Genes are fundamental instructions within our bodies, acting as blueprints for building and maintaining biological systems. They contain the information necessary for cells to produce proteins, which carry out a vast array of functions to keep us healthy. Among the many genes, the Survival Motor Neuron 2 (SMN2) gene holds particular importance. Its presence and function are significant in understanding certain genetic conditions.
The SMN2 Gene’s Distinct Function
Humans possess two highly similar genes, SMN1 and SMN2, both responsible for generating the Survival Motor Neuron (SMN) protein. This protein is found throughout the body, with its highest concentrations in the spinal cord, where it helps maintain motor neurons—specialized nerve cells that transmit signals from the brain and spinal cord to skeletal muscles, enabling movement. A subtle genetic difference sets them apart.
The key distinction lies in a single nucleotide change within the SMN2 gene, specifically a cytosine (C) to thymine (T) alteration in exon 7. This change impacts RNA splicing, a process where non-coding regions (introns) are removed from an initial RNA transcript, and coding regions (exons) are joined to form mature messenger RNA (mRNA). For SMN2, this C-to-T change disrupts a normal splicing enhancer, causing most of its mRNA to exclude exon 7.
The exclusion of exon 7 from most SMN2 transcripts results in a truncated, unstable, and largely non-functional SMN protein. In contrast, the SMN1 gene predominantly produces the full-length, functional SMN protein, making it the primary source in healthy individuals. Despite its inefficiency, the SMN2 gene still generates a small amount, approximately 10-15%, of the full-length, functional SMN protein. This limited production from SMN2 is enough for survival, leading to its designation as a “backup gene.”
How SMN2 Copy Number Impacts Disease
Spinal Muscular Atrophy (SMA) is a genetic disorder linked to a deficiency in the SMN protein, typically caused by mutations or the complete loss of the SMN1 gene. In individuals with SMA, where the SMN1 gene is non-functional, the SMN2 gene becomes the main source of SMN protein. However, as SMN2 only produces a small fraction of functional protein, the overall SMN protein level in these individuals is significantly reduced.
The number of SMN2 gene copies an individual possesses significantly influences SMA severity. People can have varying numbers of SMN2 copies, ranging from one to eight. A higher number of SMN2 copies generally leads to more full-length, functional SMN protein, as each additional copy contributes to the small percentage SMN2 produces.
The direct correlation between SMN2 copy number and disease severity is clear. Individuals with more SMN2 copies tend to have milder forms of SMA, as the increased compensatory protein provides more support for motor neuron function. For example, those with one or two SMN2 copies often experience severe muscle weakness early in life, while individuals with four or more copies might develop milder weakness that appears later. While the SMN2 copy number is a strong predictor, other genetic and unknown factors can also influence SMA presentation and progression.
SMN2 as a Therapeutic Target
The SMN2 gene’s ability to produce some functional SMN protein despite its inherent splicing inefficiency has made it a focus for developing treatments for Spinal Muscular Atrophy. These therapies aim to overcome the SMN2 gene’s natural tendency to exclude exon 7, increasing the production of full-length, functional SMN protein.
A primary therapeutic strategy involves splicing modulators like nusinersen and risdiplam. These medications target the SMN2 gene to encourage more complete SMN protein production. Nusinersen, an antisense oligonucleotide (ASO), binds to a specific site on the SMN2 pre-mRNA in intron 7, which helps prevent the splicing machinery from skipping exon 7. This action leads to more full-length, functional SMN protein.
Similarly, risdiplam is a small molecule splicing modifier that also promotes the inclusion of exon 7 in the SMN2 mRNA. It binds to two specific sites within exon 7 of the SMN2 pre-mRNA, altering its structure and promoting proper splicing. These therapies have significantly improved outcomes for individuals with SMA, enhancing motor function and survival by addressing the underlying protein deficiency.