Alternative titles; symbols
HGNC Approved Gene Symbol: STXBP2
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38): 19:7,629,793-7,647,873 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease | 613101 | Autosomal recessive | 3 |
The STXBP2 gene encodes a protein involved in vesicular cargo trafficking in various cell types, including hematopoietic cells and polarized epithelial cells at the brush border of the gut and kidney. STXBP2 is part of the SNARE complex, which is involved in membrane fusion (summary by Pagel et al., 2012; Vogel et al., 2017; Dhekne et al., 2018).
Several mammalian homologs of the C. elegans gene Unc18 have been identified, including STXBP2. These genes are conserved across species from yeast to man. See STXBP1 (602926).
Ziegler et al. (1996) identified STXBP2, which they called UNC18B, as part of a random sequencing of genes from IL2-activated human natural-killer (NK) cells. Sequence analysis of a full-length cDNA revealed that it encodes a polypeptide of 593 amino acids, which is most closely related to mouse Unc18b (95% identical) and less closely related to Unc18a (64% identical) and Unc18c (48% identical). Ziegler et al. (1996) found by Northern blot analysis that UNC18B is expressed predominantly as a 2.4-kb message in placenta, lung, liver, kidney, and pancreas, as well as in peripheral blood lymphocytes.
Zur Stadt et al. (2009) noted that the STXBP2 gene contains 19 exons.
Ziegler et al. (1996) mapped the STXBP2 gene to human chromosome 19p13.3-p13.2 and to the proximal arm of mouse chromosome 8.
Zur Stadt et al. (2009) demonstrated colocalization of STXBP2 and STX11 (605014) in CD8+ T and NK cells by immunofluorescence analysis. Stimulation with IL2 (147680) further enhanced colocalization in CD8+ and NK cells. Coimmunoprecipitation analysis demonstrated shared binding sites between STXBP2 and STX11.
Mutations in MUNC18-2 or STX11 abolish cytotoxic C lymphocytes (CTLs) and 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 of MUNC18-2, as MUNC18-1 was expressed in human CTLs and NK cells and interacted with STX3 and STX11.
Hackmann et al. (2013) determined the crystal structure of human MUNC18-2 at 2.6-angstrom resolution. Like rat Munc18-1 and Munc18-3, the structure of human MUNC18-2 was segregated into 3 domains: domain-1 and domain-2 formed half of the arch-shaped structure, with domain-3 predominantly forming the other half. The structure also contained a central cavity formed by domain-1 and domain-3 at the top of the molecule and an N-terminal peptide-binding site just beneath domain-1, comprising an acidic region and a large hydrophobic pocket. An enlarged hydrophobic patch was also present on the peptide-binding surface of MUNC18-2. Mapping of 18 disease-causing mutations directly onto the structure and subsequent analysis revealed that most mutations affected folding of the MUNC18-2 protein. However, the glu132-to-ala (E132A) mutation did not disrupt protein folding, but instead abolished the ability of MUNC18-2 to bind STX11 by destroying the N-terminal peptide interaction.
In 8 unrelated probands with familial hemophagocytic lymphohistiocytosis (FHL) mapping to chromosome 19p (FHL5; 613101), from 2 Saudi Arabian and 6 Turkish consanguineous families, zur Stadt et al. (2009) sequenced the candidate gene STXBP2 and identified homozygous mutations in STXBP2 in all 8 patients (see, e.g., 601717.0001-601717.0003). Sequence analysis in other patients from nonconsanguineous FHL families revealed homozygosity or compound heterozygosity for mutations in STXBP2 in 4 additional patients from Germany and the Czech Republic (see, e.g., 601717.0004-601717.0006), 2 of whom had been previously reported (Beutel et al., 2009; Sparber-Sauer et al., 2009). Corresponding heterozygous mutations were found in all available unaffected parents, and none of the mutations were detected in 210 chromosomes from ethnically matched controls. Zur Stadt et al. (2009) identified STX11, a mutation in which causes FHL4 (603552), as an interaction partner of STXBP2, and demonstrated that this interaction is eliminated by the missense mutations identified in the FHL5 patients, leading to decreased stability of both proteins. Activity of NK and cytotoxic T cells was markedly reduced or absent in FHL5 patients.
