HGNC Approved Gene Symbol: STX11
Cytogenetic location: 6q24.2 Genomic coordinates (GRCh38) : 6:144,139,963-144,191,939 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q24.2 | Hemophagocytic lymphohistiocytosis, familial, 4 | 603552 | Autosomal recessive | 3 |
The STX11 gene encodes syntaxin-11, a protein involved in vesicle exocytosis. Syntaxin-11 contains a C-terminal SNARE domain (summary by Muller et al., 2014). SNARE proteins play a role in regulating intracellular protein transport between donor and target membranes. This docking and fusion process involves the interaction of specific vesicle-SNAREs (e.g., VAMP, 603177) with specific cognate target-SNAREs (e.g., SNAP23, 602534) (summary by Valdez et al., 1999).
Advani et al. (1998) and Tang et al. (1998) identified human syntaxin-11 by searching EST databases for clones with sequence similarity to other syntaxin proteins. Both groups found that STX11 encodes a deduced 287-amino acid protein with several predicted coiled-coil domains. Unlike most membrane-associated proteins, STX11 lacks a hydrophobic domain but contains a cysteine-rich C terminus. Like SNAP25 (600322), STX11 may be anchored to membranes by palmitoylated cysteines. By Northern blot analysis, Tang et al. (1998) identified 2 STX11 transcripts of approximately 0.8 and 1.7 kb that are particularly abundant in heart and placenta and are detectable at low levels in other tissues but not in brain.
Using a yeast 2-hybrid system to screen a human B-lymphocyte cDNA library with SNAP23 as bait, Valdez et al. (1999) cloned STX11. They determined that STX11 has a molecular mass of 35 kD and is an integral membrane protein despite the lack of a traditional transmembrane domain. Both transfected and endogenous STX11 binds to SNAP23 in vitro and in vivo. STX11 colocalizes with mannose 6-phosphate on late endosomes and the trans-Golgi network. Immunofluorescence microscopy showed that when the cysteine cluster at the C terminus of STX11 is deleted, the punctate intracellular structure does not differ from that of the wildtype protein, demonstrating that targeting and retention of STX11 on the intracellular membrane does not depend exclusively on amino acids in the cysteine-rich domain.
The STX11 gene consists of 2 exons and covers a genomic interval of 37 kb (Zur Stadt et al., 2005).
Mutations in MUNC18-2 (STXBP2; 601717) or STX11 abolish cytotoxic C lymphocytes (CTLs) and natural killer (NK) cell cytotoxicity, resulting in immunodeficiency (see MOLECULAR GENETICS). Using purified recombinant proteins, Hackmann et al. (2013) showed that human MUNC18-2 and STX11 interacted directly and that the interaction was facilitated by the NHABC domain of STX11. The authors presented evidence that, in the absence of STX11, STX3 (600876) could interact with MUNC18-2 in activated NK cells to compensate for the missing step required for cytotoxicity. Similarly, MUNC18-1 (STXBP1; 602926) likely compensated for loss MUNC18-2, as MUNC18-1 was expressed in human CTLs and NK cells and interacted with STX3 and STX11.
Familial hemophagocytic lymphohistiocytosis (FHL; 267700) is an autosomal recessive disease that presents as a severe hyperinflammatory syndrome with activated macrophages and T lymphocytes. Zur Stadt et al. (2005) mapped one form of FHL (FHL4; 603552) to chromosome 6q24 by homozygosity mapping. They identified a 5-bp deletion (605014.0001), a large genomic deletion (605014.0002), and a nonsense mutation (Q268X; 605014.0003) in the STX11 gene, which maps to the 6q24 region.
In a mutation analysis in a group of 63 unrelated patients with FHL of different geographic origins, Zur Stadt et al. (2006) found 6 mutations in the STX11 gene, all in patients of Kurdish origin.
Yamamoto et al. (2005) excluded mutations in the STX11 gene in 30 Japanese patients with FHL.
