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).
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 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 structure. [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]
DUX4 protein 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]
A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of the full-grown organism.
Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, those that position the scapula, and those overlying the humerus bone of the upper arm. These areas can be spared, and muscles of other areas usually are affected, especially those of the chest, spine, abdomen, and shin. Almost any skeletal muscle can be affected in severe disease. Abnormally positioned, or winged, scapulas are common, as is the inability to lift the foot, known as foot drop. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15 – 30 years. FSHD can also cause hearing loss and blood vessel abnormalities in the back of the eye.
Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 193 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells.
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Structural Maintenance of Chromosomes flexible Hinge Domain Containing 1 (SMCHD1) is a protein that in humans is encoded by the SMCHD1 gene. Mutations in SMCHD1 are causative for development of facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS).
Macrosatellites are the largest of the tandem DNA repeats. Each macrosatellite repeat typically is several kilobases in length, and the entire repeat array often spans hundreds of kilobases. Reduced number of repeats on chromosome 4 causes euchromatization of local DNA and is the predominant cause of facioscapulohumeral muscular dystrophy (FSHD). Other macrosatellites are RS447, NBL2 and DXZ4, although RS447 is also commonly referred to as a "megasatellite."
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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