In affected members of 6 consanguineous families with FHL mapping to chromosome 19p13.3-p13.2, Cote et al. (2009) sequenced the STXBP2 gene and identified homozygosity for the P477L mutation (601717.0001) in 3 Saudi Arabian families and for the IVS14 splice site mutation (601717.0003) in 3 families of Turkish, Palestinian Arab, and Iranian origin, respectively.
Cetica et al. (2010) analyzed the STXBP2 gene in 28 FHL families in which mutations in known FHL genes had been excluded by sequence analysis, and identified homozygosity for 4 different missense mutations in the STXBP2 gene in 4 (14%) of the 28 families, originating from Italy, England, Kuwait, and Pakistan, respectively (see, e.g., P477L, 601717.0001 and G541S, 601717.0007).
Pagel et al. (2012) reported 37 patients from 28 families of various ethnic origins with FHL5 due to homozygous or compound heterozygous mutations in the STXBP2 gene. Some of the patients had previously been reported. There was a spectrum of mutation types, including missense, splice site, and frameshift, which were scattered across the coding region. There were some recurrent mutations: P477L was observed in patients of Arab origin, G541S mainly in white Europeans, and a splice site mutation affecting exon 15 (601717.0003) was found in 12 patients (5 homozygous and 7 compound heterozygous). Patient NK and cytotoxic T cells showed variable abnormal degranulation compared to controls.
In 6 patients from 4 unrelated families with FHL5 associated with severe enteropathy, Stepensky et al. (2013) identified biallelic mutations in the STXBP2 gene (see, e.g., 601717.0002 and 601717.0008). Functional studies of the variants were not performed, but the authors hypothesized that a block in exocytosis of PAS-positive material in intestinal epithelial cells may ultimately cause osmotic diarrhea.
In 5 unrelated children with FHL5, including 1 patient previously reported by Stepensky et al. (2013), Vogel et al. (2017) identified homozygous loss-of-function mutations in the STXBP2 gene (see, e.g., 601717.0009 and 601717.0010). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. In addition to interrupting the interaction with STX11, an interaction important for proper leukocyte function, in vitro studies showed that loss of the STXBP2 protein also abolished the interaction with STX3 (600876) in polarized epithelial cells, which is pivotal for vesicle fusion at the apical plasma membrane. Studies in an STXBP2-null human enterocyte cell line grown on a porous membrane and patient-derived cells or organoids showed that loss of STXBP2 disrupted enterocyte polarity and resulted in shortening or loss of apical microvilli and aberrant accumulation of subapical vesicles. The cellular model system thus recapitulated the MVID phenotype observed in the patients. Expression of the Ile232del mutation (601717.0002) was unable to rescue these defects in vitro. Additional in vitro studies showed that the mutations interrupted SNARE/STX3-mediated fusion of cargo vesicles at the apical membrane of polarized cells. This was associated with abnormal localization of brush border transporters, such as NHE3 (SLC9A3; 182307), at the apical membrane; these are critical for proper enterocyte function.
Pagel et al. (2012) delineated 2 main phenotypic FHL5 groups based on STXBP2 mutation type, suggesting a possible genotype/phenotype correlation. Patients without exon 15 splice site mutations had early disease onset in the first months of life and a rapidly fatal course if HSCT could not be performed. All 14 of the patients in this group had chronic diarrhea. In contrast, 13 patients with an exon 15 splice site mutation on at least 1 allele had later disease onset with a more protracted course. None of the patients in this group had diarrhea, but 9 had hypogammaglobulinemia.