Rudd et al. (2006) analyzed the STX11 gene in 34 patients with FHL from 28 unrelated families in whom PRF1 (170280) mutations had been excluded, including 2 families previously reported by Zur Stadt et al. (2005). They identified homozygosity for the 5-bp deletion and the Q268X mutation in a Turkish brother and sister and an unrelated Turkish boy, respectively. They noted that 13 individuals from 8 Turkish families had been shown to carry STX11 mutations to that date.
In 3 unrelated Pakistani children with FHL4, each born of consanguineous parents, Muller et al. (2014) identified a homozygous missense mutation in the STX11 gene (L58P; 605014.0004). Peripheral blood cells, including NK cells, from 1 of the patients showed significantly decreased STX11 protein levels compared to controls. In vitro functional expression studies in HEK293 cells showed that the mutant L58P protein was expressed, but did not bind to STXBP2 (601717). In contrast, the C-terminal Q268X mutant protein (605014.0003) did not show impaired binding to STXBP2. Muller et al. (2014) suggested that the impaired binding to STXBP2 may have led to degradation of the mutant L58P STX11 protein. The patients presented in infancy or early childhood with clinical and laboratory evidence of a hyperinflammatory state. Resting patient NK cells showed defective lytic activity and impaired degranulation.
Zur Stadt et al. (2005) identified a homozygous deletion of 5 nucleotides (369_370delAG, 374_376delCGC) in exon 2 of the STX11 gene in a large family of Kurdish origin in Turkey as the basis of familial hemophagocytic lymphohistiocytosis (FHL4; 603552). The total deletion of 5 basepairs led to a frameshift and premature termination after 59 altered residues (Val124fsTer60). This mutation was identified in 2 additional families of Kurdish origin. Rudd et al. (2006) noted that 1 of the brothers from the large Kurdish family developed myelodysplastic syndrome 6 years after the diagnosis of FHL; both brothers had more than 1 year of remission without specific treatment.
In a Turkish brother and sister with familial hemophagocytic lymphohistiocytosis, Rudd et al. (2006) identified homozygosity for 369_370delAG and 374_276delCGC mutation. Both children had severe psychomotor retardation, and the girl died at age 14 months at home with fever and cough.
In affected members of a Turkish family of Kurdish origin with familial hemophagocytic lymphohistiocytosis (FHL4; 603552), Zur Stadt et al. (2005) identified a deletion of 19,189 basepairs in the STX11 gene, including part of intron 1 and the entire coding region.
In 2 Turkish families of Kurdish origin with familial hemophagocytic lymphohistiocytosis (FHL4; 603552), Zur Stadt et al. (2005) identified a C-to-T transition at nucleotide position 802 of the STX11 gene that resulted in premature termination at gln268 (Q268X). Rudd et al. (2006) noted that a girl from 1 of the families reported by Zur Stadt et al. (2005) had developed acute myelogenous leukemia but was alive and in remission from AML and FHL at the time of writing.
In a Turkish boy with familial hemophagocytic lymphohistiocytosis, Rudd et al. (2006) identified homozygosity for the Q268X mutation. The boy had more than a year in remission without specific treatment, but died at age 12 years due to hemorrhage.
In 3 unrelated Pakistani children with familial hemophagocytic lymphohistiocytosis (FHL4; 603552), each born of consanguineous parents, Muller et al. (2014) identified a homozygous c.173T-C transition in the STX11 gene, resulting in a leu58-to-pro (L58P) substitution in the first alpha-helix of the conserved N-terminal Habc domain. All of the parents were unaffected and heterozygous for the mutation. Peripheral blood cells, including NK cells, from 1 of the patients showed significantly decreased STX11 protein levels compared to controls. In vitro functional expression studies in HEK293 cells showed that the mutant L58P protein was expressed, but did not bind to STXBP2 (601717). In contrast, the C-terminal Q268X mutant protein (605014.0003) did not show impaired binding to STXBP2. Muller et al. (2014) suggested that the impaired binding to STXBP2 may have led to degradation of the mutant L58P STX11 protein. The patients presented in infancy or early childhood with clinical and laboratory evidence of a hyperinflammatory state. Resting patient NK cells showed defective lytic activity and impaired degranulation. One of the patients also carried a heterozygous P271S variant in the UNC13D gene (608897) (frequency of 0.001 among Caucasians) and a homozygous R928C variant in the UNC13D gene (frequency of 0.01 among Caucasians); this patient had the earliest onset, at age 2 months. Two of the patients died in childhood, and the third was lost to follow-up.
