Alternative titles; symbols
HGNC Approved Gene Symbol: VAMP1
SNOMEDCT: 784380009;
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,462,237-6,470,677 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | Myasthenic syndrome, congenital, 25 | 618323 | Autosomal recessive | 3 |
| Spastic ataxia 1, autosomal dominant | 108600 | Autosomal dominant | 3 |
The VAMP1 gene encodes vesicle-associated membrane protein-1, also known as synaptobrevin-1, a small integral membrane protein involved in the synaptic vesicle cycle, particularly exocytosis, at the presynaptic nerve terminal. Neuronal VAMPs are anchored in the vesicle membrane by their C-terminal domain (summary by Bourassa et al., 2012).
See also synaptobrevin-2 (VAMP2; 185881).
Archer et al. (1990) isolated and characterized cosmid clones containing the human genes encoding synaptobrevins 1 and 2. Their coding regions are highly homologous, being interrupted at identical positions by introns of different size and sequence. The deduced 118-amino acid synaptobrevin-1 protein contains a cytoplasmic N-terminal domain rich in prolines and glycines, followed by a highly conserved hydrophilic region, a transmembrane domain, and a C-terminal intravesicular domain.
By screening a human umbilical vein endothelial cell (HUVEC) cDNA library, Isenmann et al. (1998) cloned a VAMP1 splice variant, VAMP1B, that contains an alternative exon 5 compared with the previously described variant, VAMP1A. In contrast with VAMP1A, which has only a single C-terminal intravesicular threonine following the transmembrane domain, the deduced 116-amino acid VAMP1B isoform has a shortened transmembrane domain followed by 3 charged C-terminal residues. PCR analysis detected VAMP1B expression in various human cell lines, but not in human brain. In contrast, VAMP1A was detected in brain, but not in the cell lines. Immunofluorescence analysis revealed epitope-tagged VAMP1A at the plasma membrane and in endosomes of transfected HUVECs, whereas VAMP1B colocalized with mitochondrial markers and was not detected at the plasma membrane or in association with vesicles. The shortened transmembrane domain and C-terminal charged residues of VAMP1B were required for its targeting to mitochondria.
Berglund et al. (1999) identified 4 additional splice variants of VAMP1, which they designated VAMP1C through VAMP1F, that differ in their exon-5 sequences. VAMP1C, VAMP1D, and VAMP1E encode proteins with unique short C-terminal sequences following the transmembrane region, whereas VAMP1F has a C-terminal intravesicular extension of 98 residues. RT-PCR analysis detected variable expression of VAMP1A, VAMP1B, VAMP1C, and VAMP1D in all tissues and cell types examined (brain, kidney, eosinophils, neutrophils, and peripheral blood mononuclear cells). In contrast, VAMP1E was found only in kidney and peripheral blood mononuclear cells, and VAMP1F was found only in peripheral blood mononuclear cells.
Bourassa et al., 2012 stated that the VAMP1 gene has 3 annotated isoforms: VAMP1A, VAMP1B, and VAMP1D, that differ only in their last exon. VAMP1A is expressed mostly in the nervous system; VAMP1B has a broad tissue expression, although not in human brain; and VAMP1D is not expressed in brain.
Shen et al. (2017) found expression of the VAMP1 isoforms 1A and 1D, but not isoform C, in the anterior gray column of human spinal cord as well as in skeletal muscle, suggesting that these isoforms are expressed at the motor nerve terminal.
The genes encoding synaptobrevins 1 and 2 have 5 exons whose boundaries correspond to those of the protein domains (Archer et al., 1990). Exon 1 contains part of the initiator methionine codon, whereas exon 2 encodes the variable and immunogenic N-terminal domain. The third exon comprises the highly conserved central domain, exon 4 encodes most of the transmembrane region, and exon 5 contains the last residues of the transmembrane region and the small intravesicular C terminus.
Berglund et al. (1999) found that the genomic region 3-prime to VAMP1 exon 4 is subject to complex splicing, resulting in 6 unique exon-5 sequences that give rise to 6 VAMP1 splice variants.
By Southern analysis of rodent-human somatic cell hybrids, Archer et al. (1990) assigned the SYB1 gene to chromosome 12p; by analysis of DNA from Chinese hamster-mouse somatic cell hybrids, they mapped the Syb1 gene to mouse chromosome 6.