In 2 brothers and another proband from unrelated consanguineous Saudi Arabian families, who had onset of familial hemophagocytic lymphohistiocytosis-5, with or without microvillus inclusion disease (FHL5; 613101), before 1 year of age, zur Stadt et al. (2009) identified homozygosity for a 1430C-T transition in exon 16 of the STXBP2 gene, resulting in a pro477-to-leu (P477L) substitution at a conserved residue. Analysis of CD107 degranulation in the 2 brothers revealed that activity of NK and cytotoxic T cells was markedly reduced or absent, and immunoblot analysis of cell lysates showed reduced amounts of STXBP2; markedly decreased levels of syntaxin-11 (STX11; 605014) were also observed in the sibs. Coimmunoprecipitation studies showed that ability to bind STX11 was absent with the P477L mutant. One of the brothers underwent mismatched unrelated donor hematopoietic stem cell transplantation (HSCT) at 12 months of age and had no active disease at most recent follow-up; the other brother, who had central nervous system involvement, underwent matched unrelated donor HSCT at 3 months of age but later died of venoocclusive disease.
In affected members of 3 unrelated consanguineous Saudi Arabian families with FHL5, Cote et al. (2009) identified homozygosity for the P477L mutation in the STXBP2 gene. No STXBP2 protein was detected in lymphoblasts from 2 affected female sibs of 1 family. The parents and unaffected sibs were all heterozygous for the mutated STXBP2 allele, which was not found in 80 French, 50 Turkish, or 80 Arab or Iranian controls. The 5 patients were all diagnosed between 1 and 3.5 months of age, and 3 of the 5 patients had died between 4 and 16 months of age.
In a Kuwaiti girl who was diagnosed with FHL at 7 months of age and was still alive at 3.5 years of age after undergoing matched sib donor HSCT, Cetica et al. (2010) identified homozygosity for the P477L mutation in the STXBP2 gene.
Pagel et al. (2012) identified a homozygous P477L mutation in a 2.2-year-old boy (A_679), born of consanguineous parents from the United Arab Emirates, with FHL5. He also had chronic diarrhea due to an enteropathy.
In 2 unrelated Turkish probands from consanguineous families, who had onset of familial hemophagocytic lymphohistiocytosis-5, with or without microvillus inclusion disease (FHL5; 613101), at 1.5 and 2 months of age, respectively, zur Stadt et al. (2009) identified homozygosity for a 3-bp deletion (693_695delGAT) in exon 9 of the STXBP2 gene, resulting in deletion of ile232 at a conserved residue. Coimmunoprecipitation studies showed that ability to bind STX11 was absent with the ile232 deletion. Both patients had central nervous system involvement; one underwent matched sib donor hematopoietic stem cell transplantation (HSCT) at 4.5 months of age and had no active disease at approximately 8 years of follow-up, whereas the other patient did not undergo HSCT and died.
Stepensky et al. (2013) identified a homozygous c.693_695delGAT mutation in the STXBP2 gene in 3 sibs, born of consanguineous parents (family 1), with FHL5. Two died in the first months of life from intractable diarrhea and coagulation abnormalities. The third sib had bone marrow transplantation and was alive at age 12 years, but diarrhea and enteropathy persisted after the transplant; she was on parenteral nutrition.
In 2 unrelated probands of Turkish and German origin, who had onset of familial hemophagocytic lymphohistiocytosis without microvillus inclusion disease (FHL5; 613101), at 28 and 44 months, respectively, zur Stadt et al. (2009) identified homozygosity for a G-to-C transversion at the splice acceptor site in intron 14 of the STXBP2 gene (1247-1G-C). Analysis of RNA from the Turkish patient revealed a deletion of exon 15, resulting in a frameshift and 126 new codons, in about 95% of clones, as well as 2 minor in-frame and 4 frameshift products. Analysis of CD107 degranulation in this patient revealed that activity of NK and cytotoxic T cells was markedly reduced or absent. The German patient underwent matched unrelated donor hematopoietic stem cell transplantation (HSCT) at 16 years of age but later died. The Turkish patient, who did not undergo HSCT, had recurrent reactivations that were responsive to steroids. In another 3 unrelated FHL patients, all with onset of disease after 1 year of age, the splice site mutation was found in compound heterozygosity with a missense mutation (601717.0004) and 2 different 1-bp deletions (601717.0005 and 601717.0006), respectively.
