Alternative titles; symbols
HGNC Approved Gene Symbol: SYN1
Cytogenetic location: Xp11.3-p11.23 Genomic coordinates (GRCh38): X:47,571,901-47,619,857 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.3-p11.23 | Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders | 300491 | X-linked | 3 |
| Intellectual developmental disorder, X-linked 50 | 300115 | X-linked | 3 |
The SYN1 gene encodes synapsin I, a neuronal phosphoprotein associated with the membranes of small synaptic vesicles. Synapsins may play a role in synaptic neurotransmission, neuronal development, synaptogenesis, maintenance of mature synapses, and plasticity (summary by Fassio et al., 2011).
Also known as brain protein 4.1, synapsin I is the best characterized of the nonerythroid forms of protein 4.1.
Sudhof (1990) determined that differential splicing of the primary SYN1 transcript generates 2 separate forms of synapsin I.
Klagges et al. (1996) cloned the Drosophila synapsin gene (Syn), which encodes 2 proteins, both of which contain a region with 50% amino acid identity with the human protein. The Drosophila Syn gene contains 2 open reading frames, separated by a single amber (UAG) stop codon. The authors suggested that the large synapsin isoform in Drosophila may be generated by UAG read-through, an unconventional mechanism for the generation of protein diversity from a single gene.
Sudhof (1990) reported that synapsin I is encoded by a single-copy gene containing 13 exons ranging in size from 58 bp to more than 1 kb. The exons are nonuniformly distributed over more than 30 kb of DNA.
Derry and Barnard (1991) demonstrated that the gene for tissue inhibitor of metalloproteinase (TIMP; 305370) is located within an intron of the SYN1 gene in both mouse and man. The TIMP gene is transcribed in the opposite direction to the SYN1 gene.
Yang-Feng et al. (1986) assigned the SYN1 gene to Xp11 by in situ hybridization using a rat cDNA probe. Southern blot analysis of human/Chinese hamster somatic cell hybrids carrying defined regions of the human X chromosome confirmed the in situ mapping data. They also determined the regional assignment in the mouse X chromosome. Yang-Feng et al. (1986) hypothesized that the SYN1 gene may be mutant in human X-linked disorders with primary neuronal degeneration, such as Rett syndrome (312750). According to the evidence presented by Amar et al. (1988), the mouse homolog, Syn1, is situated between Otc and Araf.
By detailed restriction mapping, Derry and Barnard (1992) demonstrated that the 5-prime end of the SYN1 gene lies within 5 kb of the properdin gene (CFP; 300383).
By in situ hybridization studies, Klagges et al. (1996) mapped the Drosophila Syn gene to a single site in the region 86A on the right arm of chromosome 3.
Giovedi et al. (2004) found that interaction between mammalian synapsin I and Rab3a (179490) regulated the activities of both proteins. Synapsin I stimulated the Rab3a cycle by increasing GTP binding, GTPase activity, and Rab3a recruitment to the synaptic vesicle membrane. Conversely, Rab3a inhibited synapsin I binding to actin and synapsin I-induced synaptic vesicle clustering.
The D-domain of Syn1 is a multifunctional domain that associates with synaptic vesicles, regulates presynaptic targeting, binds SH3 domains of interacting proteins, and contains phosphorylation sites that regulate synaptic vesicle trafficking (summary by Fassio et al., 2011).
X-Linked Epilepsy-1 With Variable Learning Disabilities and Behavior Disorders
In affected members of a family with X-linked epilepsy-1 with variable learning disabilities and behavior disorders (EPILX1; 300491), Garcia et al. (2004) identified a hemizygous nonsense mutation in the SYN1 gene (W356X; 313440.0001).
In 6 males from a large French Canadian family with EPILX1, Fassio et al. (2011) identified a hemizygous nonsense mutation in the SYN1 gene (Q555X; 313440.0002). Two of the mutation carriers had autism. Investigation of this gene in several large cohorts of patients with epilepsy and/or autism identified 3 additional variants in the SYN1 gene in 1% of patients with autism spectrum disorders (see 313440.0004) and 3.5% of patients with epilepsy (see, e.g., 313440.0003). Three of the 4 mutations affected the D-domain, which is important for protein function. When expressed in Syn1-null neurons, these 3 mutant proteins were unable to rescue impairments in the size and trafficking of synaptic vesicle pools. The findings demonstrated that SYN1 is a predisposing gene to epilepsy and autism spectrum disorders and strengthened the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both disorders.
In an Italian boy with EPILX1 originally reported by Vignoli et al. (2014), Peron et al. (2018) identified a hemizygous splice site mutation in the SYN1 gene (313440.0007). The mutation, which was found by whole-exome sequencing, was inherited from the proband's unaffected mother. A maternal uncle with a similar disorder also carried the mutation, consistent with X-linked recessive inheritance. Functional studies of the variant and studies of patient cells were not performed. Both the proband and his uncle had bathing reflex epilepsy followed by nonreflex seizures. Peron et al. (2018) suggested that truncating SYN1 mutations tend to be associated with reflex seizures triggered by water, whereas missense variants tend to be associated with intellectual disability and autism without seizures.