Gross (2014) mapped the VAMP1 gene to chromosome 12p13.31 based on an alignment of the VAMP1 sequence (GenBank BC023286) with the genomic sequence (GRCh38).
Neuronal exocytosis is triggered by calcium and requires 3 SNARE proteins: synaptobrevin on the synaptic vesicle, and syntaxin (e.g., 186590) and SNAP25 (600322) on the plasma membrane. Neuronal SNARE proteins form a parallel 4-helix bundle that is thought to drive the fusion of opposing membranes. Hu et al. (2002) demonstrated that whereas syntaxin and SNAP25 in target membranes are freely available for SNARE complex formation, availability of synaptobrevin on synaptic vesicles is very limited. Calcium at micromolar concentrations triggers SNARE complex formation and fusion between synaptic vesicles and reconstituted target membranes. Although calcium does promote interaction of SNARE proteins between opposing membranes, it does not act by releasing synaptobrevin from synaptic vesicle restriction. Hu et al. (2002) concluded that their data suggests a mechanism in which calcium-triggered membrane apposition enables syntaxin and SNAP25 to engage synaptobrevin, leading to membrane fusion.
Tucker et al. (2004) investigated the effect of synaptotagmin 1 (SYT1; 185605) on membrane fusion mediated by neuronal SNARE proteins SNAP25, syntaxin, and synaptobrevin, which were reconstituted into vesicles. In the presence of calcium, the cytoplasmic domain of SYT1 strongly stimulated membrane fusion when synaptobrevin densities were similar to those found in native synaptic vesicles. The calcium dependence of SYT1-stimulated fusion was modulated by changes in lipid composition of the vesicles and by a truncation that mimics cleavage of SNAP25 by botulinum neurotoxin A. Stimulation of fusion was abolished by disrupting the calcium-binding activity, or by severing the tandem C2 domains, of SYT1. Thus, SYT1 and SNAREs are likely to represent the minimal protein complement for calcium-triggered exocytosis.
By use of the large calyx of Held presynaptic terminal from rats, Sakaba et al. (2005) demonstrated that cleavage of different SNARE proteins by clostridial neurotoxins caused distinct kinetic changes in neurotransmitter release. When elevating calcium ion concentration directly at the presynaptic terminal with the use of caged calcium, cleavage of SNAP25 by botulinum toxin A produced a strong reduction in the calcium sensitivity for release, whereas cleavage of syntaxin using botulinum toxin C1 and synaptobrevin using tetanus toxin produced an all or nothing block without changing the kinetics of remaining vesicles. When stimulating release by calcium influx through channels, a difference between botulinum toxin C1 and tetanus toxin emerged, which suggests that cleavage of synaptobrevin modifies the coupling between channels and release-competent vesicles.
Autosomal Dominant Spastic Ataxia 1
In multiple affected members of 4 large multigenerational families from Newfoundland with autosomal dominant spastic ataxia-1 (SPAX1; 108600), as well as in 3 isolated cases from Ontario with a similar disorder, Bourassa et al. (2012) identified a heterozygous mutation in the VAMP1 gene (185880.0001). The mutation, which was found by sequencing genes within the candidate disease locus on chromosome 12p13, segregated with the disorder in the families. Bourassa et al. (2012) concluded that the mutation results in haploinsufficiency of VAMP1 in the brain.
Based on the finding of homozygous loss-of-function VAMP1 mutations in patients with autosomal recessive presynaptic congenital myasthenic syndrome-25 (CMS25; 618323) who inherited the mutations from unaffected heterozygous carriers, Monies et al. (2017) suggested that a dominant-negative effect, rather than haploinsufficiency, may be the mechanism underlying SPAX1.
Presynaptic Congenital Myasthenic Syndrome 25
In a Brazilian girl, born of consanguineous unaffected parents, with presynaptic congenital myasthenic syndrome-25 (CMS25; 618323), Shen et al. (2017) identified a homozygous 1-bp deletion (c.340delA; 185880.0002) in the VAMP1 gene, predicted to result in frameshifts and elongation of the protein: Ile114SerfsTer72 for isoform A, and Ser114ValfsTer34 for isoform D. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Expression of the mutation in HEK293 cells showed that it caused decreased levels of mutant A isoform (15% of normal) and the mutant D isoform (65% of normal). Transfection of the mutant VAMP1 isoforms into chromaffin cells resulted in significantly decreased depolarization-evoked exocytosis of catecholamine-containing vesicles (2 to 12%) compared to controls. These findings were consistent with a loss of function.
