Alternative titles; symbols
HGNC Approved Gene Symbol: STXBP1
SNOMEDCT: 768666006;
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:127,611,912-127,696,029 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Developmental and epileptic encephalopathy 4 | 612164 | Autosomal dominant; Autosomal recessive | 3 |
Within the secretory pathway, proteins and other cargo are transferred from one compartment to another by vesicular traffic. Transport vesicles bud from donor membranes and dock to specific acceptor compartments. The S. cerevisiae protein Sec1 participates in the constitutive secretory pathway between the Golgi apparatus and the plasma membrane. Pevsner et al. (1994) identified rat Stxbp1, which they called n-Sec1. The predicted 68-kD n-Sec1 protein shares 27% identity with S. cerevisiae Sec1 and 59% identity with C. elegans Unc18. RNA blot analysis showed that n-Sec1 mRNA expression was neural-specific.
Since Unc18 mutation leads to severe paralysis and presynaptic acetylcholine accumulation, Unc18 has been implicated in neurotransmitter release. Gengyo-Ando et al. (1996) identified cDNAs encoding 2 mouse Unc18 homologs, a neural-specific protein called Munc18-1 and a ubiquitous protein called Munc18-3. They used the murine cDNAs to isolate human Munc18-1 cDNAs from a fetal brain cDNA library. The sequences of the predicted 594-amino acid mouse and human Munc18-1 proteins are identical. Gengyo-Ando et al. (1996) found that Munc18-1 complemented the locomotion and cholinergic defects in Unc18 mutant animals.
By Northern blot analysis of human tissues, Swanson et al. (1998) determined that STXBP1 is expressed as a 4-kb transcript in various tissues. The highest levels of expression were observed in retina and cerebellum. RT-PCR analysis revealed an additional, alternatively spliced form of STXBP1 in retina and cerebellum. This mRNA contains an additional exon and encodes a predicted 603-amino acid protein. Two alternatively spliced forms of STXBP1 are also found in rat, and the predicted proteins are identical to their human counterparts.
Hamdan et al. (2009) stated that the STXBP1 gene contains 20 exons and that alternative splicing results in 2 isoforms with and without exon 19.
By fluorescence in situ hybridization, Swanson et al. (1998) mapped the STXBP1 gene to chromosome 9q34.1.
Pevsner et al. (1994) found that rat n-Sec1 is a neural-specific, syntaxin (see 186590)-binding protein that may participate in the regulation of synaptic vesicle docking and fusion.
Yang et al. (2000) identified high titer autoantibodies against Munc18 in the serum and CSF of a single patient with Rasmussen encephalitis, a rare disorder characterized by progressive degeneration of a single cerebral hemisphere and intractable seizures. The patient had previously been reported by Rogers et al. (1994) who identified autoantibodies against GLUR3 (GRIA3; 305915) in serum and CSF. Weak immunoreactivity to Munc18 was found in 3 of 14 additional patients with Rasmussen encephalitis, but often only on prolonged exposure or multiple experiments. As Munc18 is a cytosolic protein, Yang et al. (2000) hypothesized that humoral attack on GluR3 would first damage neurons, thus exposing Munc18 and leading to expanded immune attack. Both proteins are involved in synaptic transmission; immune attack on these proteins may have acted synergistically to produce a severe neurologic phenotype.
In adrenal chromaffin cells, Fisher et al. (2001) expressed a Munc18 mutant with reduced affinity for syntaxin, which specifically modified the kinetics of single-granule exocytotic release events, consistent with an acceleration of fusion pore expansion. This observation demonstrated that Munc18 functions in a late stage in the intracellular membrane fusion process, where its dissociation from syntaxin determines the kinetics of postfusion events.
In a study of synaptic vesicle exocytosis in C. elegans unc18 mutants, Weimer et al. (2003) found a reduction in docked vesicles at the plasma membrane active zone, suggesting that unc18 functions, either directly or indirectly, as a facilitator of vesicle docking.
Toonen et al. (2006) found that synapses from Munc18-1 +/- mice displayed increased depression during intense stimulation at glutamatergic, GABAergic, and neuromuscular synapses. This depression was due to a smaller readily releasable pool (RRP) of synaptic vesicles. Conversely, overexpression of Munc18-1 made these synapses recover faster, which was due to a larger RRP and enhanced activity-dependent RRP replenishment.
SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins comprise the core fusion machinery in which cognate vesicle-associated (v-) and target membrane-associated (t-) SNAREs assemble into SNAREpins to bring 2 membranes into close apposition and fuse. Using a reconstituted lipid bilayer system with mammalian SNARE components, Shen et al. (2007) showed that rat Munc18-1 accelerated the fusion reaction through direct contact with both t- and v-SNAREs.
During synaptic vesicle fusion, the SNARE protein syntaxin-1 (186590) exhibits 2 conformations that both bind to Munc18-1: a 'closed' conformation outside the SNARE complex and an 'open' conformation in the SNARE complex. Gerber et al. (2008) generated knockin/knockout mice that expressed only open syntaxin-1B. Syntaxin-1B(Open) mice were viable but succumbed to generalized seizures at 2 to 3 months of age. Binding of Munc18-1 to syntaxin-1B was impaired in syntaxin-1B(Open) synapses, and the size of the readily releasable vesicle pool was decreased; however, the rate of synaptic vesicle fusion was dramatically enhanced. Thus, Gerber et al. (2008) concluded that the closed conformation of syntaxin-1 gates the initiation of the synaptic vesicle fusion reaction, which is then mediated by SNARE complex/Munc18-1 assemblies.
Wierda et al. (2007) stated that MUNC18-1 is essential for presynaptic vesicle release and is rapidly phosphorylated by protein kinase C (PKC: 176960) upon depolarization. They found that diacylglycerol (DAG)- and phorbol ester-induced potentiation of excitatory postsynaptic currents in mouse neurons depended on both direct activation of Munc13 (UNC13B; 605836) and PKC-mediated phosphorylation of Munc18-1. Wierda et al. (2007) hypothesized that the 2 pathways may operate separately during different steps in the synaptic vesicle cycle or may converge and cooperate at a single step in the cycle.
Ma et al. (2013) found that Munc18-1 could displace SNAP25 (600322) from syntaxin-1 and that fusion of syntaxin-1-Munc18-1 liposomes with synaptobrevin (see 185880) liposomes required Munc13, in addition to SNAP25 and synaptotagmin-1 (185605)-Ca(2+). Moreover, when starting with syntaxin-1-SNAP25 liposomes, NSF (N-ethylmaleimide-sensitive factor)-alpha-SNAP disassembled the syntaxin-1-SNAP25 heterodimers and abrogated fusion, which then required Munc18-1 and Munc13. Ma et al. (2013) proposed that fusion does not proceed through syntaxin-1-SNAP25 heterodimers but starts with the syntaxin-1-Munc18-1 complex; Munc18-1 and Munc13 then orchestrate membrane fusion together with the SNAREs and synaptotagmin-1-Ca(2+) in an NSF- and SNAP-resistant manner.
In 4 unrelated Japanese patients with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified heterozygous missense mutations in the STXBP1 gene (602926.0001-602926.0004). The mutations were proven to occur de novo in 3 patients. All mutations occurred in the hydrophobic core of the protein and were predicted to result in destabilization and disruption of protein structure. In vitro studies of the mutant proteins suggested a tendency for aggregation. The phenotype included early-onset seizures, suppression-burst pattern on EEG, and profoundly impaired intellectual development. Saitsu et al. (2008) postulated that the mutations resulted in STXBP1 haploinsufficiency, causing impaired synaptic vesicle release and the DEE phenotype.
In 2 unrelated French Canadian patients with severe mental retardation and epilepsy, Hamdan et al. (2009) identified respective de novo heterozygous truncating mutations in the STXBP1 gene (602926.0005 and 602926.0006). The patients were ascertained from a larger group of 95 patients with idiopathic mental retardation.
In an 11-year-old boy with DEE4, who had a clinical diagnosis of Dravet syndrome, Carvill et al. (2014) identified a de novo heterozygous missense mutation in the STXBP1 gene (E283K; 602926.0008). The mutation was found by whole-exome sequencing. Targeted resequencing of 67 patients with a similar disorder identified 2 additional probands with de novo heterozygous missense mutations in the STXBP1 gene. Functional studies of the variants were not performed.