In a 7-year-old Latino boy with EPILX1, Sirsi et al. (2017) identified a hemizygous nonsense mutation in the SYN1 gene (R422X; 313440.0008). The mutation was found through a gene panel test. The patient had a family history of the disorder on the maternal side, but further genetic studies were not performed on the family. Functional studies of the variant and studies of patient cells were not performed.
In 12 patients from 10 unrelated families with EPILX1 manifest as reflex bathing epilepsy, Accogli et al. (2021) identified mutations in the SYN1 gene (see, e.g., 313440.0008-313440.0010). The mutations, which were found by various exome sequencing methods and confirmed by Sanger sequencing, were absent from the gnomAD database. Ten of the patients were males and carried a hemizygous mutation, and 2 were females with a heterozygous mutation. All but 1 were maternally inherited; the mutation in family 1 occurred de novo. All but 1 of the mutations were nonsense, frameshift, or splice site variants and were predicted to result in premature termination; there was 1 missense variant. Functional studies of the variants and studies of patient cells were not performed.
In an 8.5-year-old Han Chinese boy (family B) with EPILX1, Xiong et al. (2021) identified a hemizygous nonsense mutation in the SYN1 gene (Q482X; 313440.0011). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
X-Linked Intellectual Developmental Disorder 50
In affected members of a family (family L027, MRX50) with X-linked intellectual developmental disorder-50 (XLID50; 300115) reported by Claes et al. (1997), Guarnieri et al. (2017) identified a hemizygous missense mutation in the SYN1 gene (S79W; 313440.0005). The mutation, which was found by direct sequencing of the SYN1 gene, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HeLa cells transfected with the mutation showed that the mutant protein was expressed at normal levels and formed large abnormal perinuclear aggregates that sequestered SYP (313475) and were Triton-soluble. Ultrastructural studies showed the presence of large clusters of small clear vesicles. Similar abnormal vesicle formation was observed in murine primary hippocampal cells transfected with the mutation. Although the mutation did not appear to affect early neuronal development, neurite length, or axonal branching, electrophysiologic studies showed that it was associated with increased numbers of synaptic vesicles at the presynaptic membrane and increased frequency of miniature excitatory postsynaptic currents (mESPSCs) compared to controls. Cells transfected with the mutation showed clustering of vesicles at the synaptic boutons and decreased dispersion along axons compared to wildtype SYN1. The findings suggested that the S79W mutation perturbs spontaneous vesicle exocytosis, clustering, and lateral mobility along axons, which likely disrupts the dynamics of synaptic plasticity, resulting in learning and cognitive deficits.
In 2 brothers, born of unrelated parents from the Middle East (family 05), with XLID50, Darvish et al. (2020) identified a hemizygous missense mutation in the SYN1 gene (R420Q; 313440.0006). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. The mutation was not present in public databases, including gnomAD. Primary hippocampal neurons transfected with the mutation in vitro showed decreased expression of the mutant protein compared to controls, and also demonstrated significantly decreased neurite outgrowth compared to controls. The patients had intellectual disability and autistic features without epilepsy.
Reclassified Variants
The T567A variant (313440.0004) reported by Fassio et al. (2011) has been reclassified as a variant of unknown significance. In 2 unrelated males from a cohort segregating autism spectrum disorder, Fassio et al. (2011) identified a hemizygous missense mutation (T567A; 313440.0004) in the SYN1 gene. The mutation was not found in 709 control chromosomes.
Synapsin I had been thought to regulate synaptogenesis and neurotransmitter release from adult nerve terminals. To examine this possibility, Chin et al. (1995) generated synapsin I-deficient mice by homologous recombination. They found that outgrowth of predendritic neurites and of axons was severely retarded in the hippocampal neurons of embryonic synapsin I mutant mice. Furthermore, synapse formation was significantly delayed in these mutant neurons. The results indicated to the authors that synapsin I, indeed, plays a role in regulation of axonogenesis and synaptogenesis. In these same mice, Li et al. (1995) found that the organization of synaptic vesicles at presynaptic terminals was markedly altered: densely packed vesicles were present only in a narrow rim at active zones, whereas most vesicles were dispersed throughout the terminal area. This was in contrast to the organized vesicle clusters present in terminals of wildtype animals. Release of glutamate from nerve endings, induced by potassium ion, 4-aminopyridine, or a Ca(2+) ionophore, was markedly decreased in synapsin I mutant mice. Recovery of synaptic transmission after depletion of neurotransmitter by high-frequency stimulation was greatly delayed. Finally, synapsin I-deficient mice exhibited a strikingly increased response to electrical stimulation, as measured by electrographic and behavioral seizures. The results indicated to the authors that synapsin I plays a key role in the regulation of nerve terminal function in mature synapses, as well as a function in neuronal development as found by Chin et al. (1995).
