HGNC Approved Gene Symbol: SYT2
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:202,590,596-202,710,454 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | Myasthenic syndrome, congenital, 7A, presynaptic, and distal motor neuropathy, autosomal dominant | 616040 | Autosomal dominant | 3 |
| Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive | 619461 | Autosomal recessive | 3 |
Synaptotagmins, like SYT2, are integral membrane proteins of synaptic vesicles thought to serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis (Hilbush and Morgan, 1994). SYT2 is the major isoform expressed at the neuromuscular junction (NMJ) (summary by Donkervoort et al., 2020).
By molecular cloning, Geppert et al. (1991) identified the Syt2 gene in mouse and rat. Syt2 and Syt1 (185605) are 88% identical in the cytoplasmic region. RNA blots demonstrated complementary patterns of expression for Syt2 and Syt1, with Syt1 preferentially expressed in rostral brain regions and Syt2 predominantly expressed in caudal brain regions.
Lee et al. (2004) found that rat Wnk1 (605232) selectively bound to and phosphorylated Syt2 calcium-binding C2 domains. Endogenous Wnk1 and Syt2 coimmunoprecipitated and colocalized on a subset of secretory granules in a rat insulinoma cell line. Phosphorylation by Wnk1 increased the amount of Ca(2+) required for Syt2 binding to phospholipid vesicles. Lee et al. (2004) concluded that phosphorylation of SYT2 by WNK1 can regulate Ca(2+) sensing and the subsequent Ca(2+)-dependent interactions mediated by synaptotagmin C2 domains.
Sun et al. (2007) reported a quantitative description of asynchronous neurotransmitter release in calyx-of-Held synapses. They showed that deletion of Syt2 in mice selectively abolishes synchronous release, allowing the study of pure asynchronous release in isolation. Using photolysis experiments of caged calcium ion, Sun et al. (2007) demonstrated that asynchronous release displays a calcium ion cooperativity of approximately 2 with a calcium ion affinity of about 44 micromolar, in contrast to synchronous release, which exhibits a calcium ion cooperatively of approximately 5 with a calcium ion affinity of about 38 micromolar. The results revealed that release triggered in wildtype synapses at low calcium ion concentrations is physiologically asynchronous, and that asynchronous release completely empties the readily releasable pool of vesicles during sustained elevations of calcium ion. Sun et al. (2007) proposed a dual calcium ion-sensor model of release that quantitatively describes the contributions of synchronous and asynchronous release under conditions of different presynaptic calcium ion dynamics.
By immunohistochemical analysis, Tejero et al. (2016) showed that expression of Syt2 and its interacting protein, Sv2b (185861), was decreased in neuromuscular synapses of a spinal muscular atrophy (SMA) mouse model (SMN-delta-7 mice; see 600354), with the reduction correlating with the degree of muscle vulnerability. Additionally, expression of Syt1, another protein essential for synchronous release, was downregulated in nerve terminals of highly affected muscles, but not in low vulnerability muscles, in SMA mice. Consistent with reduction of Syt1, Syt2, and Sv2 in most affected SMA neuromuscular synapses, functional analysis revealed highly reduced evoked release, altered short-term plasticity, low release probability, and inability to modulate normally the number of functional release sites. Further analysis revealed regulated expression of Syt1, Syt2, and Sv2b in nerve terminals during postnatal development in SMA mice. Expression of Syt1, Syt2, and Sv2b was significantly decreased as early as postnatal day-3 in SMA mice compared with wildtype, an age at which pre- and postsynaptic postnatal maturation changes are still mild. The authors proposed that reduction of Syt2 and Sv2b is a key factor in functional synaptic alteration in SMA, and that downregulation of Syt1 plays a determinant role in muscle vulnerability in SMA.
SYT2 binds to SNARE proteins, including SNAP25 (600322) and complexin (605032), which play critical roles in evoked transmitter release at the neuromuscular junction (NMJ) (Maselli et al., 2020).
