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SIGMAR1
sigma receptor chaperone 1
SIGMAR1 encodes the sigma-1 receptor, a protein that regulates cellular stress responses and helps maintain neuronal health. The SIGMAR1 gene provides instructions for making the sigma-1 receptor, a unique protein that acts as a molecular chaperone at contact sites between the endoplasmic reticulum and mitochondria.
SIGMAR1 is located on the short (p) arm of chromosome 9, at band 9p13.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 9 in the library →Overview
SIGMAR1 is located on chromosome 9 and encodes a 223-amino-acid protein known as the sigma-1 receptor. Despite its name, this receptor does not function like typical cell-surface receptors; instead, it operates as an intracellular chaperone protein that helps other proteins maintain their proper shape and function during cellular stress. The sigma-1 receptor is particularly abundant in the nervous system, where it supports neuronal survival and function.
Pathogenic variants in SIGMAR1 are inherited in an autosomal recessive pattern, meaning two altered copies of the gene must be present for disease to develop. These variants have been associated with motor neuron disorders and hereditary neuropathies, conditions that affect the nerves controlling movement and sensation. The gene's role in maintaining cellular resilience under stress appears central to its importance in neurological health.
What the gene does
The sigma-1 receptor functions primarily as a molecular chaperone at specialised contact points between the endoplasmic reticulum and mitochondria, two critical cellular compartments. At these sites, the protein regulates calcium transfer between organelles, helping cells respond appropriately to stress signals. When cells experience stress, the sigma-1 receptor stabilises other proteins and prevents them from misfolding or aggregating.
The protein also modulates several cellular signalling pathways, including those involving ion channels and neurotransmitter receptors. In neurons, the sigma-1 receptor appears to protect against oxidative stress and supports the health of long neuronal projections called axons. Research suggests the receptor may influence lipid metabolism and membrane dynamics, though the precise mechanisms remain areas of active investigation. The protein's ability to sense and respond to cellular stress makes it particularly important in tissues with high metabolic demands, such as motor neurons and sensory nerve fibres.
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Chromosome location
SIGMAR1 is located on the short arm of chromosome 9 at position 13.3 (9p13.3). The gene spans approximately 6.6 kilobases of genomic DNA and contains four exons. The relatively compact structure of the gene means the entire coding sequence is contained within a small chromosomal region.
Protein structure
The sigma-1 receptor is a 223-amino-acid protein with several functionally important regions. The N-terminal region includes a targeting sequence to endoplasmic reticulum-associated lipid droplets, which directs the protein to specific membrane compartments. A critical region important for ligand-binding enables the receptor to interact with various small molecules and regulatory compounds. The protein also contains a C-terminal hydrophobic region, which likely contributes to membrane association and protein-protein interactions. The overall structure allows the sigma-1 receptor to function at the interface between cellular membranes, where it can sense stress signals and coordinate cellular responses.
Key variants
Pathogenic variants in SIGMAR1 can disrupt the protein's chaperone function or its ability to localise correctly within cells. Most disease-causing variants are missense changes that alter single amino acids, potentially affecting the protein's stability or its interactions with other cellular components. Some variants may reduce the protein's expression levels or cause it to misfold. Because SIGMAR1-related conditions follow autosomal recessive inheritance, individuals typically need pathogenic variants in both copies of the gene to develop symptoms.
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.14_20dup | p.Arg8fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.194T>A | p.Leu65Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Amyotrophic lateral sclerosis type 16 |
c.19del | p.Arg7fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 2 |
c.283dup | p.Leu95fs | Pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 2 |
c.304G>C | p.Glu102Gln | Pathogenic | ★★☆☆ | Autosomal recessive distal spinal muscular atrophy 2 |
c.125_126del | p.Ile42fs | Pathogenic | ★☆☆☆ | Amyotrophic lateral sclerosis type 16 |
c.13del | p.Val5fs | Pathogenic | ★☆☆☆ | Autosomal recessive distal spinal muscular atrophy 2 |
c.217_220del | p.Val73fs | Pathogenic | ★☆☆☆ | Autosomal recessive distal spinal muscular atrophy 2 |
c.238C>T | p.Gln80Ter | Pathogenic | ★☆☆☆ | Autosomal recessive distal spinal muscular atrophy 2 |
c.374C>A | p.Ser125Ter | Pathogenic | ★☆☆☆ | Autosomal recessive distal spinal muscular atrophy 2 |
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
Variants in SIGMAR1 have been linked to a spectrum of neurological conditions, particularly those affecting motor neurons and peripheral nerves. These conditions can present as motor neuron disease, resembling amyotrophic lateral sclerosis in some cases, or as hereditary neuropathies affecting sensation and movement. The age of onset and severity can vary considerably between affected individuals, even within the same family. Some people develop predominantly motor symptoms, whilst others experience more sensory involvement or pain. The shared feature across these presentations appears to be vulnerability of nerve cells to stress and gradual neuronal dysfunction.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SIGMAR1 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
SIGMAR1 is included on several NHS Genomic Medicine Service gene panels used for diagnosing inherited neurological conditions. The gene appears with green classification on the Amyotrophic lateral sclerosis/motor neuron disease panel, the Hereditary neuropathy panel, and the Hereditary neuropathy or pain disorder panel. Green classification indicates strong evidence supporting the gene's role in these conditions. Testing for SIGMAR1 variants may be considered when individuals present with clinical features consistent with motor neuron disease or hereditary neuropathy, particularly when family history suggests autosomal recessive inheritance.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
There are no specific lifestyle modifications established for SIGMAR1-related conditions. Management focuses on supporting quality of life and should be guided by specialist neurological care tailored to the specific condition and symptoms present.
Supplement considerations
No specific dietary supplements have been established as beneficial for SIGMAR1-related conditions. Any nutritional support should be discussed with healthcare professionals managing the individual's neurological condition.
Frequently asked questions
How is SIGMAR1 different from typical receptors?
Unlike most receptors that sit on the cell surface and respond to external signals, the sigma-1 receptor operates inside cells as a chaperone protein. It helps other proteins maintain their proper structure during cellular stress rather than transmitting signals from outside the cell.
What does autosomal recessive inheritance mean for SIGMAR1?
Autosomal recessive inheritance means a person needs to inherit a pathogenic variant from both parents to develop a SIGMAR1-related condition. Individuals with only one altered copy are typically carriers who do not show symptoms but can pass the variant to their children.
Can SIGMAR1 variants cause different types of nerve problems?
Yes, variants in SIGMAR1 have been associated with a range of neurological presentations, from motor neuron disease affecting movement to hereditary neuropathies affecting sensation and pain perception. The specific symptoms and age of onset can vary between affected individuals.