In affected members of a family with X-linked epilepsy and variable learning disabilities and behavior disorders (EPILX1; 300491), Garcia et al. (2004) identified a hemizygous c.1197G-A transition in exon 9 of the SYN1 gene, resulting in a trp356-to-ter (W356X) substitution. The mutation was also present in obligate carrier females.
In 6 male members of a large French Canadian family with X-linked epilepsy and/or autism spectrum disorders (EPILX1; 300491), Fassio et al. (2011) identified a hemizygous gln555-to-ter (Q555X) substitution in exon 12 of the SYN1 gene. The mutation, which was found by linkage analysis followed by candidate gene sequencing, was not found in 418 control chromosomes. In vitro functional expression assays showed that the mutation virtually abolished the DE-domain binding to synaptic vesicles. The mutation also abolished or dramatically reduced phosphorylation of the protein and abolished binding to the SH3 domains of interacting proteins. Expression of the mutant protein in Syn1-null hippocampal cells caused impaired axonal elongation and impaired synaptic trafficking by decreasing release of synaptic vesicles, particularly from the readily releasable pool. These findings were consistent with a complete loss of function.
Using lentivirus-infected mouse hippocampal neurons, Lignani et al. (2013) found that the human Q555X mutation interfered with the ability of SYN1 to interact with mouse Syn2 (600755) isoforms and altered the subcellular distribution of SYN1 compared with wildtype SYN1. The Q555X mutation impaired synchronous coupling of synaptic vesicles to vesicle release machinery, reduced the probability of vesicle release in excitatory synapses, and decreased the pool of readily releasable vesicles in inhibitory synapses. The net effect was an excitatory/inhibitory imbalance with network hyperexcitability.
In 4 unrelated patients, 2 males and 2 females, with X-linked partial epilepsy and/or autism spectrum disorders (EPILX1; 300491), Fassio et al. (2011) identified a hemizygous or heterozygous 1648G-A transition in exon 12 of the SYN1 gene, resulting in an ala55-to-thr (A550T) substitution in the D-domain of the protein. The mutation was not found in 709 control chromosomes. All of the patients were of French Canadian origin, and haplotype analysis indicated a founder effect. In vitro functional expression assays showed that the mutation impaired normal synaptic vesicle trafficking in mouse hippocampal cells lacking the Syn1 gene. There was impaired release of vesicles from the reserve and readily releasable pools, consistent with a loss of function. The mutant protein did not properly localize to the presynapse. The mutation did not affect phosphorylation of the SYN1 protein or binding to SH3 domains of other proteins.
This variant, formerly titled INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 50, has been reclassified based on a review of the gnomAD database by Hamosh (2022).
In 2 unrelated males from a cohort segregating autism spectrum disorder (XLID50; 300115), Fassio et al. (2011) identified a hemizygous c.1699A-C transversion in exon 12 of the SYN1 gene, resulting in a thr567-to-ala (T567A) substitution in the D-domain of the protein. The mutation was not found in 709 control chromosomes. In vitro functional expression assays showed that the mutation impaired normal synaptic vesicle trafficking in mouse hippocampal cells lacking the Syn1 gene. There was impaired release of vesicles from the reserve and readily releasable pools, consistent with a loss of function. The mutant T567A protein did not properly localize to the presynapse. One of the patients also carried an ala51-to-glu (A51G) substitution in the SYN1 gene on the same allele, which may have caused an effect on protein function, but functional studies were not performed on the A51G variant. The T567A mutation did not affect phosphorylation of the SYN1 protein or binding to SH3 domains of other proteins.
Hamosh (2022) found that the T567A variant was present in 350 of 74,909 alleles in the gnomAD database, for an allele frequency of 0.004672. In the African/African American population, the variant was present in 314 of 6,438 alleles, including 5 homozygotes and 94 hemizygotes, for an allele frequency of 0.04877 (September 28, 2022).
