Exon – Structure, Types, Functions

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Exons are coding sections of an RNA transcript, or the DNA encoding it, that are translated into protein. Exons can be separated by intervening sections of DNA that do not code for proteins, known as introns. Following transcription, new, immature strands of messenger RNA, called pre-mRNA, may contain both introns and exons. These pre-mRNA molecules go through a modification process in the nucleus called splicing during which the noncoding introns are cut out and only the coding exons remain. Splicing produces a mature messenger RNA molecule that is then translated into a protein.

Exon skipping is a therapeutic approach that is feasible for various genetic diseases and has been studied and developed for over two decades. This approach uses antisense oligonucleotides (AON) to modify the splicing of pre-mRNA to correct the mutation responsible for a disease, or to suppress a particular gene expression, as in allergic diseases. Antisense-mediated exon skipping is most extensively studied in Duchenne muscular dystrophy (DMD) and has developed from in vitro proof-of-concept studies to clinical trials targeting various single exons such as exon 45 (casimersen), exon 53 (NS-065/NCNP-01, golodirsen), and exon 51 (eteplirsen). Eteplirsen (brand name Exondys 51), is the first approved antisense therapy for DMD in the USA, and provides a treatment option for ~14% of all DMD patients, who are amenable to exon 51 skipping. Eteplirsen is granted accelerated approval and marketing authorization by the US Food and Drug Administration (FDA), on the condition that additional postapproval trials show clinical benefit. Permanent exon skipping achieved at the DNA level using clustered regularly interspaced short palindromic repeats (CRISPR) technology holds promise in current preclinical trials for DMD. In hopes of achieving clinical success parallel to DMD, exon skipping and splice modulation are also being studied in other muscular dystrophies, such as Fukuyama congenital muscular dystrophy (FCMD), dysferlinopathy including limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal anterior compartment myopathy (DMAT), myotonic dystrophy, and merosin-deficient congenital muscular dystrophy type 1A (MDC1A). This chapter also summarizes the development of antisense-mediated exon skipping therapy in diseases such as Usher syndrome, dystrophic epidermolysis bullosa, fibrodysplasia ossificans progressiva (FOP), and allergic diseases.

An exon is a region of the genome that ends up within an mRNA molecule. Some exons are coding, in that they contain information for making a protein, whereas others are non-coding. Genes in the genome consist of exons and introns.

What is Exon?

Exons are that part of the RNA that code for proteins. Now, RNA, when it first gets transcribed, is a very, very long piece of RNA molecule. And really, the important parts of that RNA are the exons. There are large, large chunks of RNA that get excised out. Now, it's important to remember that because I use the term excised doesn't mean that exons go away. The exons are what stay in the mature mRNA and eventually code for amino acids. Many times, including medical students like my wife, will forget whether it's the exons that code for the amino acids or the introns that code for the amino acids. Let me set the record straight that it's the exons that code for the amino acids, because sometimes people try to remember that exons get excised, but that's not true. It's that introns interfere. So you always have to remember that introns interfere, and the introns get excised out of the RNA to leave a string of exons together that will eventually code for the amino acids.

• An exon is any portion of a gene that will be included in the mature RNA generated by that gene once the introns have been eliminated by RNA splicing.

• Exon refers to both the DNA sequence within a gene as well as the associated RNA transcript sequence.

• Introns are deleted and exons are covalently linked during RNA splicing as part of the process of producing mature RNA. In the same way that the complete set of genes for a species comprises the genome, the complete set of exons comprises the exome.

• American biochemist Walter Gilbert coined the term exon in 1978: “The notion of the cistron… must be replaced by that of a transcription unit containing regions that will be lost from the mature messenger – which I suggest we call introns (for intragenic regions) – alternating with regions that will be expressed – exons.”

• This specification was initially intended for pre-translationally spliced protein-coding transcripts.

• Later, the word grew to encompass sequences deleted from rRNA, tRNA, and other noncoding RNAs, as well as RNA molecules originating from various sections of the genome that are ligated through trans-splicing.

Structure of Exon

• Exons consist of DNA sequences that are ultimately translated into amino acids and proteins. In the DNA of eukaryotic organisms, exons may be continuous or discontinuous.

• When the gene is translated into pre-mRNA, both introns and exons are included in the transcript.

• The introns are then removed from the pre-mRNA by splicing them out of the molecule. The length of mature mRNAs ranges from a few hundred to several thousand nucleotides.

• Exons and short untranslated regions (UTRs) are components of mature mRNA. The last reading frame comprises of nucleotides organised in triplets and is composed of exons.

• The reading frame begins with a start codon (often AUG) and concludes with a stop codon.

• As each amino acid is encoded by a three-nucleotide sequence, the nucleotides are organised into triplets.

• The illustration represents a gene with three exons. Despite an initial length of almost 13,000 bp, the final gene is 1317 bp in length.

Function of Exon

• Exons are DNA sequences that code for proteins. Different exons code for distinct protein domains. Domains may be encoded by a single exon or numerous exons that have been spliced together. Through exon shuffling, the presence of exons and introns allows for higher molecular evolution.

• When exons on sister chromosomes are switched during recombination, exon shuffling occurs. This permits the creation of new genes.

• Through alternative splicing, exons also allow various proteins to be translated from the same gene. When the introns are eliminated, this technique permits the exons to be organised in numerous configurations. Different configurations may involve the removal of an entire exon, the inclusion of a portion of an exon, or the addition of a portion of an intron.

• Alternative splicing can occur at the same region to generate many forms of a gene with a similar function, such as the human slo gene, or in distinct cell or tissue types, such as the mouse alpha-amylase gene. Alternative splicing and alternative splicing errors can lead to a variety of illnesses, including alcoholism and cancer.