In 3 probands with FHL5 from consanguineous families of Turkish, Palestinian Arab, and Iranian origin, respectively, Cote et al. (2009) identified homozygosity for the 1247-1G-C mutation in the STXBP2 gene. Sequencing of RT-PCR products revealed that rather than leading to a premature stop codon, the splice mutation resulted in exchange of the first 17 amino acids of exon 15 for 19 new amino acids from the intronic sequence, in-frame with the last 20 amino acids of wildtype exon 15. The parents were all heterozygous for the mutated STXBP2 allele, which was not found in 80 French, 50 Turkish, or 80 Arab or Iranian controls. Lymphoblasts from the Turkish and the Iranian patients showed markedly decreased STXBP2 protein expression. In the Turkish patient, his homozygous brother who remained asymptomatic at 2.6 years of age, and the Iranian patient, cultured NK cells exhibited impaired cytotoxic granule exocytosis; the defect was overcome by ectopic expression of wildtype STXBP2. The 3 symptomatic probands were diagnosed between 8 years and 12.5 years of age. The Iranian patient died at 20 years of age after HSCT and had a sister who died at age 22 months with a retrospective diagnosis of FHL5.
Pagel et al. (2012) identified the c.1247-1G-C mutation in 12 patients with FHL5; 5 patients were homozygous and 7 were compound heterozygous with another pathogenic STXBP2 variant. Some of the patients had previously been reported. Analysis of patient cells identified a predominant abnormal transcript, predicted to result in premature termination (Val417LeufsTer126). In vitro studies indicated that this truncated protein was unable to interact with STX11 (605014). Defective NK-cell degranulation improved after IL2 stimulation and CTL cytotoxicity was normal in those patients tested, suggesting that the exon 15 splice site mutation may have residual function. Pagel et al. (2012) observed that patients carrying the exon 15 mutation on at least 1 allele had slightly later disease onset, a more protracted course, and lack of microvillus inclusion disease (MVID) compared to patients without an exon 15 splice site mutation.
In a German patient with onset of familial hemophagocytic lymphohistiocytosis-5 without microvillus inclusion disease (FHL5; 613101) at 28 months of age, zur Stadt et al. (2009) identified compound heterozygosity for a splice site mutation (601717.0003) and a 626T-C transition in exon 8 of the STXBP2 gene, resulting in a leu209-to-pro (L209P) substitution. Analysis of CD107 degranulation in this patient revealed that activity of NK and cytotoxic T cells was markedly reduced or absent. The patient had central nervous system involvement and recurrent reactivations with spontaneous remissions or response to steroids.
In a German patient with onset of familial hemophagocytic lymphohistiocytosis-5 without microvillus inclusion disease (FHL5; 613101) at 15 months of age, zur Stadt et al. (2009) identified compound heterozygosity for a splice site mutation (601717.0003) and a 1-bp deletion (260delT) in exon 5 of the STXBP2 gene, resulting in a frameshift and premature termination of the protein. The patient underwent matched unrelated donor hematopoietic stem cell transplantation at 7 years of age but later died.
In a Czech patient with onset of familial hemophagocytic lymphohistiocytosis-5 without microvillus inclusion disease (FHL5; 613101) at 15 months of age, who underwent mismatched unrelated donor hematopoietic stem cell transplantation at 28 months of age and had no active disease at last follow-up, zur Stadt et al. (2009) identified compound heterozygosity for a splice site mutation (601717.0003) and a 1-bp deletion (706delG) in exon 9 of the STXBP2 gene, resulting in a frameshift and premature termination of the protein.
