STX11 – Familial Hemophagocytic Lymphohistiocytosis

STX11 encodes syntaxin-11, a SNARE protein essential for cytotoxic granule exocytosis in natural killer and CD8⁺ T cells. Biallelic loss-of-function variants in STX11 cause autosomal recessive familial hemophagocytic lymphohistiocytosis (FHL) type 4, presenting with fever, cytopenias, hepatosplenomegaly, and hemophagocytosis—the hallmark features of hereditary hemophagocytic lymphohistiocytosis.

Autosomal recessive inheritance is supported by multiple consanguineous pedigrees. In one Kurdish kindred, five affected siblings harbored a homozygous 5 bp deletion in STX11 (c.802C>T (p.Gln268Ter)) (PMID:15703195). In a multi-ethnic cohort of 70 patients, 14 individuals from 10 unrelated families carried biallelic STX11 variants, including nonsense and frameshift changes (PMID:18710388), establishing robust segregation.

The spectrum of STX11 variants includes missense, nonsense, and frameshift alleles. A recurrent N-terminal missense variant, c.173T>C (p.Leu58Pro), abolishes binding to Munc18-2 and impairs NK cell degranulation (PMID:24459464) and is observed in multiple unrelated families. Other protein-truncating alleles (e.g., c.599_602del (p.Ala200fs), c.554dup (p.Trp186fs)) further underscore loss of function as the primary mechanism.

Functional studies in Stx11⁻/⁻ mice demonstrate severely reduced CTL and NK cytotoxicity, uncontrolled hyperinflammation after viral challenge, and T-cell exhaustion limiting fatal disease, mirroring human FHL4 (PMID:23190531). In patient cells, STX11 deficiency abolishes granule exocytosis and CD107a surface mobilization in lymphocytes and neutrophils; reconstitution rescues these defects (PMID:23042080).

No pathogenic STX11 mutations were found in 30 Japanese FHL patients, indicating population-specific prevalence but not disputing causality (PMID:16180048).

Integration of genetic segregation across >20 families and concordant functional data from patient cells and animal models meets definitive ClinGen criteria for gene-disease validity. Key take-home: STX11 genotyping and functional degranulation assays are critical for early diagnosis and selection of hematopoietic stem cell transplantation in FHL4.

References

• Human molecular genetics • 2005 • Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. PMID:15703195
• British journal of haematology • 2008 • Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis. PMID:18710388
• Frontiers in immunology • 2014 • An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2. PMID:24459464
• Blood • 2013 • Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell exhaustion limits fatal disease. PMID:23190531
• European journal of immunology • 2013 • Syntaxin 11 is required for NK and CD8⁺ T-cell cytotoxicity and neutrophil degranulation. PMID:23042080
• Journal of human genetics • 2005 • Mutations of syntaxin 11 and SNAP23 genes as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people. PMID:16180048

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