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STXBP2
syntaxin binding protein 2
STXBP2 is located on the short (p) arm of chromosome 19, at band 19p13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The STXBP2 gene provides instructions for making syntaxin binding protein 2, a protein that coordinates the release of specialised vesicles called secretory lysosomes in immune cells. Cytotoxic T lymphocytes and natural killer cells depend on these vesicles to deliver molecules that destroy infected or malignant targets. When STXBP2 function is impaired, immune cells cannot properly release their cytotoxic contents, leading to uncontrolled immune activation and inflammation.
Mutations in this gene are inherited in an autosomal recessive manner, meaning two altered copies must be present for disease to develop. Carriers of a single pathogenic variant typically remain healthy. The primary condition associated with STXBP2 variants is haemophagocytic lymphohistiocytosis type 5, a life-threatening disorder characterised by excessive immune system activation.
What the gene does
Syntaxin binding protein 2 functions as a regulatory component of the cellular machinery responsible for membrane fusion and vesicle release. In cytotoxic lymphocytes and natural killer cells, the protein governs how lytic granules dock and fuse with the cell membrane, allowing perforin and granzymes to be released and trigger target cell death. This process enables the immune system to eliminate pathogens and abnormal cells effectively.
Beyond immune function, the protein participates in other secretory pathways, including platelet dense granule release and digestive enzyme secretion from intestinal cells. Through precise timing and regulation of vesicle fusion events, STXBP2 ensures that secretory processes respond appropriately to cellular signals. Disruption of this regulatory function impairs the ability of immune cells to eliminate threats whilst also affecting haemostasis and intestinal barrier function.
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Chromosome location
STXBP2 is located on the short arm of chromosome 19 at position 13.2, designated cytogenetically as 19p13.2. The gene spans approximately 120 kilobases of genomic DNA and contains 18 exons that encode the complete protein. This chromosomal region contains several genes involved in immune function and cellular trafficking.
Protein structure
The syntaxin binding protein 2 protein comprises 593 amino acids and contains multiple functional regions that mediate its interactions with SNARE complex components. A disordered region spanning amino acids 444 to 466 provides flexibility that may facilitate conformational changes during the vesicle fusion cycle. The protein's architecture enables it to bind both syntaxin proteins and components of the membrane fusion machinery, positioning it as a molecular switch that controls secretory events in response to cellular cues.
Key variants
Pathogenic variants in STXBP2 include missense mutations, nonsense mutations, and small deletions or insertions that disrupt protein function. Many disease-causing variants affect regions critical for SNARE complex binding or protein stability. Loss-of-function variants that eliminate protein expression or severely impair function are typically associated with earlier disease onset and more severe clinical manifestations.
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.1138G>T | p.Glu380Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 5 |
c.1213C>T | p.Arg405Trp | Pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis |
c.1525C>T | p.Gln509Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 5 |
c.1611T>G | p.Tyr537Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 5 |
c.1697G>A | p.Gly566Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis |
c.34dup | p.Glu12fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 5 |
c.560C>T | p.Pro187Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis |
c.80del | p.Glu27fs | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 5 |
c.87+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis 5 |
c.902+5G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemophagocytic lymphohistiocytosis |
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
Biallelic pathogenic variants in STXBP2 cause haemophagocytic lymphohistiocytosis type 5, a severe autosomal recessive disorder characterised by excessive activation of immune cells and uncontrolled inflammation. Affected individuals typically present in infancy or early childhood with fever, enlarged liver and spleen, low blood cell counts, and neurological symptoms. The condition arises because cytotoxic lymphocytes cannot effectively eliminate activated immune cells, leading to a self-perpetuating cycle of inflammation. Some individuals with STXBP2 variants may also experience bleeding tendencies or intestinal inflammation due to the protein's role in platelet and intestinal cell function.
Inheritance pattern
Conditions caused by pathogenic STXBP2 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
STXBP2 is included on multiple NHS Genomic Medicine Service gene panels with green (high evidence) classifications. The gene appears on panels for bleeding and platelet disorders, inherited bleeding disorders, infantile enterocolitis and monogenic inflammatory bowel disease, primary immunodeficiency or monogenic inflammatory bowel disease, intestinal failure or congenital diarrhoea, and gastrointestinal epithelial barrier disorders. These panel memberships reflect the diverse clinical manifestations that can result from STXBP2 dysfunction across immune, haematological, and gastrointestinal systems.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a STXBP2 variant?
Carriers have one altered copy of STXBP2 and one working copy. 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 altered copies and developing the condition.
How is haemophagocytic lymphohistiocytosis type 5 diagnosed?
Diagnosis combines clinical findings such as persistent fever, low blood counts, and enlarged liver and spleen with laboratory markers of excessive immune activation. Genetic testing confirms the diagnosis by identifying biallelic pathogenic variants in STXBP2.
Are STXBP2 variants common in specific populations?
Pathogenic STXBP2 variants are rare in all populations. The overall prevalence of familial haemophagocytic lymphohistiocytosis is estimated at approximately 1 in 50,000 to 1 in 100,000 live births, with STXBP2-related cases representing a subset of these.