Anatomy of A Gene

Developing gene therapies to treat rare and ultra-rare neuromuscular disorders requires a sound understanding of the anatomy of genes and the various methods by which genetic mutations can be targeted. From our antisense oligonucleotide therapeutic for SCA3 in collaboration with Leiden University Medical Center to our gene replacement strategy for ADSSL1 gene-related myopathy with Boston Children’s Hospital, Cure Rare Disease is employing a variety of techniques to treat genetic diseases.

What is a gene?

A gene is a section of DNA that is described as the basic unit of inheritance. Genes have information coded in the form of nucleotides, which are the building blocks of DNA and RNA. DNA is double-stranded, meaning that the nucleotide bases of two separate chains connect to one another to form the double helix shape. Each individual strand has directionality, with a 5’ end and a 3’ end that direct DNA replication and gene transcription.

Although people often associate DNA with making proteins, only around 1% of the human genome consists of portions that code for proteins. It is believed that some of the noncoding portions of DNA play a role in regulating gene expression, but the function of many noncoding sections is still not fully understood. In the past, non-coding DNA was referred to as “junk DNA,” but this term is used much less frequently as scientists improve our understanding of these regions. 

Promoters, enhancers, and silencers

The promoter region of a gene is found just upstream of the sequence that is transcribed. Its role is to initiate transcription by binding proteins including RNA polymerase and various transcription factor proteins.

Enhancer regions work to increase the rate of transcription. Though they are different from promoters, both have important regulatory roles in gene function. Enhancers are not always close to the gene that they target either: they can be found anywhere from just upstream of the promoter region to many thousands of base pairs away. 

Alternatively, silencers are regions of DNA that can bind with repressor proteins to prevent transcription from taking place. If the promoter region is like a light switch that can turn on when the relevant proteins bind, enhancers increase the intensity of the light while silencers dim it. 

Introns and exons

Introns and exons both consist of sequences of nucleotides in genes. Exons are coding sequences, while introns are non-coding sequences. Although introns do not code for proteins, they are very important for regulation of gene expression. They allow for a process called alternative splicing, in which different combinations of exons can be present in the final messenger RNA molecule, meaning multiple proteins can be made from a single gene. Splicing is the process by which introns are removed from the immature messenger RNA (or pre-mRNA) and the remaining exons are spliced together. In alternative splicing, as shown in the figure below, certain exons might be included or excluded from the final mature mRNA molecule.

Terminator sequence

The terminator sequence is located at the end of the gene. This region signals to proteins involved in transcription to detach from the DNA, producing a complete molecule of pre-mRNA . After the pre-mRNA is processed to make mature RNA, it can leave the nucleus of the cell so that the next step, translation into a protein, can occur. 

The dystrophin gene

The dystrophin gene, with 79 exons, is one of  the largest known genes in the human genome. Many different mutations in this gene, including exon deletions and duplications, can result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Cure Rare Disease is currently developing several therapeutics to treat numerous mutations that cause DMD and BMD.

Treating rare genetic disorders begins with characterization of the root genetic mutation. Understanding the different parts of a gene and how they interact with one another is a key to advancing life-saving therapeutics for these diseases.