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STX11
syntaxin 11
STX11 is located on the long (q) arm of chromosome 6, at band 6q24.2. Arm ratio per GRCh38 - banding schematic.
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Overview
STX11 encodes syntaxin 11, a membrane-associated protein that plays an essential role in the degranulation process of cytotoxic lymphocytes and natural killer cells. These immune cells rely on the controlled release of granules containing toxic molecules to eliminate infected or abnormal cells. Syntaxin 11 coordinates the fusion of these granules with the cell membrane, enabling their contents to be released into target cells.
When both copies of STX11 carry pathogenic variants, the resulting protein dysfunction prevents effective granule release, impairing the immune system's ability to terminate immune responses appropriately. This leads to haemophagocytic lymphohistiocytosis type 4, a potentially life-threatening condition in which immune cells become overactive and damage tissues throughout the body. The condition follows an autosomal recessive inheritance pattern.
What the gene does
Syntaxin 11 functions as a SNARE protein, a family of molecules that mediate membrane fusion events within cells. Specifically, syntaxin 11 operates as a target SNARE (t-SNARE) on the plasma membrane of immune cells, where it coordinates the docking and fusion of cytotoxic granules. During an immune response, cytotoxic T lymphocytes and natural killer cells form intimate contacts with target cells and must rapidly release perforin and granzymes to destroy them.
The protein achieves this by forming complexes with other SNARE molecules, bringing granule membranes into close apposition with the plasma membrane and enabling lipid bilayer fusion. This process requires precise spatial and temporal regulation to ensure that cytotoxic contents are released only at the immunological synapse, the specialised contact zone between killer cell and target. Syntaxin 11 collaborates with additional regulatory proteins to couple immune cell activation signals to the degranulation machinery, ensuring that granule release occurs only when appropriate. Without functional syntaxin 11, cytotoxic granules accumulate within immune cells, unable to discharge their contents effectively.
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Chromosome location
STX11 is located on the long arm of chromosome 6 at position 6q24.2. This chromosomal region contains multiple genes involved in immune function and cellular trafficking. The gene's position places it within a genomic landscape that has been associated with various immunological processes.
Protein structure
Syntaxin 11 comprises 287 amino acids and contains characteristic structural features typical of SNARE proteins. The protein includes a coiled coil region spanning amino acids 41-71, which facilitates protein-protein interactions necessary for SNARE complex assembly. A t-SNARE coiled-coil homology domain extends from amino acids 204-266, forming the core structural element that enables syntaxin 11 to engage with complementary SNARE partners during membrane fusion. These coiled-coil regions adopt an extended helical structure that interacts with corresponding domains on other SNARE molecules, forming a stable four-helix bundle that drives membrane merger.
Key variants
Pathogenic variants in STX11 typically result in loss of protein function through mechanisms including premature termination, frameshift changes, or missense substitutions that disrupt critical structural domains. Because haemophagocytic lymphohistiocytosis type 4 follows autosomal recessive inheritance, affected individuals carry variants in both gene copies. Carriers of a single pathogenic variant generally do not develop symptoms but can pass the variant to their children.
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.173T>C | p.Leu58Pro | Pathogenic | ★★☆☆ | STX11-related disorder |
c.391C>T | p.Gln131Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 4 |
c.396C>A | p.Tyr132Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 4 |
c.484C>T | p.Gln162Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 4 |
c.554dup | p.Trp186fs | Pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 4 |
c.581_584del | p.Leu194fs | Pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 4 |
c.645dup | p.Arg216fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 4 |
c.697del | p.Val233fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis |
c.73G>T | p.Glu25Ter | Pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 4 |
c.83C>A | p.Ser28Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 4 |
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 STX11 cause haemophagocytic lymphohistiocytosis type 4, a condition characterised by uncontrolled activation of immune cells leading to widespread inflammation and tissue damage. Affected individuals typically present in infancy or early childhood with fever, enlarged liver and spleen, low blood cell counts, and evidence of excessive immune activation. The condition can be triggered by infections or may occur spontaneously. Without treatment, haemophagocytic lymphohistiocytosis type 4 can be fatal, although therapeutic options including immunosuppression and haematopoietic stem cell transplantation have improved outcomes in recent years.
Inheritance pattern
Conditions caused by pathogenic STX11 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
Within the UK's NHS Genomic Medicine Service, STX11 appears on clinical gene panels including the Primary immunodeficiency or monogenic inflammatory bowel disease panel (green classification, R15), reflecting its relevance to diagnosing severe immune disorders. The gene is also included on the COVID-19 research panel (green classification), acknowledging potential connections between immune regulatory mechanisms and infectious disease responses.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of an STX11 variant?
Carriers have one working copy and one non-working copy of STX11. They typically do not develop haemophagocytic lymphohistiocytosis themselves but can pass the variant to their children. If both parents are carriers, each child has a 25% chance of inheriting two variants and being affected.
How is haemophagocytic lymphohistiocytosis type 4 diagnosed?
Diagnosis typically involves clinical assessment of symptoms such as persistent fever and enlarged organs, laboratory findings including low blood counts and elevated inflammation markers, and genetic testing to identify pathogenic STX11 variants. Specialised immunological tests may assess natural killer cell function.
Can STX11 variants affect immune function in carriers?
Research suggests that most carriers with a single pathogenic variant maintain normal immune function and do not experience symptoms of haemophagocytic lymphohistiocytosis. The condition requires loss of function in both gene copies to manifest clinically.