89, P0CJ90, P19601, P35713, P52945, P56916, P82976, Q13461, Q15270, Q3LU41, Q62066, Q62782, Q63250, Q6RFH8, Q7RTU5, Q7YRX0, Q8TAK6, Q8WY41, Q96IS3, Q99811, Q9C009, Q9DE09, Q9ET58

Diamond homologs: A0A1W2PPF3, A1YEY5, A1YFI3, A1YG57, A2T733, A2T7P4, A6NLW8, A6NNA5, F1NEA7, G5EBU4, G5EDS1, O18381, O35137, O35160, O42250, O43186, O43316, O43812, O54751, O70137, O73917, O75360, O75364, O95076, P09088, P0CJ85, P0CJ86, P0CJ87, P0CJ88, P0CJ89, P0CJ90, P21711, P22810, P26367, P26630, P29454, P32242, P32243, P34764, P34765

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DUX4	“up-regulates quantity by expression”	HEY1	“transcriptional regulation”
DUX4	“up-regulates quantity by expression”	PITX1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:190173972:T:C	F67L	0.999
4:190173973:T:C	F67S	0.999
4:190173974:T:A	F67L	0.999
4:190173974:T:G	F67L	0.999
4:190174197:T:C	F142L	0.999
4:190174198:T:C	F142S	0.999
4:190174199:T:A	F142L	0.999
4:190174199:T:G	F142L	0.999
4:190174110:T:C	F113L	0.997
4:190174112:T:A	F113L	0.997
4:190174112:T:G	F113L	0.997
4:190174198:T:G	F142C	0.997
4:190173985:G:T	R71M	0.996
4:190173885:T:C	F38L	0.995
4:190173887:T:A	F38L	0.995
4:190173887:T:G	F38L	0.995
4:190173973:T:G	F67C	0.995
4:190173979:A:T	N69I	0.995
4:190174125:T:C	F118L	0.995
4:190174127:T:A	F118L	0.995
4:190174127:T:G	F118L	0.995
4:190174186:T:C	I138T	0.995
4:190174197:T:G	F142V	0.995
4:190174202:G:C	Q143H	0.995
4:190174202:G:T	Q143H	0.995
4:190174203:A:G	N144D	0.995
4:190174204:A:G	N144S	0.995
4:190174204:A:T	N144I	0.995
4:190174205:T:A	N144K	0.995
4:190174205:T:G	N144K	0.995

dbSNP variants (sampled 300 via entrez): RS11507935 (4:190177923 T>A,C,G), RS1156309966 (4:190173440 A>C), RS1156357366 (4:190182989 G>A,C,T), RS1156394693 (4:190183559 A>C), RS1156497387 (4:190174664 G>T), RS1156636527 (4:190180130 T>C,G), RS1156701120 (4:190181429 C>G,T), RS1156897685 (4:190182132 G>T), RS1156991797 (4:190175793 G>A,C,T), RS1157151595 (4:190176069 T>A,C), RS1157201558 (4:190176372 C>A,G,T), RS1157206781 (4:190184208 A>T), RS1157505680 (4:190185532 C>T), RS1157602105 (4:190179452 A>C,G,T), RS1158097499 (4:190183217 A>T)

Disease associations

OMIM: gene MIM:606009 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
facioscapulohumeral muscular dystrophy 1	Limited	Autosomal dominant

Mondo (1): facioscapulohumeral muscular dystrophy 1 (MONDO:0008030)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536391	Facioscapulohumeral muscular dystrophy 1a (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
butyraldehyde	increases expression	1
tebuconazole	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Cadmium	increases abundance, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1

Cellosaurus cell lines

148 cell lines: 69 transformed cell line, 61 cancer cell line, 8 telomerase immortalized cell line, 5 induced pluripotent stem cell, 3 embryonic stem cell, 2 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0092	NALM-6	Cancer cell line	Male
CVCL_0U51	NALM-6/SP-B	Cancer cell line	Male
CVCL_4V57	NALM6/Clo	Cancer cell line	Male
CVCL_4W71	POLK F171A MSH-	Cancer cell line	Male
CVCL_4W72	POLK KO hetero MSH-	Cancer cell line	Male
CVCL_4W73	POLK KO homo MSH-	Cancer cell line	Male
CVCL_6B27	FSHDCl17	Telomerase immortalized cell line	Sex unspecified
CVCL_8173	BLIN-1	Cancer cell line	Male
CVCL_8260	LR10.6	Cancer cell line	Male
CVCL_8270	PBEI	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07038200	PHASE3	RECRUITING	A Study to Evaluate Del-brax (Also Referred to as AOC 1020) in Participants With FSHD
NCT04004000	PHASE2	TERMINATED	Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1 With Extension
NCT06222827	PHASE2	ACTIVE_NOT_RECRUITING	Study to Evaluate the Efficacy and Safety of Satralizumab in FSHD1
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT07435129	PHASE2	NOT_YET_RECRUITING	Phase 2 Study Evaluating Apitegromab for the Treatment of FSHD
NCT05747924	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT02541292	Not specified	UNKNOWN	Muscle Inflammation and Fat Infiltration in Patients Affected by FSHD
NCT02948244	Not specified	COMPLETED	Effect of Creatine Monohydrate on Functional Muscle Strength in Children With FSHD
NCT04369209	Not specified	RECRUITING	A Registered Cohort Study on FSHD1
NCT04635891	Not specified	RECRUITING	Motor Outcomes to Validate Evaluations in FSHD (MOVE FSHD)
NCT04907162	Not specified	COMPLETED	Musculoskeletal Nociceptive Pain in Participants With Neuromuscular Disorders
NCT05272969	Not specified	UNKNOWN	Pompe & Pain - Study to Assess Nociceptive Pain in Adult Patients With Pompe Disease
NCT05295277	Not specified	UNKNOWN	Validation of Optical Genome Mapping for the Identification of Constitutional Genomic Variants in a Postnatal Cohort
NCT05409079	Not specified	UNKNOWN	Schulze Muscular Dystrophy Ability Clinical Study
NCT05902884	Not specified	UNKNOWN	New Biomarkers in Facioscapulohumeral Muscular Dystrophy, Multispectral Optoacoustic Tomography.
NCT06078852	Not specified	RECRUITING	Longitudinal Study on Diaframmatic Ultrasound in FSHD Patients
NCT06712043	Not specified	NOT_YET_RECRUITING	Testing a Tailored Home Exercise Program to Reduce Pain and Fatigue in Patients with FSHD.
NCT07331025	Not specified	COMPLETED	Ultrasound Detection of Early Facial Muscle Changes in FSHD: Thickness and Echo Intensity Findings
NCT07409142	Not specified	RECRUITING	BetterLife FSHD: A Patient-driven Health and Research Platform