DUX4
Double homeobox, 4 also known as DUX4 is a protein which in humans is encoded by the DUX4 gene.[3] Its misexpression is the cause of facioscapulohumeral muscular dystrophy (FSHD).
Gene
| CEN | centromeric end | TEL | telomeric end |
| NDE box | non-deleted element | PAS | polyadenylation site |
| triangle | D4Z4 repeat | trapezoid | partial D4Z4 repeat |
| white box | pLAM | gray boxes | DUX4 exons 1, 2, 3 |
| arrows | |||
| corner | promoters | straight | RNA transcripts |
| black | sense | red | antisense |
| blue | DBE-T | dashes | dicing sites |
This gene is located within a D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4q35. The D4Z4 repeat array contains 11-150 D4Z4 repeats in the general population; a highly homologous D4Z4 repeat array has been identified on chromosome 10. The gene consists of three exons. Exons 1 and 2 are present in each D4Z4 repeat. Only one copy of exon 3 is present, telomeric to the D4Z4 repeat array.[4] The open reading frame (ORF) is entirely contained within exon 1 and contains two homeoboxes.[4] Exons 2 and 3 encode for the three prime untranslated region (3′-UTR).[4] In certain haplotypes, exon 3 contains a polyadenylation signal.[4] There was no evidence for transcription from the standard cDNA libraries however RT-PCR and in-vitro expression experiments indicate that the ORF is transcribed.[5]
The repeat-array and ORF are conserved in other mammals.
Structure
DUX4 protein is 424 amino acids long.[4] Two homeodomains are situated at the N-terminus. A transcription-activating domain (TAD) and p300-binding domain are situated at the C-terminus. The TAD encompasses a potential nine amino acid TAD (9aaTAD).[4]
The two homeodomains and TAD have well-defined tertiary structures.[4] The region between the second homeodomain and TAD is predicted to be disordered.[4]
DUX4 transcripts can be spliced to produce either DUX4-S (short) or DUX4-FL (full length) mRNAs. DUX4-FL mRNA encodes for the entire DUX4 protein. DUX4-S mRNA encodes for a partial DUX4 protein, which lacks the transcription-activating domain.[4]
Function
The DUX4 protein is a transcriptional activator of many genes, one example being paired-like homeodomain transcription factor 1 (PITX1).[5] It likely stimulates zygotic genome activation.[citation needed]
The two homeodomains allow DUX4 protein to bind to DNA.[4] The C-terminal domain is involved in target gene activation.[4]
DUX is normally expressed in the testes, thymus, and cleavage-stage embryos.[6]
Clinical significance
Inappropriate expression of DUX4 in muscle cells is the cause of facioscapulohumeral muscular dystrophy (FSHD).[7][8]
Overexpression of DUX4 due to translocations can cause B-cell leukemia.[6] A translocation that merges DUX4 with CIC can cause an aggressive type of sarcoma.[9]
In common biomedical model organisms, rhesus macaques and crab-eating macaques, the D4Z4 array syntenic to the human Chr4 array is different from its human counterpart.[10] In macaques, all copies are towards the centromeric end, with the most centromeric copy potentially being the one that expresses. In macaques, in between DUX4 copies, there is a NUMT sequence. The NUMT sequence changed the methylation landscape, making this hypermethylated region fragmental.
Development of drugs
The "antisense oligonucleotide conjugate" delpacibart braxlosiran (aka Del-brax) aimed at suppressing expression of DUX4 was under development by Avidity Biosciences, which was continued by Novartis after their acquisition of Avidity in 2025.[11]
See also
References
- ^ a b c ENSG00000283949 GRCh38: Ensembl release 89: ENSG00000260596, ENSG00000283949 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Gabriëls J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, et al. (August 1999). "Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element". Gene. 236 (1): 25–32. doi:10.1016/S0378-1119(99)00267-X. PMID 10433963.
- ^ a b c d e f g h i j k Schätzl, T; Kaiser, L; Deigner, HP (12 March 2021). "Facioscapulohumeral muscular dystrophy: genetics, gene activation, and downstream signalling with regard to recent therapeutic approaches: an update". Orphanet Journal of Rare Diseases. 16 (1): 129. doi:10.1186/s13023-021-01760-1. PMC 7953708. PMID 33712050.
- ^ a b "Entrez Gene: DUX4 Double homeobox, 4".
- ^ a b Lee JK, Bosnakovski D, Toso EA, Dinh T, Banerjee S, Bohl TE, et al. (December 2018). "Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA". Cell Reports. 25 (11): 2955–2962.e3. doi:10.1016/j.celrep.2018.11.060. PMC 6463520. PMID 30540931.
- ^ Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, et al. (September 2010). "A unifying genetic model for facioscapulohumeral muscular dystrophy". Science. 329 (5999): 1650–3. Bibcode:2010Sci...329.1650L. doi:10.1126/science.1189044. PMC 4677822. PMID 20724583.
- ^ Jones TI, Chen JC, Rahimov F, Homma S, Arashiro P, Beermann ML, et al. (October 2012). "Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis". Human Molecular Genetics. 21 (20): 4419–30. doi:10.1093/hmg/dds284. PMC 3459465. PMID 22798623.
- ^ Wong D, Yip S (April 2020). "Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor". The Journal of Pathology. 250 (5): 532–540. doi:10.1002/path.5400. PMID 32073140.
- ^ Fu, Lianting; Chen, Jieyi; Lian, Da; Du, Siyuan; Wu, Dongya; Yang, Chentao; Wang, Ziyi; Ma, Hongyi; Li, Zhengtong; Lake, Nicole J.; Yang, Xiangyu; Shi, Yongyong; Zhang, Guojie; Ma, Kaiyue; Mao, Yafei (2026-05-15). "A long-read human pangenome initiative for comprehensive interpretation of nuclear-embedded mitochondrial DNA". Nature Communications. 17 (1): 4371. doi:10.1038/s41467-026-71348-5. ISSN 2041-1723.
- ^ Wu, Gwendolyn (11 June 2026). "Novartis RNA drug acquired in $12B Avidity deal notches a trial win". Biopharma Dive. Retrieved 12 June 2026.
Further reading
- Sutliff NA, Chao E, Bennett SR, Nip Y, Lakhdari O, Canton DA, Zhu Y, Tapscott SJ (12 December 2025). "Identification of KHDC1L, a DUX4-regulated protein, as a novel plasma biomarker in facioscapulohumeral muscular dystrophy". Human Molecular Genetics (Article). 35 (2) ddaf183. doi:10.1093/hmg/ddaf183.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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