HGNC Approved Gene Symbol: STX1B
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38) : 16:30,989,256-31,010,638 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Generalized epilepsy with febrile seizures plus, type 9 | 616172 | Autosomal dominant | 3 |
Syntaxins are cellular receptors for transport vesicles (see 603765). One of these proteins, designated syntaxin 1B (STX1B), is directly implicated in the process of calcium-dependent synaptic transmission in rat brain (Smirnova et al., 1993). The expression of this protein is transiently induced by long-term potentiation of synaptic responses in the rat hippocampus. The protein may play an important role in the excitatory pathway of synaptic transmission, which is known to be implicated in several neurologic diseases.
Vardar et al. (2020) noted that human STX1B contains an N-terminal H(abc) domain formed by 3 helices, H(a), H(b), and H(c), followed by the SNARE domain and a transmembrane region.
Smirnova et al. (1996) mapped the human STX1B gene to 16p11.2 by fluorescence in situ hybridization. The gene was found at a single locus. Chromosome rearrangements with breaks in 16p11 are observed in myxoid liposarcoma and in acute myeloid leukemia.
Smirnova et al. (1996) noted that a tumor that displays neuroendocrine properties, small cell lung cancer (182280), has been observed in about 60% of patients with Lambert-Eaton myasthenic syndrome, an autoimmune disease of neurotransmission that is characterized by muscle weakness (Vincent et al., 1989). Autoantibodies from these patients recognize the presynaptic N-type calcium channel and synaptotagmin (185605), 2 proteins that are involved in synaptic transmission and interact with syntaxin.
In affected members of the families with generalized epilepsy with febrile seizures plus-9 (GEFSP9; 616172) reported by Lerche et al. (2001) and Weber et al. (2008), Schubert et al. (2014) identified different heterozygous truncating mutations in the STX1B gene (601485.0001 and 601485.0002, respectively). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Sequencing of this gene in 3 additional cohorts of patients with seizures identified a mutation in 1 of 299 probands with febrile seizures or epileptic encephalopathies; in 1 of 81 adults with various forms of epilepsy and intellectual disability; and in 1 of 68 patients with epileptic encephalopathies. Schubert et al. (2014) noted the wide phenotypic spectrum of epilepsy associated with STX1B mutations, ranging from incomplete penetrance without symptoms to simple febrile seizures to severe epileptic encephalopathies. The findings implicated the STX1B gene and the presynaptic release machinery in fever-associated epilepsy syndromes.
Functional Studies of STX1B Mutations
By rescue analysis in Stx1-/- mouse hippocampal neurons, Vardar et al. (2020) showed that the STX1B indel mutation (601485.0002) compromised general STX1B function in neuronal survival, whereas the STX1B gly226-to-arg (G226R; 601485.0005) and val216-to-glu (V216E; 601485.0004) did not. The indel mutation, which is within the first helix of the H(abc) domain, interfered with proper STX1B folding and destabilized the protein, although the mutant protein was able to form functional SNARE complexes. The G226R and V216E mutants could also form stable SNARE complexes, but they showed altered interaction with Munc18-1 (602926), which differentially affected their neurotransmission. Synaptic transmission was unaltered in Stx1b +/- mouse neurons exogenously expressing any of the 3 mutants.
Schubert et al. (2014) found that morpholino knockout of the stx1b gene in zebrafish resulted in abnormal episodic behavior, including repetitive fin fluttering, increased orofacial movements, and myoclonus-like jerks, as well as abnormal spontaneous epileptiform brain activity with polyspiking discharges and high-frequency oscillations. Elevation of temperature increased the occurrence of epileptiform events, specifically high-frequency oscillations.
In affected members of a large 5-generation German family with generalized epilepsy with febrile seizures plus-9 (GEFSP9; 616172), originally reported by Lerche et al. (2001), Schubert et al. (2014) identified a heterozygous c.166C-T transition in the STX1B gene, resulting in a gln56-to-ter (Q56X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases, or in 188 German controls. One unaffected family member also carried the mutation, consistent with incomplete penetrance.