In a Caucasian girl from the United Kingdom with familial hemophagocytic lymphohistiocytosis-5 without microvillus inclusion disease (FHL5; 613101), Cetica et al. (2010) identified homozygosity for a 1621G-A transition in exon 18 of the STXBP2 gene, resulting in a gly541-to-ser (G541S) substitution at a highly conserved residue. The mutation was not found in 120 healthy Caucasian controls. Biochemical analysis revealed that G541S mutant disrupts association of STXBP2 with STX11 (605014). Granule release assay using the patient's lymphocytes showed minimal release in NK cells and completely absent release in CD3(+)CD8 cells; cytotoxic T-cell lymphocytes from the patient showed a reduced but not absent cell-killing capacity. She was still alive at 2.75 years of age after undergoing matched unrelated donor HSCT.
In 3 unrelated children (A_376, A_032, and A_474) of European descent with FHL5, Pagel et al. (2012) identified compound heterozygous mutations in the STXBP2 gene. All 3 carried G541S on 1 allele and a putatively pathogenic variant on the other allele (a splice site mutation in exon 2, I104F, and L534P, respectively). Functional studies of the latter variants were not performed. The patients had onset of the disease in the first months of life; 1 died at age 7 months. One patient had chronic diarrhea due to enteropathy, and the other 2 had sensorineural hearing loss.
Pagel et al. (2012) also reported a 19-year-old German girl (A_711) with later onset of FHL5 who was compound heterozygous for G541S and a splicing defect affecting exon 15 (c.1356+1G-A). Functional studies of the splice site mutation were not performed. The patient was diagnosed at age 13 years and underwent HSCT at age 17. She did not have enteropathy.
In a female infant, born of consanguineous Pakistani parents (family 4) with familial hemophagocytic lymphohistiocytosis-5 with microvillus inclusion disease (FHL5; 613101), Stepensky et al. (2013) identified a homozygous c.1214G-A transition (c.1214G-A, NM_006949.2) in the STXBP2 gene, resulting in an arg405-to-gln (R405Q) substitution. Functional studies of the variant and studies of patient cells were not performed. The patient had chronic diarrhea and failure to thrive in addition to cardinal features of the disease, and underwent bone marrow transplant at 12 months of age.
In a boy (patient 3) with familial hemophagocytic lymphohistiocytosis-5 with microvillus inclusion disease (FHL5; 613101), Vogel et al. (2017) identified a homozygous G-to-A transition (c.902+5G-A), predicted to result in a splicing defect. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
In 2 brothers (patients 4 and 5), born of consanguineous Pakistani parents, with familial hemophagocytic lymphohistiocytosis-5 with microvillus inclusion disease (FHL5; 613101), Vogel et al. (2017) identified a homozygous 1-bp deletion (c.1146delC) in the STXBP2 gene, resulting in a frameshift and premature termination (Lys383ArgfsTer4). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed, but it was predicted to result in a loss of function.
Beutel, K., Gross-Wieltsch, U., Wiesel, T., Stadt, U. Z., Janka, G., Wagner, H. J. Infection of T lymphocytes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children of non-Asian origin. Pediat. Blood Cancer 53: 184-190, 2009. [PubMed: 19353621] [Full Text: https://doi.org/10.1002/pbc.22037]
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zur Stadt, U., Rohr, J., Seifert, W., Koch, F., Grieve, S., Pagel, J., Strauss, J., Kasper, B., Nurnberg, G., Becker, C., Maul-Pavicic, A., Beutel, K., Janka, G., Griffiths, G., Ehl, S., Hennies, H. C. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am. J. Hum. Genet. 85: 482-492, 2009. [PubMed: 19804848] [Full Text: https://doi.org/10.1016/j.ajhg.2009.09.005]