Our bodies operate based on instructions in our DNA. DNA is organized into segments called genes, providing specific instructions for building and maintaining cells. Small changes, or “variants,” can occur within these instructions. These variations are DNA sequence differences that influence body function.
Understanding Introns
A gene’s structure is not a continuous block of instructions; instead, it is segmented. Within each gene, there are coding regions known as exons, which contain the direct instructions for building proteins. Interspersed between these exons are non-coding regions called introns. While introns do not directly code for protein sequences, they are transcribed into an RNA molecule along with the exons.
Following transcription, a process called splicing occurs. During splicing, the non-coding intron sequences are cut out from the RNA molecule. The remaining exon sequences are then joined together to form a mature messenger RNA (mRNA). This mRNA molecule then carries the complete protein-building instructions to the cellular machinery responsible for protein synthesis. Although introns are removed, their presence and surrounding sequences are important for the processing of the genetic message.
What is an Intron Variant?
An intron variant is a change in the DNA sequence within a non-coding intron region. These alterations can be as small as a single nucleotide change, known as a point mutation, where one DNA building block is swapped for another. Larger changes, such as the insertion or deletion of multiple nucleotides, can also occur within an intron. Despite being located in a region that does not directly code for protein, the position of an intron variant can impact its effect. Variants situated near the boundaries where introns meet exons, or within specific regulatory sequences inside the intron, are most impactful.
How Intron Variants Affect Gene Expression
Intron variants can disrupt the process of gene expression, primarily by interfering with RNA splicing. One common mechanism involves altering splice sites, which are DNA sequences at the boundaries of exons and introns that signal where to cut. A variant at a splice donor site, at the beginning or end of an intron, can prevent the removal of the intron entirely or lead to incorrect cutting. This disruption results in an mRNA molecule that either retains part or all of an intron or lacks a portion of an exon.
Variants can also create new, unintended sequences within an intron or even an exon that mimic natural splice sites. The splicing machinery may then recognize these cryptic sites, leading to the inclusion of non-coding intronic sequences or the exclusion of coding exonic sequences in the final mRNA. For instance, if a cryptic splice site is created within an exon, it can cause the premature termination of protein synthesis or the production of an altered protein. This phenomenon, where an entire exon is either skipped or inappropriately included, is known as exon skipping or exon inclusion, respectively, and alters the protein’s blueprint.
Beyond direct splice site disruption, intron variants can affect regulatory elements located within the intron. These intronic regulatory sequences, such as enhancers or silencers, do not directly participate in splicing but instead influence the efficiency or accuracy of transcription or splicing. A variant in one of these elements might reduce the amount of mRNA produced or alter how the gene is spliced, even if the primary splice sites remain intact. The combined effect of these mechanisms is the production of an incorrect or non-functional protein, or no protein at all, which can have downstream consequences for cellular processes.
Intron Variants and Human Health
The altered gene expression resulting from intron variants can have significant implications for human health. When mis-splicing occurs, the resulting messenger RNA (mRNA) may carry instructions for a protein that is truncated, non-functional, or has an altered structure. For example, if an intron is not fully removed, the retained sequence can introduce a premature stop signal, leading to a shortened protein. Conversely, if an exon is skipped, a portion of the protein’s functional domain might be missing, rendering it ineffective.
These protein abnormalities can disrupt cellular processes and contribute to the development of genetic disorders. Intronic variants have been identified as causative factors in a range of conditions, including cystic fibrosis, where errors in the CFTR protein affect chloride ion transport, and spinal muscular atrophy, linked to defects in SMN1 protein production. Other hereditary conditions, such as some forms of inherited cancers or neurological disorders, have also been associated with splicing defects caused by intronic changes. The clinical impact of an intron variant can vary widely, from a mild phenotype to severe disease, depending on the specific gene affected and the extent to which protein function is compromised.