Double homeobox, 4 also known as DUX4 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

which in humans is encoded by the ''DUX4''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. Its misexpression is the cause of

facioscapulohumeral muscular dystrophy 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, ...

(FSHD).

Gene

A schematic of D4Z4 locus on chromosome 4

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. The

open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...

(ORF) is entirely contained within exon 1 and contains two homeoboxes. Exons 2 and 3 encode for the

three prime untranslated region In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...

(3′-UTR). In certain haplotypes, exon 3 contains a polyadenylation signal. There was no evidence for transcription from standard cDNA libraries however RTPCR and in-vitro expression experiments indicate that the ORF is transcribed. The repeat-array and ORF are conserved in other mammals.

Structure

DUX4 protein is 424

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

s long. 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). The two homeodomains and TAD have well-defined tertiary structure. The region between the second homeodomain and TAD is predicted to be disordered. ''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.

Function

DUX4 protein a transcriptional activator of many genes, one example being paired-like homeodomain transcription factor 1 (

PITX1 Paired-like homeodomain 1 is a protein that in humans is encoded by the ''PITX1'' gene. Function This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are invo ...

). It likely stimulates zygotic genome activation. The two homeodomains allow DUX4 protein to bind to DNA. The C-terminal domain is involved in target gene activation. DUX is normally expressed in the

testes A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoste ...

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...

, and cleavage-stage embryos.

Clinical significance

Inappropriate expression of DUX4 in

muscle cells A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a mus ...

is the cause of

(FSHD). Overexpression of DUX4 due to

translocations In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...

can cause B-cell leukemia. A translocation that merges DUX4 with CIC can cause an aggressive type of

sarcoma A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal ( connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sar ...

References

Genes Human proteins {{gene-4-stub

Gene

Structure

Function

Clinical significance

See also

References