Alt. symbols: UNC18B | Hunc18b

Approved name: syntaxin binding protein 2
Alt. names: syntaxinbinding protein 2 | protein unc18 homolog B | unc18B

Location: 19p13.2: 7636772 - 7647873 (+)
Gene type: protein_coding, 23 transcripts.

Scores: LoFtool: 0.607000 | pLI: 0.00007763 | LOEUF: 0.842

HGNC: 11445

NCBI: 6813, RefSeq: NG_016709.1

Ensembl: ENSG00000076944.18

LRG_165 | Status: public

OMIM: 601717

Expression | ProteinAtlas

STXBP2 encodes the syntaxin binding protein 2, which, together with Syntaxin 11, plays a role in the docking and fusion of granules with the plasma membrane during the cytotoxicity procedure mediated by natural killer (NK) cells and CD8+ T cells, known as cytotoxic lymphocytes (CTLs). Membrane fusion of the lytic vesicles is mediated by binding of STXBP2 to Syntaxin 11 and to the exocytic SNARE complex. STXBP2 is localized predominantly on secretory lysosomes of CTLs, although lower levels are observed also on the plasma membrane. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

STXBP2 mutations have been shown to cause defective NK cell function and lead to massive tissue infiltration by activated lymphocytes and macrophages. Biallelic missense, nonsense, frameshift, in-frame deletions, and splice site mutations in STXBP2 are associated with autosomal recessive familial hemophagocytic lymphohistiocytosis (fHLH) type 5 or FHL5 [MIM: 613101]. Heterozygous STXBP2 variants have also been implicated in cases of digenic pathogenesis together with heterozygous variants in oth er genes involved in cytotoxic lymphocyte degranulation, such as RAB27A, PRF1, MUNC13-4, or LYST (PMID: 24916509, 30782130). Parentally inherited compound heterozygous mutations in STXBP2 (p.C158Wfs*78 and p.P334L) were reported in one individual with a diagnosis of CVID, very low B cells and history of severe EBV infection but without a clinical picture notable for macrophage activation syndrome or HLH (PMID: 27379089). Overlapping symptoms with CVID such as hypogammaglobulinemia have been increasingly described in patients with FHL5, especially those harboring exon 15 splice-site mutations. Of note, Meeths et al. (2010) reported 11 patients with FHL5 amongst whom ~1/3 showed clinical findings such as colitis, bleeding disorders, and hypogammaglobulinemia (PMID: 20558610). Similarly, Rohr et al. (2010) identified 4 of 6 patients with STXBP2 mutations and hypogammaglobulinemia who developed atypical HLH subsequent to features of immunodeficiency (PMID: 20823128). A subset of these patients showed quantitative B cell defects including reduced memory B cells. Pagel et al. (2012) extended these observations by adding sensorineural hearing loss as a recurrent clinical feature and reported an additional 7 patients with FHL5 and chronic hypogammaglobulinemia requiring immunoglobulin replacement therapy. They noted that, in addition to a tendency towards antibody deficiency, patients with exon 15 splice-site mutations tended to develop clinical manifestations significantly later than patients with other mutations, were less likely to develop early onset diarrhea, and showed less severe impairment of degranulation and cytotoxic function of NK and cytotoxic T cells. Esmaeilzadeh et al. (2015) reported yet another case – a patient homozygous for the exon 15 splice site mutation presenting with autoimmune hepatitis, neurological involvement and recurrent infections associated with hypogammaglobulinemia (PMID: 25491289). In keeping with the late-onset disease associated with STXBP2, Wang et al. (2017) reported a previously healthy 19 year old female who presented with CMV enteritis and hypogammaglobulinemia and was found to have a heterozygous STXBP2 mutation (with additional functional studies pending) in JACI Feb 2017 Abstract 334 (https://doi.org/10.1016/j.jaci.2016.12.344). Minson et al. (2021) identified homozygous STXBP2 mutations in a previously healthy 45-year-old Ashkenazi Jewish woman who initially presented with an insidious course concerning for T cell malignancy and then developed florid HLH upon G-CSF treatment – it remains unclear if her lack of known hypogammaglobulinemia prior to this acute exacerbation was because levels were normal or because there had been no reason to check (PMID: 34336208). [Load More]