Crystal Structure
Jin et al. (2006) reported the structure of the receptor-binding domain of botulinum neurotoxin serotype B (BoNT/B) bound to the luminal domain of synaptotagmin-2, determined at 2.15-angstrom resolution. On binding, a helix is induced in the luminal domain, which binds to a saddle-shaped crevice on a distal tip of BoNT/B. This crevice is adjacent to the nonoverlapping ganglioside-binding site of BoNT/B. Synaptotagmin-2 interacts with BoNT/B with nanomolar affinity, at both neutral and acidic endosomal pH. Biochemical and neuronal ex vivo studies of structure-based mutations indicated high specificity and affinity of the interaction, and high selectivity of BoNT/B among synaptotagmin-1 and -2 isoforms. Synergistic binding of both synaptotagmin and ganglioside imposes geometric restrictions on the initiation of BoNT/B translocation after endocytosis.
Chai et al. (2006) reported the crystal structure of full-length BoNT/B in complex with the synaptotagmin-2 (Syt2) recognition domain at 2.6-angstrom resolution. The structure of the complex revealed that Syt-II forms a short helix that binds to a hydrophobic groove within the binding domain of BoNT/B. In addition, the mutagenesis of amino acid residues within this interface on Syt-II affects binding of BoNT/B. Structural and sequence analysis revealed that this hydrophobic groove is conserved in the BoNT/G and BoNT/B subtypes, but varies in other clostridial neurotoxins. Furthermore, molecular docking studies using the ganglioside G(T1b) indicated that its binding site is more extensive than previously proposed and might form contacts with both BoNT/B and synaptotagmin.
Schauder et al. (2014) presented the crystal structure of a fragment of human extended SYT2 (E-SYT2) at 2.44-angstrom resolution, including an SMP domain and 2 adjacent C2 domains. The SMP domain has a beta-barrel structure similar to protein modules in the tubular lipid-binding (TULIP) superfamily. The SMP domain dimerizes to form an approximately 90-angstrom-long cylinder traversed by a channel lined entirely with hydrophobic residues, with the 2 C2A-C2B fragments forming arched structures flexibly linked to it. Structural analysis complemented by mass spectrometry revealed the presence of glycerophospholipids in the E-SYT2 SMP channel, indicating a direct role for extended synaptotagmins in lipid transport.
By analysis of an interspecific backcross panel, Jones et al. (1995) demonstrated that the mouse Syt2 gene maps close to Ren1 on mouse chromosome 1, in a region of homology of synteny between mouse chromosome 1 and human chromosome 1q that includes about 40 mapped genes (Seldin et al., 1993). The human SYT2 gene presumably is located in that region. Kwon et al. (1995) likewise mapped Syt2 to mouse chromosome 1 and predicted that the human SYT2 gene is located on 1q.
Stumpf (2021) mapped the SYT2 gene to chromosome 1q32.1 based on an alignment of the SYT2 sequence (GenBank BC100817) with the genomic sequence (GRCh38).
Autosomal Dominant Presynaptic Congenital Myasthenic Syndrome 7A And Distal Motor Neuropathy
In 2 unrelated Caucasian families with autosomal dominant presynaptic congenital myasthenic syndrome-7A and distal motor neuropathy (CMS7A; 616040), Herrmann et al. (2014) identified 2 different heterozygous missense mutations in the SYT2 gene (D307A, 600104.0001 and P308L, 600104.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Transfection of D362A (the Drosophila mutation corresponding to human D307A) in the Drosophila ortholog Dsyt1 was unable to rescue neurotransmitter release defects in Dsyt1-null flies. Flies transfected with the mutation lacked synchronous neurotransmitter release at the neuromuscular junction (NMJ), showed enhanced asynchronous release, and exhibited increased spontaneous fusion rates with a strong dominant-negative effect. The findings indicated that the D362A mutation abolished the ability of the protein to support calcium-triggered neurotransmitter release in peripheral motor nerve terminals, resulting in muscle weakness.
