Survival Motor Neuron (SMN) genes, SMN1 and SMN2, produce a protein found throughout the body. This protein is important for the proper functioning and survival of motor neurons, specialized nerve cells in the spinal cord. Motor neurons transmit signals from the brain to muscles, enabling movement. Understanding the differences between SMN1 and SMN2 is important for comprehending their role in health and certain conditions.
The Role of SMN1 and SMN2
The SMN protein is necessary for the assembly of small nuclear ribonucleoproteins (snRNPs), which are components of the spliceosome. This cellular machine removes non-coding regions from RNA molecules during pre-messenger RNA (pre-mRNA) splicing. Without sufficient functional SMN protein, motor neurons can become unhealthy and eventually die, leading to muscle weakness and wasting. Both SMN1 and SMN2 genes produce the SMN protein, yet they differ significantly in the type and quantity of protein they generate.
SMN1 produces a full-length, functional SMN protein. In contrast, the SMN2 gene, which is nearly identical to SMN1, primarily produces a shorter, less functional version. This difference stems from a single nucleotide change in exon 7 of the SMN2 gene.
This subtle genetic alteration, a cytosine to thymine change at position 6 within exon 7, affects the pre-mRNA splicing process. As a result, approximately 90% of the transcripts from the SMN2 gene skip exon 7, leading to a truncated and unstable protein that is quickly degraded. While SMN2 does produce a small amount of full-length, functional SMN protein, it is significantly less efficient than SMN1, yielding only about 10% of the functional protein.
SMN Genes and Spinal Muscular Atrophy
Spinal Muscular Atrophy (SMA) is a genetic condition characterized by the progressive degeneration of motor neurons in the spinal cord, leading to muscle weakness and atrophy. This disorder primarily arises from a deficiency in functional SMN protein, most commonly due to mutations or deletions in both copies of the SMN1 gene.
In individuals with SMA, the SMN2 gene becomes the primary source of SMN protein. However, as SMN2 predominantly produces the truncated, non-functional protein, it cannot fully compensate for the missing SMN1 function. This insufficient production of full-length SMN protein leads to the characteristic symptoms of SMA, including muscle weakness, difficulty with movement, and in severe cases, problems with breathing and swallowing.
The number of SMN2 gene copies present in an individual can significantly influence the severity of SMA. People generally have between one and four copies of the SMN2 gene, though some may have up to eight. A higher number of SMN2 copies typically results in the production of more full-length SMN protein, which can lead to a later onset of symptoms and a milder disease course. This direct relationship between SMN2 copy number and disease severity underscores its role as a disease-modifying gene.
How SMN2 Becomes a Therapeutic Target
The inherent ability of the SMN2 gene to produce some amount of functional SMN protein, despite its predominant production of a truncated version, makes it an important target for therapeutic interventions in SMA. Strategies aim to increase the output of full-length SMN protein from the existing SMN2 gene, thereby compensating for the deficiency caused by the non-functional SMN1 gene. The core principle involves manipulating the pre-mRNA splicing process of SMN2.
Researchers focus on “gene modifiers” or “splicing modulators” that can influence how the SMN2 gene’s pre-mRNA is processed. These approaches seek to override the natural tendency of SMN2 to skip exon 7 during splicing. By promoting the inclusion of exon 7, these modulators encourage SMN2 to produce more full-length, functional SMN protein. This can be achieved by targeting specific sequences within the SMN2 gene’s RNA that regulate splicing.
For example, some therapeutic approaches involve molecules that bind to certain regulatory elements on the SMN2 pre-mRNA, such as intronic splicing silencers, to prevent the exclusion of exon 7. By blocking these silencers, the splicing machinery is redirected to include exon 7, leading to the synthesis of a stable and functional SMN protein. This method leverages the body’s own genetic machinery to increase the availability of the needed protein.