The Survival Motor Neuron 1 (\(SMN1\)) gene provides the blueprint for the SMN protein, which is widely expressed across the body’s tissues. The SMN protein is a fundamental component of cellular machinery, and its proper function is essential for the health of nerve cells.
Defining the SMN1 Gene
The \(SMN1\) gene is located on the long arm of chromosome 5 (\(5q13.2\)), within a complex, duplicated segment of the genome. The gene is composed of nine coding segments, called exons, which contain the instructions necessary to produce the complete, functional Survival Motor Neuron (SMN) protein. Most people have two copies of \(SMN1\), inheriting one copy from each parent. \(SMN1\) is the main source of the fully functional SMN protein required for normal physiological processes.
The Essential Role of the SMN Protein
The SMN protein is found in virtually all cells but is highly concentrated in motor neurons, the specialized nerve cells in the spinal cord that control muscle movement. The protein functions as part of the SMN complex, which acts as a molecular chaperone. Its primary role is overseeing the assembly of small nuclear ribonucleoproteins (snRNPs), the foundational components of the spliceosome.
The spliceosome is the cellular machinery responsible for pre-messenger RNA (pre-mRNA) splicing. This process involves removing non-coding segments and stitching together coding segments (exons) to create mature messenger RNA (mRNA). If SMN protein is deficient, spliceosome assembly is compromised, leading to errors in protein production. This failure disproportionately affects motor neurons, which are highly sensitive to disruptions in their protein synthesis machinery.
The Link to Spinal Muscular Atrophy
Spinal Muscular Atrophy (SMA) is a neurodegenerative disorder resulting from a loss of function in the \(SMN1\) gene. In about 95% of SMA cases, both copies of \(SMN1\) are either missing or converted into the nearly identical \(SMN2\) gene. Without sufficient functional SMN protein, motor neurons in the spinal cord degenerate and die.
Since these nerve cells transmit signals to muscles, their loss causes progressive muscle weakness and wasting (atrophy). SMA severity is directly related to the residual amount of functional SMN protein, which dictates the rate of motor neuron loss. The disease is classified into types, such as Type 1 (most severe, infantile onset) through Type 4 (milder, adult onset), which correlate with the age of onset and the highest motor function achieved.
The Critical Role of the SMN2 Gene
The variability in SMA severity is due to the neighboring \(SMN2\) gene, located in the same duplicated region of chromosome 5. \(SMN2\) is nearly identical to \(SMN1\), but a single nucleotide change in exon 7 alters how the gene is processed. This change causes \(SMN2\) to be predominantly spliced incorrectly, excluding exon 7 from the final mRNA transcript. The resulting protein (SMN-delta7) is truncated, unstable, and largely non-functional.
Only 10% to 15% of \(SMN2\) transcripts yield the full-length, functional SMN protein, allowing \(SMN2\) to act as a modifying gene. Individuals with SMA have a variable number of \(SMN2\) copies, ranging from one to eight. More copies lead to increased functional SMN protein, resulting in a later onset and milder clinical presentation. \(SMN2\) has become a primary target for therapeutic interventions aimed at increasing functional SMN protein production.