In a 50-year-old woman and her similarly affected mother with CMS7A, Montes-Chinea et al. (2018) identified a heterozygous missense mutation in the SYT2 gene (I371K; 600104.0003). The mutation occurred at a conserved residue in the C2B domain. The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. Family history revealed several other similarly affected family members, but they were not studied. Studies of the orthologous mutation in Drosophila showed that it had a dominant-negative effect on calcium-triggered synaptic transmission. The patients had clear clinical and electrophysiologic evidence of both impaired presynaptic neuromuscular transmission and a distal motor neuropathy.
In a 30-year-old man with CMS7A, Fionda et al. (2021) identified a de novo heterozygous mutation in the SYT2 gene (600104.0004). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Although functional studies of the variant and studies of patient cells were not performed, molecular modeling showed that the deletion occurred in the calcium-binding C2B domain and would most likely interfere with proper protein function.
In a 26-year-old man with CMS7A, Maselli et al. (2021) identified a de novo heterozygous missense mutation in the SYT2 gene (L365P; 600104.0005). The substitution occurred in the C2B domain, which is critical for evoked transmitter release at the NMJ. Functional studies of the variant were not performed.
Autosomal Recessive Presynaptic Congenital Myasthenic Syndrome 7B
In a 2-year-old girl, born of consanguineous parents, with autosomal recessive presynaptic congenital myasthenic syndrome-7B (CMS7B; 619461), Maselli et al. (2020) identified a homozygous frameshift mutation in the SYT2 gene (600104.0006). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Molecular modeling indicated that the mutation does not affect residues directly involved in calcium binding, but it does replace critical residues that mediate SYT-SNARE interactions and synaptic vesicle fusion and neurotransmitter release.
In 2 unrelated patients with CMS7B, Bauche et al. (2020) identified homozygous loss-of-function mutations in the SYT2 gene (see, e.g., 600104.0007). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Analysis of the NMJ in skeletal tissue from 1 patient showed disruption of the pre- and postsynaptic architectures and only partial innervation with thin and fragmented terminal axons. There was a 2-fold reduction in SYT2 expression with a compensatory increase in SYT1 (185605) expression.
In 7 patients from 5 unrelated families with CMS7B, Donkervoort et al. (2020) identified homozygous loss-of-function mutations in the SYT2 gene (see, e.g., 600104.0008 and 600104.0009). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutations occurred throughout the gene. Functional studies of the variants and studies of patient cells were not performed, but the authors concluded that the disorder was largely driven by impaired presynaptic transmission at the NMJ with secondary axonal degeneration. Haploinsufficiency for SYT2 does not appear to cause disease, as heterozygous carrier parents were unaffected.
In 4 affected members of a 3-generation American family with autosomal dominant presynaptic congenital myasthenic syndrome-7A and distal motor neuropathy (CMS7A; 616040), Herrmann et al. (2014) identified a heterozygous c.920A-C transversion in the SYT2 gene, resulting in an asp307-to-ala (D307A) substitution at a residue that coordinates calcium binding to the C2B domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in the Exome Variant Server database or in 3,000 local control individuals. Studies of the homologous mutation in Drosophila showed that the mutation caused disruption of synaptic vesicle exocytosis in a dominant-negative manner.
In 6 affected members of a 3-generation family from the United Kingdom with presynaptic congenital myasthenic syndrome-7A and distal motor neuropathy (CMS7A; 616040), Herrmann et al. (2014) identified a heterozygous c.923C-T transition in the SYT2 gene, resulting in a pro308-to-leu (P308L) substitution at a residue that coordinates calcium binding to the C2B domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was filtered against the Exome Sequencing Project and 1000 Genomes Project databases, and was not found in 334 in-house control exomes.
