The Survival Motor Neuron (SMN) protein is essential for the health and maintenance of specialized nerve cells called motor neurons, which control muscle movement. These motor neurons, located in the spinal cord and brainstem, gradually die without sufficient SMN protein. The human genome contains two nearly identical genes responsible for producing this protein: SMN1 and SMN2, which are both located on chromosome 5. Both genes share the primary function of generating the SMN protein, but a subtle difference in their genetic code drastically alters their efficiency. This molecular distinction explains why the presence of the SMN2 gene is generally not enough to compensate for the loss of its counterpart, leading to the condition known as Spinal Muscular Atrophy (SMA).
The Critical Molecular Difference Between SMN1 and SMN2
The SMN1 and SMN2 genes are highly homologous, differing by only a handful of nucleotides. A single nucleotide change separates the two genes functionally: a C (cytosine) to T (thymine) substitution found within exon 7 of the SMN2 gene.
In the SMN1 gene, the presence of the cytosine nucleotide at this position creates a functional site known as an exonic splicing enhancer (ESE). This enhancer acts like a molecular signal, ensuring that exon 7 is correctly recognized and included during the process of transcription, resulting in a full-length messenger RNA (mRNA) transcript. The full-length mRNA then produces a stable, fully functional SMN protein.
Conversely, the single C-to-T substitution in SMN2 effectively destroys the exonic splicing enhancer signal. Without this recognition signal, the cellular machinery often fails to include exon 7 in the final mRNA product, a process called alternative splicing. The resulting transcript, which lacks exon 7, is unstable and quickly degraded, or it produces a truncated, non-functional protein (\(\text{SMN}\Delta 7\)).
While SMN1 produces almost exclusively the full-length, functional protein, the SMN2 gene is inefficient. The majority of the protein produced by SMN2 is the unstable, truncated form. Only 10% to 15% of the transcripts from SMN2 incorporate exon 7 correctly, resulting in a low level of functional SMN protein. This inefficiency explains why SMN2 cannot fully replace the function of a lost SMN1 gene.
Gene Dosage and the Severity of Spinal Muscular Atrophy
Spinal Muscular Atrophy occurs when an individual inherits two non-functional copies of the SMN1 gene, usually due to a homozygous deletion. Since the body cannot produce sufficient stable SMN protein from SMN1, the functional protein level depends solely on the output of the less efficient SMN2 gene. This establishes the concept of “gene dosage,” where the number of SMN2 copies directly influences the clinical severity of SMA.
The disease severity is inversely correlated with the SMN2 copy number; more copies lead to a milder presentation. Each additional copy contributes a small amount of functional protein, cumulatively raising the total SMN protein level. This slight increase often determines the type of SMA a patient develops.
Patients with the most severe forms, such as Type 0 or Type 1, typically have only one or two copies of SMN2. This low level of functional SMN protein leads to early-onset symptoms and significant motor neuron loss. Conversely, individuals with three or four copies generally experience a milder course, often classified as Type 2 or Type 3 SMA.
Type 2 patients often have three SMN2 copies, allowing them to sit independently but not walk. The mildest forms, such as Type 3, are associated with three or four copies, providing enough SMN protein for independent walking. The presence of SMN2, despite its inefficiency, acts as a modifier, transforming what would otherwise be a fatal condition into a spectrum of disease severity.
Therapeutic Strategies Targeting SMN2
The unique relationship between the two genes provides a clear path for therapeutic intervention aimed at compensating for the lost SMN1 function. Since SMN2 is present in all SMA patients, one major strategy focuses on maximizing functional protein production from this existing gene using SMN2 splicing modulators.
Splicing Modulators
These small-molecule drugs (e.g., Risdiplam) or antisense oligonucleotides (ASOs) (e.g., Nusinersen) interfere with the splicing process. An ASO is designed to bind to a specific sequence in intron 7 of the SMN2 gene, near the exon 7 splicing site. This binding blocks molecules that normally cause exon 7 to be skipped, forcing the cell’s machinery to include the exon in the final mRNA transcript.
By promoting the inclusion of exon 7, these splicing modulators significantly increase the amount of full-length, stable SMN protein produced from SMN2. This strategy leverages the patient’s own genetic backup to raise the overall level of functional SMN protein. Enhancing the output of the SMN2 gene has represented a major breakthrough in SMA treatment.
Gene Replacement Therapy
Gene replacement therapy is a different approach that bypasses SMN2 by supplying the missing function of SMN1. This treatment, exemplified by Onasemnogene abeparvovec, uses a modified adeno-associated virus (AAV) vector to deliver a functional copy of the human SMN1 gene. The viral vector transports the correct genetic instructions directly into the motor neuron cells.
Once inside the cell’s nucleus, the delivered SMN1 gene acts as a new template, allowing continuous production of stable, full-length SMN protein. This method permanently restores the correct genetic function, independent of the variable copy number or splicing inefficiency of the patient’s SMN2 genes. Both strategies demonstrate how understanding the SMN1 and SMN2 difference has led to effective, targeted treatments for SMA.