SMN1 Gene vs. SMN2 Gene
What's the Difference?
The SMN1 gene and SMN2 gene are both involved in the production of the survival motor neuron (SMN) protein, which is essential for the normal functioning of motor neurons. However, there are some key differences between these two genes. The SMN1 gene is the primary gene responsible for producing functional SMN protein, while the SMN2 gene is considered a backup or modifier gene. This is because a single nucleotide difference in the SMN2 gene leads to the exclusion of exon 7 during RNA splicing, resulting in the production of a truncated and less stable form of the SMN protein. Consequently, individuals with mutations in the SMN1 gene, leading to its loss or reduced function, rely on the SMN2 gene to produce some functional SMN protein. However, the amount of functional protein produced by the SMN2 gene is typically not sufficient to fully compensate for the loss of SMN1, resulting in the development of spinal muscular atrophy (SMA).
Comparison
| Attribute | SMN1 Gene | SMN2 Gene |
|---|---|---|
| Gene Name | SMN1 | SMN2 |
| Chromosome Location | 5q13.2 | 5q13.2 |
| Number of Exons | 9 | 9 |
| Protein Coding | Yes | Yes |
| Splice Variants | No | Yes |
| Functional Protein | Yes | Yes (partially functional) |
| Role in Spinal Muscular Atrophy (SMA) | Defective or absent SMN1 gene causes SMA | SMN2 gene produces reduced levels of functional SMN protein in SMA |
Further Detail
Introduction
The survival motor neuron (SMN) genes, SMN1 and SMN2, play a crucial role in the development and maintenance of motor neurons. Mutations in these genes are associated with spinal muscular atrophy (SMA), a genetic disorder characterized by the degeneration of motor neurons and subsequent muscle weakness. While both genes share a high degree of similarity, they also exhibit distinct attributes that contribute to their functional differences. In this article, we will explore and compare the attributes of the SMN1 and SMN2 genes.
Gene Structure
The SMN1 and SMN2 genes are located on chromosome 5q13 and consist of nine exons. Exons are the coding regions of genes that are transcribed into messenger RNA (mRNA) and eventually translated into proteins. Both genes encode the survival motor neuron protein (SMN), which is essential for the assembly of small nuclear ribonucleoproteins (snRNPs) involved in pre-mRNA splicing. However, a critical difference lies in exon 7, which plays a crucial role in determining the functional differences between SMN1 and SMN2.
Exon 7 Splicing
In SMN1, exon 7 is constitutively included in the mature mRNA, resulting in the production of a full-length, functional SMN protein. This full-length protein is crucial for motor neuron survival and function. In contrast, SMN2 exhibits alternative splicing of exon 7, leading to the production of two distinct mRNA isoforms: one including exon 7 (SMNΔ7) and one lacking exon 7 (SMNΔ7). The majority of SMN2 transcripts exclude exon 7, resulting in the production of an unstable and truncated SMN protein.
Protein Stability
The difference in exon 7 splicing between SMN1 and SMN2 has significant implications for protein stability. The full-length SMN protein produced by SMN1 is stable and functional, allowing for proper motor neuron development and maintenance. In contrast, the truncated SMN protein produced by SMN2 lacks critical domains and is rapidly degraded within cells. This reduced stability of the SMN protein in SMN2 contributes to the severity of SMA symptoms observed in individuals with SMN2 gene mutations.
Copy Number Variation
Another important attribute that distinguishes SMN1 and SMN2 is copy number variation. Most individuals have two copies of the SMN1 gene, while the number of SMN2 gene copies can vary. Typically, individuals with SMA have a homozygous deletion of the SMN1 gene, resulting in a complete loss of functional SMN protein. However, the number of SMN2 gene copies can modify the disease severity. Individuals with a higher number of SMN2 gene copies tend to exhibit milder SMA symptoms due to the increased production of residual functional SMN protein.
Therapeutic Implications
The distinct attributes of SMN1 and SMN2 have significant implications for the development of SMA therapeutics. Since SMN2 can produce some functional SMN protein, strategies aimed at increasing the inclusion of exon 7 in SMN2 transcripts have been explored. This approach, known as exon skipping, aims to modify the splicing pattern of SMN2 to resemble that of SMN1, resulting in the production of more full-length SMN protein. Additionally, gene replacement therapies have been developed to introduce functional copies of the SMN1 gene into SMA patients, compensating for the loss of SMN protein.
Conclusion
In conclusion, while the SMN1 and SMN2 genes share a high degree of similarity, their distinct attributes contribute to their functional differences. The constitutive inclusion of exon 7 in SMN1 results in the production of a stable and functional SMN protein, crucial for motor neuron survival. In contrast, the alternative splicing of exon 7 in SMN2 leads to the production of an unstable and truncated SMN protein. Copy number variation of SMN2 further modifies disease severity. Understanding these attributes is essential for the development of effective therapeutic strategies for SMA.
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