Human genes are fundamental blueprints for body development and function. They influence health. The SMN2 gene is significant for its impact on health conditions.
What is SMN2?
The SMN2 gene (Survival Motor Neuron 2) produces the Survival Motor Neuron (SMN) protein. This protein is important for motor neuron maintenance and function. Motor neurons transmit signals from the brain and spinal cord to muscles. Without sufficient SMN protein, motor neurons cannot function correctly, leading to muscle weakness and wasting.
Humans also possess an SMN1 gene, which is similar to SMN2. While both genes produce the SMN protein, a difference in their genetic code impacts output. A single nucleotide change (cytosine to thymine) within exon 7 of SMN2 causes it to predominantly produce a shorter, less functional SMN protein. This change affects how the gene’s instructions are read, often leading to exon 7 exclusion during alternative splicing.
SMN2’s Role in Spinal Muscular Atrophy
SMN2 is relevant in Spinal Muscular Atrophy (SMA), a genetic disorder causing progressive motor neuron loss. SMA is caused by SMN1 gene mutation or deletion, reducing full-length, functional SMN protein. This leads to motor neuron degeneration, muscle weakness, and atrophy.
In individuals with SMA, the SMN2 gene acts as a backup gene. Despite its tendency to produce mostly truncated, non-functional SMN protein, SMN2 still produces a small amount (10-15%) of full-length, functional SMN protein. This small quantity becomes the primary source of functional SMN protein in the absence of a working SMN1 gene. The amount of functional SMN protein generated by SMN2 directly influences SMA symptom severity; more functional protein leads to a milder disease course.
SMN2-Targeting Therapies
Therapies for Spinal Muscular Atrophy leverage SMN2 to increase functional SMN protein production. These treatments modify SMN2 processing, boosting full-length protein output. One approach uses antisense oligonucleotides (ASOs), synthetic nucleic acid strands designed to bind specific RNA sequences.
Nusinersen, an FDA-approved ASO, works by binding to a specific site on the SMN2 pre-messenger RNA (mRNA). This prevents splicing machinery from excluding exon 7, ensuring more full-length SMN mRNA. This increases functional SMN protein available to motor neurons, preserving their health and function. Nusinersen is administered directly into the spinal fluid.
Another therapeutic strategy uses oral small molecules like Risdiplam. Risdiplam targets SMN2 as a splicing modifier, increasing exon 7 inclusion during mRNA splicing. This results in higher functional SMN protein levels throughout the body. These therapies advance SMA management by directly addressing the protein deficiency.
The Significance of SMN2 Copy Number
Individuals can have varying SMN2 gene copies, from one to four or more. This variability is an important factor in determining SMA clinical presentation and severity. More SMN2 copies correlate with a milder SMA phenotype.
This correlation exists because each additional SMN2 copy provides more potential for functional SMN protein production, even if each gene predominantly yields the truncated version. For instance, four SMN2 copies produce more functional SMN protein than two, leading to a less severe disease course. This direct relationship makes SMN2 copy number an important prognostic indicator.
SMN2 copy number assessment is often standard in SMA diagnosis. This test helps clinicians predict disease severity and guide treatment. Understanding SMN2 copy number provides information to tailor management and anticipate disease progression.