Kovacevic et al. (2018) found that expression of human STXBP1 with DEE4-causing mutations in Stxbp1 +/- mouse neurons produced normal phenotypes, whereas expression of the same mutants in Stxbp1 -/- mouse neurons produced diverse phenotypes consistent with haploinsufficiency. Further analysis showed that the STXBP1 mutants exhibited severely reduced cellular stability, especially when expressed in HEK293 cells, but also when expressed in primary mouse neurons.
In 2 sibs with DEE4, Lammertse et al. (2020) identified a homozygous missense mutation in the STXBP1 gene (L446F; 602926.0009). The patients' mother and asymptomatic sib were heterozygous for the mutation; the father was not available for study. Expression of STXBP1 with the L446F mutation in STXBP1-null mouse neurons resulted in shorter dendrites and fewer synapses per dendrite compared to cells expressing wildtype STXBP1. Patch-clamp studies in the mutant cells demonstrated an increased evoked synaptic transmission and impaired recovery after high-frequency stimulation. This appeared to be due to an increased synaptic vesicle response after stimulation with a single action potential. Lammertse et al. (2020) concluded that the L446F mutation leads to a gain-of-function pathogenic mechanism.
In a review of clinical and molecular data from 271 patients with DEE4, Xian et al. (2022) identified 54 recurrent mutations in the STXBP1 gene. Sixteen of the mutations were identified in 5 or more patients, with the most common mutations being R406H (in 20 patients), R406C (in 20 patients), and R292H (in 18 patients). Compared to the entire cohort of patients, those with recurrent mutations did not show an overall phenotypic similarity. However, patients with R406H and R406C mutations were more likely to have a burst suppression pattern on EEG and spastic tetraplegia, and less likely to have ataxia, compared to the rest of the cohort. Additionally, patients with premature termination mutations or deletions in the STXBP1 gene were more likely to have infantile spasms, hypsarrhythmia on EEG, ataxia, hypotonia, and neonatal seizure onset compared to patients with missense mutations.
Verhage et al. (2000) abolished Munc18-1 in mice by homologous recombination. This resulted in a completely paralyzed organism. Null mutant embryos were alive until birth but died immediately after birth, probably because they could not breathe. Despite the general, complete, and permanent loss of synaptic transmission in knockout mice, their brains were assembled correctly. Neuronal proliferation, migration, and differentiation into specific brain areas were unaffected. By embryonic day 12, brains from null mutant and control littermates were morphologically indistinguishable. At birth, late-forming brain areas such as the neocortex appeared identical in null mutant and control littermates. After initial brain assembly, extensive cell death of mature neurons was observed in null mutants, occurring first in lower brain areas that mature and form synapses relatively early. The degeneration in the mutant brains exhibited all characteristics of apoptosis. Ablation of Munc18-1 renders the brain synaptically silent, identifying Munc18-1 as the currently most upstream essential protein in neurotransmitter release. Verhage et al. (2000) concluded that synaptic connectivity does not depend on neurotransmitter secretion, but its maintenance does. Neurotransmitter secretion probably functions to validate already established synaptic connections.
Kovacevic et al. (2018) found that Stxbp1 +/- mice of different genomic backgrounds recapitulated the human DEE4 phenotype, with epileptic spasms, often during inactivity, accompanied by slow-wave discharges that could be suppressed partially by the antiepileptic drug levetiracetam. Stxbp1 +/- mice also showed impaired behavioral flexibility, increased anxiety, and hyperactivity.
In a Japanese man (patient 3) with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified a heterozygous c.1631G-A transition in the STXBP1 gene, resulting in a gly544-to-asp (G544D) substitution. The patient developed seizures by age 10 days with a suppression-burst pattern on EEG, although the seizures remitted by 3 months of age. At age 37 years, he had profoundly impaired intellectual development and spastic paraplegia. The mutation was not found in 500 control chromosomes.
In a Japanese boy (patient 6) with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified a de novo heterozygous c.539G-A transition in the STXBP1 gene, resulting in a cys180-to-tyr (C180Y) substitution. He had infantile onset of tonic and myoclonic seizures with suppression-burst pattern and hypsarrhythmia, delayed brain myelination, and spastic quadriplegia. In vitro studies showed that the mutant protein had impaired structural stability, lower thermostability, and decreased binding to several functional synaptic proteins. Saitsu et al. (2008) concluded that this patient had impaired release of synaptic vesicles.