In 4 patients from 2 unrelated consanguineous families with CMS25, Salpietro et al. (2017) identified homozygous mutations in the VAMP1 gene (185880.0003 and 185880.0004). The mutations, which were found by whole-exome or whole-genome sequencing, segregated with the disorder in the families.
In 2 unrelated Saudi patients (16W-0091 and 16W-0082) with CMDS25, Monies et al. (2017) identified homozygous mutations in the VAMPS1 gene (185880.0005 and 185880.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families; the unaffected parents were heterozygous carriers of the mutations. Functional studies of the variants and studies of patient cells were not performed, but both were predicted to result in a loss of function. The patients were part of a large cohort of 1,000 Saudi families with suspected Mendelian disorders who underwent whole-exome sequencing.
The 'lethal-wasting' (lew) mouse is a spontaneous autosomal recessive mutant that manifests as a neurologic phenotype characterized by generalized lack of movement, wasting and prewean death by age 15 days. By positional cloning, Nystuen et al. (2007) determined that the lew phenotype results from a 190G-T transversion in the coding region of the Vamp1 gene, predicted to result in truncation of nearly half of the protein. Western blot analysis showed no detectable Vamp1 protein in mutant mice. The authors noted that the phenotype was milder than that of Vamp2 (185881)-null mice, which die at birth. By immunostudies of normal mice, Nystuen et al. (2007) showed that Vamp1 is expressed primarily in certain neuronal tissues, including the retina and areas of the diencephalon and midbrain such as the zona incerta (subthalamus) and rostral periolivary region. The findings suggested that Vamp1 has a vital role in a subset of central nervous system tissues.
Salpietro et al. (2017) found that the neuromuscular synapses in Vamp1-null lew mice were markedly smaller than those in controls. Electrophysiologic studies showed that mutant mice had a severe reduction in endplate potentials and that low-frequency repetitive stimulation (10 Hz) caused synaptic facilitation, suggesting a presynaptic defect.
In multiple affected members of 4 large multigenerational families from Newfoundland with autosomal dominant spastic ataxia-1 (SPAX1; 108600), as well as in 3 isolated cases from Ontario with a similar disorder, Bourassa et al. (2012) identified a heterozygous T-to-G transversion in the VAMP1 gene. Three of the families had been reported by Meijer et al. (2002). The mutation, which was found by sequencing genes within the candidate disease locus on chromosome 12p13, segregated with the disorder in the families and was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in 708 in-house control exomes or in 169 controls from Newfoundland. The mutation in isoforms VAMP1A and VAMP1B is c.340+2T-G in intron 4, resulting in a splice site mutation and premature termination, whereas the mutation in isoform VAMP1D is c.342T-G, resulting in a ser114-to-arg (S114R) substitution. Considering the structure of the VAMP1 isoforms and their tissue-specific expression, Bourassa et al. (2012) concluded that the mutation results in alternative splicing with the production of an abnormal inactive isoform in neurons, resulting in haploinsufficiency of VAMP1 in the brain. This would result in decreased neurotransmitter exocytosis and neurologic symptoms. However, no biopsy or autopsy tissue from the patients was available.
In a Brazilian girl, born of consanguineous unaffected parents, with presynaptic congenital myasthenic syndrome-25 (CMS25; 618323), Shen et al. (2017) identified a homozygous 1-bp deletion (c.340delA) in the VAMP1 gene, predicted to result in frameshifts and elongation of the protein: Ile114SerfsTer72 for isoform A (c.340delA, NM_014231.4), and Ser114ValfsTer34 for isoform D (c.340delA, NM_199245.2). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found once in the heterozygous state in the ExAC database (1 in 11,574 Latino alleles). Expression of the mutation in HEK293 cells showed that it caused decreased levels of mutant A isoform (15% of normal) and the mutant D isoform (65% of normal). Transfection of the mutant VAMP1 isoforms into chromaffin cells resulted in significantly decreased depolarization-evoked exocytosis of catecholamine-containing vesicles (2 to 12%) compared to controls. These findings were consistent with a loss of function.