In affected members of a large 4-generation German family with GEFSP9 (616172), originally reported by Weber et al. (2008), Schubert et al. (2014) identified a heterozygous complex insertion/deletion mutation in the STX1B gene (c.133_134insGGATGTGCATTG, resulting in Lys45delinsArgMetCysIleGlu, and c.135_136AC-GA, resulting in a leu46-to-met (L46M) substitution). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases, or in 188 German controls. Two unaffected family members carried the mutation, consistent with incomplete penetrance.
In a Dutch patient with GEFSP9 (616172), Schubert et al. (2014) identified a heterozygous c.140C-A transversion in the STX1B gene, resulting in a ser47-to-ter (S47X) substitution. The mutation was not present in the patient's unaffected father, but maternal DNA was not available. The patient was ascertained from a cohort of 299 unrelated probands with epilepsies who were tested for STX1B mutations.
In an adult Swiss patient with GEFSP9 (616172), Schubert et al. (2014) identified a heterozygous c.657T-A transversion in the STX1B gene, resulting in a val216-to-glu (V216E) substitution at a highly conserved residue in the SNARE motif. Parental DNA was not available. The patient was ascertained from a cohort of 81 adults with various forms of epilepsy and intellectual disability. The V216E variant was unable to rescue the seizure phenotype of zebrafish with morpholino knockdown of stx1b, indicating that the mutation results in a loss of function. The patient had onset of seizures at age 3.5 years, and showed speech delay, moderate intellectual disability, ataxia, and cerebellar atrophy.
In a German patient with a severe form of GEFSP9 (616172) manifest as myoclonic-astatic epilepsy, Schubert et al. (2014) identified a de novo heterozygous c.676G-C transversion in the STX1B gene, resulting in a gly226-to-arg (G226R) substitution at a highly conserved residue in the SNARE motif. The patient was ascertained from a larger cohort of 68 patients with epileptic encephalopathy. Functional studies of the variant were not performed.
Lerche, H., Weber, Y. G., Baier, H., Jurkat-Rott, K., Kraus de Camargo, O., Ludolph, A. C., Bode, H., Lehmann-Horn, F. Generalized epilepsy with febrile seizures plus: further heterogeneity in a large family. Neurology 57: 1191-1198, 2001. [PubMed: 11591834] [Full Text: https://doi.org/10.1212/wnl.57.7.1191]
Schubert, J., Siekierska, A., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., de Kovel, C. G. F., Thiele, H., Konrad, K., and 36 others. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nature Genet. 46: 1327-1332, 2014. [PubMed: 25362483] [Full Text: https://doi.org/10.1038/ng.3130]
Smirnova, T., Miniou, P., Viegas-Pequignot, E., Mallet, J. Assignment of the human syntaxin 1B gene (STX) to chromosome 16p11.2 by fluorescence in situ hybridization. Genomics 36: 551-553, 1996. [PubMed: 8884284] [Full Text: https://doi.org/10.1006/geno.1996.0506]
Smirnova, T., Stinnakre, J., Mallet, J. Characterization of a presynaptic glutamate receptor. Science 262: 430-433, 1993. [PubMed: 8105537] [Full Text: https://doi.org/10.1126/science.8105537]
Vardar, G., Gerth, F., Schmitt, X. J., Rautenstrauch, P., Trimbuch, T., Schubert, J., Lerche, H., Rosenmund, C., Freund, C. Epilepsy-causing STX1B mutations translate altered protein functions into distinct phenotypes in mouse neurons. Brain 143: 2119-2138, 2020. [PubMed: 32572454] [Full Text: https://doi.org/10.1093/brain/awaa151]
Vincent, A., Lang, B., Newsom-Davis, J. Autoimmunity to the voltage-gated calcium channel underlies the Lambert-Eaton myasthenic syndrome, a paraneoplastic disorder. Trends Neurosci. 12: 496-502, 1989. [PubMed: 2480664] [Full Text: https://doi.org/10.1016/0166-2236(89)90109-4]
Weber, Y. G., Jacob, M., Weber, G., Lerche, H. A BFIS-like syndrome with late onset and febrile seizures: suggestive linkage to chromosome 16p11.2-16q12.1. Epilepsia 49: 1959-1964, 2008. [PubMed: 18479394] [Full Text: https://doi.org/10.1111/j.1528-1167.2008.01646.x]