In a Japanese girl (patient 7) with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified a de novo heterozygous c.1328T-G transversion in the STXBP1 gene, resulting in a met443-to-arg (M443R) substitution. She developed intractable seizures at 2 months of age, and later showed profoundly impaired psychomotor development. Brain MRI showed delayed myelination.
In a Japanese boy (patient 11) with developmental and epileptic encephalopathy-4 (DEE4; 612164), Saitsu et al. (2008) identified a de novo heterozygous c.251T-A transversion in the STXBP1 gene, resulting in a val84-to-asp (V84D) substitution. The patient developed tonic seizures at age 2 months with suppression-burst pattern and hypsarrhythmia, and later showed profound mental retardation.
In a 15-year-old French Canadian boy with developmental and epileptic encephalopathy (DEE4; 612164), Hamdan et al. (2009) identified a de novo heterozygous c.1162C-T transition in exon 14 of the STXBP1 gene, resulting in an arg388-to-ter (R388X) substitution, predicted to truncate the domain-3 region, which together with domain-1 provides a binding surface for syntaxin-1 (186590). The patient had severe mental retardation, with hypotonia, abnormal gait, tremor, and seizures. Onset of seizures occurred at age 2 years, 9 months.
In a 27-year-old French Canadian man with developmental and epileptic encephalopathy (DEE4; 612164), Hamdan et al. (2009) identified a de novo heterozygous G-to-A transition in intron 3 of the STXBP1 gene, resulting in the creation of a stop codon downstream of exon 3. The mutation truncated the domain-1 region, which is implicated in binding to syntaxin-1. The patient had severe mental retardation, with hypotonia, abnormal gait, tremor, and seizures. Onset of seizures occurred at age 6 weeks.
This variant is classified as a variant of unknown significance because its contribution to nonsyndromic mental retardation has not been confirmed.
By targeted sequencing of the STXBP1 gene in 50 patients with nonsyndromic mental retardation, Hamdan et al. (2011) identified 1 patient of French Canadian origin with a de novo heterozygous 1-bp deletion (1206delT) in domain 3 of the gene, resulting in a frameshift and premature termination (Y402X). The variation was not found in 190 French Canadian controls. The patient was a 21-year-old man who showed global developmental delay and severe mental retardation with limited speech. He had no history of seizures, but did have diffuse tremor of the extremities and an abnormal gait. EEG showed intermittent slow dysfunction in the temporal area; brain CT was normal. Hamdan et al. (2011) suggested that this variant may be pathogenic because truncation of the C. elegans ortholog downstream of Y402 results in defects in synaptic vesicle docking (Weimer et al., 2003) and Stxbp1 haploinsufficiency causes impaired neurotransmission in mice (Toonen et al., 2006).
In an 11-year-old boy (T1915) with developmental and epileptic encephalopathy (DEE4; 612164), who was clinically diagnosed with Dravet syndrome, Carvill et al. (2014) identified a de novo heterozygous c.847G-A transition in the STXBP1 gene, resulting in a glu283-to-lys (E283K) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database. Functional studies of the variant were not performed.
In 2 sibs with autosomal recessive developmental and epileptic encephalopathy (DEE4; 612164), Lammertse et al. (2020) identified homozygosity for a c.1336C-T transition in exon 15 of the STXBP1 gene, resulting in a leu446-to-phe (L446F) substitution at a conserved residue. The mutation was identified by whole-exome sequencing. The patients' mother and an asymptomatic sib were mutation carriers; the father was not available for study. Expression of STXBP1 with the L446F mutation in STXBP1-null mouse neurons resulted in shorter dendrites and fewer synapses per dendrite compared to cells expressing wildtype STXBP1.
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Lammertse, H. C. A., van Berkel, A. A., Iacomino, M., Toonen, R. F., Striano, P., Gambardella, A., Verhage, M., Zara, F. Homozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission. Brain 143: 441-451, 2020. [PubMed: 31855252] [Full Text: https://doi.org/10.1093/brain/awz391]
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