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SPG11
SPG11 vesicle trafficking associated, spatacsin
The SPG11 gene provides instructions for producing the spatacsin protein, which is primarily active in the nervous system and is associated with conditions like spastic paraplegia type 11. The SPG11 gene encodes the spatacsin protein, a crucial component of the nervous system.
SPG11 is located on the long (q) arm of chromosome 15, at band 15q21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The SPG11 gene, also known as KIAA1840 or FLJ21439, contains the genetic blueprint for spatacsin, a protein expressed throughout the nervous system. While its precise molecular function is still under investigation, spatacsin is thought to be involved in vital cellular processes within neurons. Pathogenic changes in SPG11 are associated with hereditary spastic paraplegia and related neurodegenerative disorders.
What the gene does
Spatacsin, the protein produced from the SPG11 gene, is predominantly found within the nervous system. Although its exact role remains to be fully elucidated, research suggests it may play a part in regulating gene expression, influencing which genes are turned on or off. Additionally, spatacsin is theorised to be involved in the crucial process of protein trafficking, which is the movement of proteins to their correct locations within a cell. There is also evidence to suggest a role for spatacsin in maintaining the integrity and function of axons, the specialised projections of nerve cells that transmit electrical impulses throughout the body.
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Chromosome location
The SPG11 gene is situated on chromosome 15 at position 15q21.1. This location specifies its precise address on the long arm (q) of chromosome 15, within band 21.1. The gene provides instructions for a protein that is 2443 amino acids in length.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the SPG11 gene can alter the spatacsin protein, potentially impacting its normal function. Over 65 different mutations have been identified in SPG11 that are associated with disease. These genetic changes can lead to a range of clinical presentations, particularly affecting neurological health. The specific effect of an altered spatacsin protein on the nervous system can vary depending on the nature and location of the variant.
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.1372C>T | p.Gln458Ter | Pathogenic/Likely pathogenic | ★★☆☆ | SPG11-related disorder |
c.142dup | p.Arg48fs | Pathogenic/Likely pathogenic | ★★☆☆ | SPG11-related disorder |
c.2625C>G | p.Tyr875Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 11 |
c.2984_2985del | p.Tyr995fs | Pathogenic/Likely pathogenic | ★★☆☆ | Amyotrophic lateral sclerosis type 5 |
c.3662_3665del | p.Ile1221fs | Pathogenic | ★★☆☆ | Hereditary spastic paraplegia |
c.4492_4493del | p.Val1498fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 11 |
c.5109_5115dup | p.Lys1706delinsGlyTyrTer | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 11 |
c.5290dup | p.Thr1764fs | Pathogenic/Likely pathogenic | ★★☆☆ | SPG11-related disorder |
c.6271C>T | p.Gln2091Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 11 |
c.6859C>T | p.Gln2287Ter | Pathogenic | ★★☆☆ | Hereditary spastic paraplegia 11 |
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
Pathogenic variants in the SPG11 gene are primarily associated with Spastic paraplegia type 11, an autosomal recessive form of Hereditary spastic paraplegia. This condition typically involves progressive stiffness and weakness in the legs. SPG11 variants have also been linked to other neurological disorders such as Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth disease, highlighting the gene's broad impact on nervous system function.
- Hereditary spastic paraplegia (all)
- Spastic paraplegia type 11 Dedicated page coming soon
UK clinical status
The SPG11 gene is recognised within the UK's National Health Service (NHS) Genomic Medicine Service. It is included on several green-lighted PanelApp panels, indicating strong evidence for its association with disease. These panels cover conditions such as Hereditary spastic paraplegia (including adult and childhood onset forms), Intellectual disability, Leukodystrophy, Foetal anomalies, Neurodegenerative disorders, and Paediatric motor neuronopathies.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the SPG11 gene?
The SPG11 gene provides instructions for making the spatacsin protein, which is believed to be involved in regulating gene expression, protein trafficking, and maintaining the axons of nerve cells within the nervous system.
What conditions are associated with variants in the SPG11 gene?
Variants in the SPG11 gene are most commonly associated with Spastic paraplegia type 11, an inherited neurological disorder. It has also been linked to other conditions such as Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth disease.
How is SPG11 inherited?
Spastic paraplegia type 11, linked to SPG11, is typically inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.
References
- Denora PS, Schlesinger D, Casali C. Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion. Human mutation. 2009. PMID: 19105190
- Stevanin G, Azzedine H, Denora P. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain : a journal of neurology. 2008. PMID: 18079167
- Paisan-Ruiz C, Dogu O, Yilmaz A. SPG11 mutations are common in familial cases of complicated hereditary spastic paraplegia. Neurology. 2008. PMID: 18337587
- Paisan-Ruiz C, Nath P, Wood NW. Clinical heterogeneity and genotype-phenotype correlations in hereditary spastic paraplegia because of Spatacsin mutations (SPG11). European journal of neurology. 2008. PMID: 18717728
- Stevanin G, Santorelli FM, Azzedine H. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nature genetics. 2007. PMID: 17322883
- Hehr U, Bauer P, Winner B. Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. Annals of neurology. 2007. PMID: 18067136