In affected members of a family (family L027) with X-linked intellectual developmental disorder-50 (XLID50; 300115) reported by Claes et al. (1997), Guarnieri et al. (2017) identified a hemizygous c.236C-G transversion in exon 1 of the SYN1 gene, resulting in a ser79-to-trp (S69W) substitution at a highly conserved residue in domain B, which facilitates SYN1 interaction with synaptic vesicles. The mutation, which was found by direct sequencing of the SYN1 gene, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HeLa cells transfected with the mutation showed that the mutant protein was expressed at normal levels and formed large abnormal perinuclear aggregates that sequestered SYP (313475) and were Triton-soluble. Ultrastructural studies showed the presence of large clusters of small clear vesicles. Similar abnormal vesicle formation was observed in murine primary hippocampal cells that were transfected with the mutation. Although the mutation did not appear to affect early neuronal development, neurite length, or axonal branching, electrophysiologic studies showed that it was associated with increased numbers of synaptic vesicles at the presynaptic membrane and increased frequency of miniature excitatory postsynaptic currents (mESPSCs) compared to controls. Cells transfected with the mutation showed clustering of vesicles at the synaptic boutons and decreased dispersion along axons compared to wildtype SYN1. The findings suggested that the S79W mutation perturbs spontaneous vesicle exocytosis, clustering, and lateral mobility along axons, which likely disrupts the dynamics of synaptic plasticity, resulting in learning and cognitive deficits.
In 2 brothers, born of unrelated parents from the Middle East (family 05), with X-linked intellectual developmental disorder-50 (XLID50; 300115), Darvish et al. (2020) identified a hemizygous c.1259G-A transition in the SYN1 gene, resulting in an arg420-to-gln (R420Q) substitution at a highly conserved residue. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. The mutation was not present in public databases, including gnomAD. Another brother was similarly affected, but he had died and genetic material was not available for study. Primary hippocampal neurons transfected with the mutation in vitro showed decreased expression of the mutant protein compared to controls, and also demonstrated significantly decreased neurite outgrowth compared to controls. The patients had intellectual disability and autistic features without epilepsy.
In an Italian boy with X-linked epilepsy with variable learning disabilities and behavior disorders (EPILX1; 300491) originally reported by Vignoli et al. (2014), Peron et al. (2018) identified a hemizygous G-to-T intronic transversion (c.527+1G-T) in the SYN1 gene, predicted to result in a frameshift and premature termination. The mutation, which was found by whole-exome sequencing, was inherited from the proband's unaffected mother. A maternal uncle with a similar disorder also carried the mutation, consistent with X-linked recessive inheritance. The variant was not present in the ExAC, ClinVar, and 1000 Genomes Project databases. Functional studies of the variant and studies of patient cells were not performed. Both the proband and his uncle had bathing reflex epilepsy followed by nonreflex seizures. Peron et al. (2018) suggested that truncating SYN1 mutations tend to be associated with reflex seizures triggered by water, whereas missense variants tend to be associated with intellectual disability and autism without seizures.
In a 7-year-old Latino boy with X-linked epilepsy with variable learning disabilities and behavior disorders (EPILX1; 300491), Sirsi et al. (2017) identified a hemizygous c.1264C-T transition (c.1264C-T, NM_006950.3) in exon 10 of the SYN1 gene, resulting in an arg422-to-ter (R422X) substitution. The mutation was found through a gene panel test. The patient had a family history of the disorder on the maternal side, but further genetic studies were not performed on the family. Functional studies of the variant and studies of patient cells were not performed. The patient had reflex bathing epilepsy, developmental delay, and autism spectrum disorder.
In an 18-year-old male patient (family 1) with EPILX1, Accogli et al. (2021) identified a de novo hemizygous c.1264C-T transition (c.1264C-T, NM_006950.3) in the SYN1 gene, resulting in an arg422-to-ter (R422X) substitution. The patient had bathing epilepsy, nocturnal seizures, speech delay, aggressive behavior, and ADHD.
In 2 brothers (family 5) with X-linked epilepsy and variable learning disabilities and behavior disorders (EPILX1; 300491), Accogli et al. (2021) identified a hemizygous 1-bp duplication (c.1406dupA, NM_006950.3) in the SYN1 gene, resulting in a frameshift and premature termination (Pro470AlafsTer214). The mutation, which was found by whole-exome sequencing, was inherited from the mother. Their sister was also similarly affected, which may have been due to skewed X-inactivation. Functional studies of the variant and studies of patient cells were not performed.
In a 47-year-old man (family 10) with X-linked epilepsy and variable learning disabilities and behavior disorders (EPILX1; 300491), Accogli et al. (2021) identified a hemizygous 1-bp deletion (c.1266delA, NM_006950.3), resulting in a frameshift and premature termination (Gln423SerfsTer244). The mutation was found through gene panel sequencing and was presumed to have been carried by the unaffected mother, since 7 maternal male relatives were similarly affected. Functional studies of the variant and studies of patient cells were not performed. The proband had onset of reflex bathing epilepsy at 15 years of age. He also had mild developmental delay with impaired intellectual development, speech delay, and autistic traits.
In an 8.5-year-old Han Chinese boy (family B) with X-linked epilepsy and variable learning disabilities and behavior disorders (EPILX1; 300491), Xiong et al. (2021) identified a hemizygous c.1444C-T transition (c.1444C-T, NM_133499) in exon 12 of the SYN1 gene, resulting in a gln482-to-ter (Q482X) substitution. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
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