In a 50-year-old woman and her similarly affected mother with presynaptic congenital myasthenic syndrome-7A and distal motor neuropathy (CMS7A; 616040), Montes-Chinea et al. (2018) identified a heterozygous c.1112T-A transversion in the SYT2 gene, resulting in an ile371-to-lys (I371K) substitution at a conserved residue in the C2B domain. The mutation, which was found by Sanger sequencing, was not present in the gnomAD database. Family history revealed several other similarly affected family members, but they were not studied. Expression of the orthologous mutation in the Drosophila homolog (dsyt1) was unable to rescue reduced viability in dsyt1-null flies, caused an additional decrease in viability compared to complete gene loss, and resulted in defects in calcium-triggered synaptic transmission, all in a dominant-negative manner. The patients had clear clinical and electrophysiologic evidence of both impaired presynaptic neuromuscular transmission and a distal motor neuropathy.
In a 30-year-old man with presynaptic congenital myasthenic syndrome-7A and distal motor neuropathy (CMS7A; 616040), Fionda et al. (2021) identified a de novo heterozygous in-frame 15-bp deletion (c.1082_1096del, NM_177402.4) in exon 9 of the SYT2 gene, resulting in the deletion of 5 amino acids (Asp361_Leu365del). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Although functional studies of the variant and studies of patient cells were not performed, molecular modeling showed that the deletion occurred in the calcium-binding C2B domain and would most likely interfere with proper protein function.
In a 26-year-old man with presynaptic congenital myasthenic syndrome-7A and distal motor neuropathy (CMS7A; 616040), Maselli et al. (2021) identified a de novo heterozygous c.1094C-T transition (c.1094C-T, NM_177402.4) in the SYT2 gene, resulting in a leu365-to-pro (L365P) substitution in the C2B domain, which is critical for evoked transmitter release at the NMJ. Functional studies of the variant were not performed.
In a 2-year-old girl, born of consanguineous parents, with autosomal recessive presynaptic congenital myasthenic syndrome-7B (CMS7B; 619461), Maselli et al. (2020) identified a homozygous 1-bp deletion (c.1191delG, NM_177402) in exon 9 of the SYT2 gene, resulting in a frameshift and premature termination (Arg397SerfsTer37) in the C-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Molecular modeling indicated that the mutation does not affect residues directly involved in calcium binding, but it does replace critical residues that mediate SYT-SNARE interactions and synaptic vesicle fusion and neurotransmitter release.
In a 4-year-old girl (patient 1), born of consanguineous parents, with autosomal recessive presynaptic congenital myasthenic syndrome-7B (CMS7B; 619461), Bauche et al. (2020) identified a homozygous G-to-A transition (c.465+1G-A, NM_177402.4) in intron 4 of the SYT2 gene, resulting in a splicing defect, the in-frame skipping of exon 4, and deletion of part of the C2A calcium-binding site. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of the NMJ in patient skeletal tissue showed disruption of the pre- and postsynaptic architectures and only partial innervation with thin and fragmented terminal axons. There was a 2-fold reduction in SYT2 expression with a compensatory increase in SYT1 (185605) expression. The findings were consistent with a loss of function.
In 3 patients (P3, P6, and P7) from 2 unrelated consanguineous Egyptian families with autosomal recessive presynaptic congenital myasthenic syndrome-7B (CMS7B; 619461), Donkervoort et al. (2020) identified a homozygous 1-bp duplication (c.725dupA, NM_177402.5) in exon 6 of the SYT2 gene, resulting in a frameshift and premature termination (Val243GlyfsTer13). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
In 2 sibs (P4 and P5), born of consanguineous parents, with autosomal recessive presynaptic congenital myasthenic syndrome-7B (CMS7B; 619461), Donkervoort et al. (2020) identified a homozygous c.805G-T transversion (c.805G-T, NM_177402.5) in exon 7 of the SYT2 gene, resulting in a glu269-to-ter (E269X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
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