In 2 sibs, born of consanguineous Kuwaiti parents (family 1), with presynaptic congenital myasthenic syndrome-25 (CMS25; 618323), Salpietro et al. (2017) identified a homozygous 14-bp deletion (c.51_64del, NM_014231) in the VAMP1 gene, predicted to result in a frameshift and premature termination (Gly18TrpfsTer5). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database. Analysis of patient cells showed a mild reduction of mutant cDNA, suggesting possible nonsense-mediated mRNA decay.
In 2 sibs, born of consanguineous Israeli parents (family 2), with presynaptic congenital myasthenic syndrome-25 (CMS25; 618323), Salpietro et al. (2017) identified a homozygous c.146G-C transversion (c.146G-C, NM_014232) in the VAMP1 gene, resulting in an arg49-to-pro (R49P) substitution at a conserved residue in the active domain of the protein. The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. The variant was found once in the heterozygous state in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In a Saudi patient (16W-0091) with presynaptic congenital myasthenic syndrome-25 (CMS25; 618323), Monies et al. (2017) identified a homozygous G-to-A transition in the VAMP1 gene (c.129+1G-A, NM_014231), predicted to result in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected parents were heterozygous for the mutation. Functional studies of the variants and studies of patient cells were not performed, but it was predicted to result in a loss of function.
In a Saudi patient (16W-0082) with presynaptic congenital myasthenic syndrome-25 (CMS25; 618323), Monies et al. (2017) identified a homozygous 2-bp deletion (c.128_129del, NM_001297438) in exon 2 of the VAMP1 gene, predicted to result in a frameshift and premature termination (Glu43fs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; the unaffected parents were heterozygous for the mutation. Functional studies of the variants and studies of patient cells were not performed, but it was predicted to result in a loss of function.
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Bourassa, C. V., Meijer, I. A., Merner, N. D., Grewal, K. K., Stefanelli, M. G., Hodgkinson, K., Ives, E. J., Pryse-Phillips, W., Jog, M., Boycott, K., Grimes, D. A., Goobie, S., Leckey, R., Dion, P. A., Rouleau, G. A. VAMP1 mutation causes dominant hereditary spastic ataxia in Newfoundland families. Am. J. Hum. Genet. 91: 548-552, 2012. [PubMed: 22958904] [Full Text: https://doi.org/10.1016/j.ajhg.2012.07.018]
Gross, M. B. Personal Communication. Baltimore, Md. 7/25/2014.
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Nystuen, A. M., Schwendinger, J. K., Sachs, A. J., Yang, A. W., Haider, N. B. A null mutation in VAMP1/synaptobrevin is associated with neurological defects and prewean mortality in the lethal-wasting mouse mutant. Neurogenetics 8: 1-10, 2007. [PubMed: 17102983] [Full Text: https://doi.org/10.1007/s10048-006-0068-7]
Sakaba, T., Stein, A., Jahn, R., Neher, E. Distinct kinetic changes in neurotransmitter release after SNARE protein cleavage. Science 309: 491-494, 2005. [PubMed: 16020741] [Full Text: https://doi.org/10.1126/science.1112645]
Salpietro, V., Lin, W., Delle Vedove, A., Storbeck, M., Liu, Y., Efthymiou, S., Manole, A., Wiethoff, S., Ye, Q., Saggar, A., McElreavey, K., Krishnakumar, S. S., and 10 others. Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome. Ann. Neurol. 81: 597-603, 2017. [PubMed: 28253535] [Full Text: https://doi.org/10.1002/ana.24905]
Shen, X.-M., Scola, R. H., Lorenzoni, P. J., Kay, C. S. K., Werneck, L. C., Brengman, J., Selcen, D., Engel, A. G. Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome. Ann. Clin. Transl. Neurol. 4: 130-138, 2017. Note: Erratum: Ann. Clin. Transl. Neurol. 4: 356 only, 2017. [PubMed: 28168212] [Full Text: https://doi.org/10.1002/acn3.387]
Tucker, W. C., Weber, T., Chapman, E. R. Reconstitution of Ca(2+)-regulated membrane fusion by synaptotagmin and SNAREs. Science 304: 435-438, 2004. [PubMed: 15044754] [Full Text: https://doi.org/10.1126/science.1097196]