Advani, R. J., Bae, H.-R., Bock, J. B., Chao, D. S., Doung, Y.-C., Prekeris, R., Yoo, J.-S., Scheller, R. H. Seven novel mammalian SNARE proteins localize to distinct membrane compartments. J. Biol. Chem. 273: 10317-10324, 1998. [PubMed: 9553086] [Full Text: https://doi.org/10.1074/jbc.273.17.10317]
Hackmann, Y., Graham, S. C., Ehl, S., Honing, S., Lehmberg, K., Arico, M., Owen, D. J., Griffiths, G. M. Syntaxin binding mechanism and disease-causing mutations in Munc18-2. Proc. Nat. Acad. Sci. 110: E4482-E4491, 2013. [PubMed: 24194549] [Full Text: https://doi.org/10.1073/pnas.1313474110]
Muller, M.-L., Chiang, S. C. C., Meeths, M., Tesi, B., Entesarian, M., Nilsson, D., Wood, S. M., Nordenskjold, M., Henter, J.-I., Naqvi, A., Bryceson, Y. T. An N-terminal missense mutation in STX11 causative of FHL4 abrogates syntaxin-11 binding to Munc18-2. Front. Immun. 4: 515, 2014. Note: Electronic Article. [PubMed: 24459464] [Full Text: https://doi.org/10.3389/fimmu.2013.00515]
Rudd, E., Goransdotter Ericson, K., Zheng, C., Uysal, Z., Ozkan, A., Gurgey, A., Fadeel, B., Nordenskjold, M., Henter, J.-I. Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies. J. Med. Genet. 43: e14, 2006. [PubMed: 16582076] [Full Text: https://doi.org/10.1136/jmg.2005.035253]
Tang, B. L., Low, D. Y. H., Hong, W. Syntaxin 11: a member of the syntaxin family without a carboxyl terminal transmembrane domain. Biochem. Biophys. Res. Commun. 245: 627-632, 1998. [PubMed: 9571206] [Full Text: https://doi.org/10.1006/bbrc.1998.8490]
Valdez, A. C., Cabaniols, J.-P., Brown, M. J., Roche, P. A. Syntaxin 11 is associated with SNAP-23 on late endosomes and the trans-Golgi network. J. Cell Sci. 112: 845-854, 1999. [PubMed: 10036234] [Full Text: https://doi.org/10.1242/jcs.112.6.845]
Yamamoto, K., Ishii, E., Horiuchi, H., Ueda, I., Ohga, S., Nishi, M., Ogata, Y., Zaitsu, M., Morimoto, A., Hara, T., Imashuku, S., Sasazuki, T., Yasukawa, M. Mutations of syntaxin 11 and SNAP23 as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people. J. Hum. Genet. 50: 600-603, 2005. [PubMed: 16180048] [Full Text: https://doi.org/10.1007/s10038-005-0293-1]
Zur Stadt, U., Beutel, K., Kolberg, S., Schneppenheim, R., Kabisch, H., Janka, G., Hennies, H. C. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. Hum. Mutat. 27: 62-68, 2006. [PubMed: 16278825] [Full Text: https://doi.org/10.1002/humu.20274]
Zur Stadt, U., Schmidt, S., Kasper, B., Beutel, K., Diler, A. S., Henter, J. I., Kabisch, H., Schneppenheim, R., Nurnberg, P., Janka, G., Hennies, H. C. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum. Molec. Genet. 14: 827-834, 2005. [PubMed: 15703195] [Full Text: https://doi.org/10.1093/hmg/ddi076]