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SMN1
survival of motor neuron 1, telomeric
The SMN1 gene encodes the Survival of Motor Neuron (SMN) protein, critical for maintaining motor neurons and processing messenger RNA. The SMN1 gene plays a vital role in human health by producing the SMN protein, essential for the proper function and survival of motor neurons, which transmit signals for muscle movement.
SMN1 is located on the long (q) arm of chromosome 5, at band 5q13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The SMN1 gene, or survival of motor neuron 1, telomeric, is crucial for producing the SMN protein, which is found throughout the body but is most abundant in the spinal cord. This protein is a component of the SMN complex, essential for maintaining motor neurons. Motor neurons are specialised nerve cells located in the spinal cord and brainstem that send signals to skeletal muscles, enabling movement. Defects in SMN1 are a primary cause of Spinal Muscular Atrophy.
What the gene does
The SMN protein encoded by the SMN1 gene is a key part of the SMN complex, which has several important cellular roles. This complex is involved in the processing of messenger RNA (mRNA) molecules. mRNA starts as a preliminary draft (pre-mRNA) and undergoes multiple processing steps to become its final, mature form. The SMN complex helps assemble the cellular machinery required for this pre-mRNA processing. Furthermore, the SMN complex contributes to the development of dendrites and axons, which are specialised outgrowths from nerve cells necessary for transmitting impulses between neurons and from neurons to muscles. While SMN2, a gene similar to SMN1, also produces SMN protein, only one functional version is generated, with other versions being smaller and rapidly broken down.
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Chromosome location
The SMN1 gene is situated on chromosome 5, specifically at position 5q13.2. This gene is referred to as 'telomeric' due to its proximity to the telomere end of the long arm of chromosome 5. It is closely located to SMN2, a gene with a high degree of similarity to SMN1.
Protein structure
The SMN protein, comprising 294 amino acids, features several distinct functional regions. The N-terminal portion includes a Disordered region (amino acids 1-32) and a region that Interacts with GEMIN2 (amino acids 26-51). Another Disordered region is found between amino acids 59-88. A Tudor Domain spans amino acids 91-151, and a region Required for interaction with RPP20/POP7 is present from amino acids 97-209. Further downstream, a Disordered region occurs between amino acids 156-222. The protein also contains a P2 binding site for SNRPB (amino acids 240-267) and a region Involved in homooligomerization (amino acids 252-280). The C-terminus includes a region Required for interaction with SYNCRIP (amino acids 279-294).
Key variants
Variants within the SMN1 gene can lead to a reduction or absence of functional SMN protein. These genetic changes are typically deletions or subtle alterations that affect the gene's ability to produce its vital protein. The severity of conditions associated with SMN1 variants can vary depending on the specific type of genetic change and how it impacts protein production.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.399_402del | p.Glu134fs | Pathogenic | ★★☆☆ | not provided |
c.469C>T | p.Gln157Ter | Pathogenic | ★★☆☆ | Werdnig-Hoffmann disease |
c.510_511del | p.Ser170fs | Pathogenic | ★★☆☆ | not provided |
c.549del | p.Lys184fs | Pathogenic | ★★☆☆ | Spinal muscular atrophy |
c.584del | p.Pro195fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.597dup | p.Met200fs | Pathogenic/Likely pathogenic | ★★☆☆ | Werdnig-Hoffmann disease |
c.796T>C | p.Ser266Pro | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.835-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Kugelberg-Welander disease |
c.835-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Werdnig-Hoffmann disease |
c.835G>C | p.Gly279Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Spinal muscular atrophy |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Mutations in the SMN1 gene are the primary cause of Spinal Muscular Atrophy (SMA), a group of inherited conditions characterised by progressive muscle weakness and wasting due to the loss of motor neurons. SMA encompasses a spectrum of severity, including SMA type II (Dubowitz), SMA type III (Kugelberg-Welander), and SMA type IV (adult-onset). These conditions differ in their age of onset and the extent of muscle impairment experienced by affected individuals.
- Spinal muscular atrophy
- SMA type II (Dubowitz) Dedicated page coming soon
- SMA type III (Kugelberg-Welander) Dedicated page coming soon
- SMA type IV (adult-onset) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic SMN1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the SMN1 gene is part of several NHS national Genomic Medicine Service (GMS) pathways, reflecting its clinical significance. It is included on PanelApp for conditions such as Arthrogryposis (green, R83), Foetal anomalies (green, R21), Hereditary neuropathy (green), Hereditary neuropathy or pain disorder (green, R78), Paediatric motor neuronopathies (green), and Spinal muscular atrophy - Diagnostic (green, R71). These inclusions mean that genetic testing for SMN1 variants is considered clinically appropriate for diagnosis within these specified contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the SMN1 gene?
The SMN1 gene provides instructions for making the survival motor neuron (SMN) protein. This protein is essential for the maintenance and function of motor neurons, which are nerve cells that control muscle movement, and is also involved in processing messenger RNA.
What health conditions are associated with SMN1 gene variants?
Variants in the SMN1 gene are primarily associated with Spinal Muscular Atrophy (SMA). This condition causes progressive muscle weakness and wasting, with different types such as SMA type II, SMA type III, and SMA type IV, varying in severity and age of onset.
How does the SMN1 gene differ from the SMN2 gene?
The SMN1 and SMN2 genes are very similar, both producing SMN protein. However, SMN2 typically produces only a small amount of functional SMN protein, while SMN1 is responsible for the majority of functional protein production. SMN2 can partially compensate for the loss of SMN1 function.
References
- Fuller HR, Gillingwater TH, Wishart TM. Commonality amid diversity: Multi-study proteomic identification of conserved disease mechanisms in spinal muscular atrophy. Neuromuscular disorders : NMD. 2016. PMID: 27460344
- Farrar MA, Kiernan MC. The Genetics of Spinal Muscular Atrophy: Progress and Challenges. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2015. PMID: 25413156
- Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurologic clinics. 2015. PMID: 26515624
- Blauw HM, Barnes CP, van Vught PW. SMN1 gene duplications are associated with sporadic ALS. Neurology. 2012. PMID: 22323753
- Corcia P, Camu W, Praline J. The importance of the SMN genes in the genetics of sporadic ALS. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 2009. PMID: 19922137
- Kolb SJ, Battle DJ, Dreyfuss G. Molecular functions of the SMN complex. Journal of child neurology. 2007. PMID: 17761654
- Cartegni L, Hastings ML, Calarco JA. Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. American journal of human genetics. 2006. PMID: 16385450
- Corcia P, Camu W, Halimi JM. SMN1 gene, but not SMN2, is a risk factor for sporadic ALS. Neurology. 2006. PMID: 16931506
- Gubitz AK, Feng W, Dreyfuss G. The SMN complex. Experimental cell research. 2004. PMID: 15120993
- Prior TW, Swoboda KJ, Scott HD. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. American journal of medical genetics. Part A. 2004. PMID: 15378550