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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. 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 fac ...

(FSHD).

Gene

A schematic of D4Z4 locus on chromosome 4

This gene is located within a D4Z4

macrosatellite In genetics, macrosatellites are the largest of the tandem repeats within DNA. Each macrosatellite repeat typically is several thousand base pairs in length, and the entire repeat array often spans hundreds of kilobases. Reduced number of repeats ...

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 An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence i ...

. 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, reading frames 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 reading frames ...

(ORF) is entirely contained within exon 1 and contains two

homeobox A homeobox is a Nucleic acid sequence, 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 ...

es. 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 Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...

signal. There was no evidence for transcription from the standard cDNA libraries however

RT-PCR Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase chain ...

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 over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s long. Two homeodomains are situated at the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

. A transcription-activating domain (TAD) and ''p300''-binding domain are situated at the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

. The TAD encompasses a potential nine amino acid TAD (9aaTAD). The two homeodomains and TAD have well-defined tertiary structures. 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

The DUX4 protein is a transcriptional activator of many genes, one example being paired-like homeodomain transcription factor 1 ( PITX1). 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 ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...

thymus The thymus (: thymuses or thymi) is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus ...

, and

cleavage Cleavage may refer to: Science * Cleavage (crystal), the way in which a crystal or mineral tends to split * Cleavage (embryo), the division of cells in an early embryo * Cleavage (geology), foliation of rock perpendicular to stress, a result of ...

-stage

embryos An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

Clinical significance

Inappropriate expression of DUX4 in

muscle cells A muscle cell, also known as a myocyte, is a mature contractile cell in the muscle of an animal. In humans and other vertebrates there are three types: skeletal, smooth, and cardiac (cardiomyocytes). A skeletal muscle cell is long and threadli ...

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 three main types: "reciprocal", "nonreciprocal" and "Robertsonian" transloc ...

can cause B-cell leukemia. A translocation that merges DUX4 with

CIC CIC may refer to: Organizations Canada * Cadet Instructors Cadre, a part of the Canadian Armed Forces * Canadian Infantry Corps, renamed in 1947 to Royal Canadian Infantry Corps * Canadian International Council * Canadian Islamic Congress * Chemi ...

can cause an aggressive type of

sarcoma A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues. Sarcom ...

References

Genes Human proteins {{gene-4-stub

Gene

Structure

Function

Clinical significance

See also

References