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).
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.
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]
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]
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]
This article incorporates text from the United States National Library of Medicine, which is in the public domain.