HGNC Approved Gene Symbol: SYP
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:49,187,815-49,200,193 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Intellectual developmental disorder, X-linked 96 | 300802 | X-linked recessive | 3 |
Synaptophysin is an integral membrane protein that regulates synaptic vesicle endocytosis. It is the most abundant synaptic vesicle protein by mass, accounting for about 10% of total vesicle protein (Kwon and Chapman, 2011).
Sudhof et al. (1987) presented the nucleotide and derived amino acid sequences of human and rat synaptophysin. The deduced human and rat proteins contain 296 and 307 amino acids, respectively, and both contain 4 transmembrane domains.
Kwon and Chapman (2011) stated that SYP has a short N-terminal segment, followed by 4 transmembrane domains and a long C-terminal tail. Both N- and C-terminal tails are located on the cytoplasmic surface of synaptic vesicles, and the C-terminal tail is phosphorylated. The 2 intravesicular loops of SYP contain disulfide bonds, and the first loop has an N-glycosylation site.
Ozcelik et al. (1990) concluded that the SYP gene has 7 exons distributed over about 20 kb.
By linkage analysis performed using CEPH families, Ozcelik et al. (1990) mapped the SYP locus to Xp11.23-p11.22. Regionalization of the gene on the X chromosome was also done with hamster/human hybrid cells in which various portions of the human X chromosome were present. Using a RFLP of SYP, Ozcelik et al. (1990) concluded that SYP lies between TIMP and DXS14. Ozcelik et al. (1990) mapped the Syp gene to the X chromosome in the mouse by the study of somatic hybrid cells between mouse and hamster or rat, with regionalization by the study of hybrid cells containing rearranged mouse X chromosomes.
Cremin et al. (1993) found that SYP and the TFE3 gene (314310) are closely linked to the gene for Wiskott-Aldrich syndrome (301000).
Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked intellectual developmental disorder. They identified 4 independent mutations in the SYP gene (313475.0001-313475.0004) that segregated precisely with the phenotype (XLID96; 300802) in affected family members and were not detected in any unaffected family members. In addition to X-linked intellectual developmental disorder, some affected family members had epilepsy.
Using gene targeting, McMahon et al. (1996) disrupted the murine Syp gene. Mutant mice were viable and fertile with no detectable changes in brain. The authors concluded that Syp, one of the major synaptic vesicle membrane proteins, is not essential for synaptic transmission. They hypothesized that the function of Syp is either redundant or that it has a more subtle function not apparent in the assays used.
Janz et al. (1999) generated mice lacking Syngr1 (603925) and bred them to the Syp knockout generated by McMahon et al. (1996) to create double-knockout mice deficient in both Syp and Syngr1. Short- and long-term synaptic plasticity was severely reduced in the Syngr1/Syp double-knockout mice.
Using optical imaging and electrophysiologic experiments with cultured wildtype and Syp -/- mouse hippocampal neurons, Kwon and Chapman (2011) found that Syp was required for efficient endocytosis of synaptic vesicles. The defect in Syp -/- neurons was most evident following rapid and sustained stimulation. Voltage clamp experiments with Syp -/- neurons showed pronounced synaptic depression during sustained activity and slower recovery of the recycling vesicle pool following depletion. Neurotransmitter release probability, postsynaptic responses, and short-term synaptic plasticity appeared normal in Syp -/- neurons. Expression of C-terminally truncated Syp in Syp -/- neurons rescued endocytosis that occurred during the recovery period following activity, but not endocytosis that occurred during activity. Kwon and Chapman (2011) concluded that Syp has 2 structural elements that regulate vesicle retrieval during and after stimulation.
In a family segregating X-linked intellectual developmental disorder-96 (XLID96; 300802), Tarpey et al. (2009) identified a 1-basepair insertion at nucleotide 274 of the SYP gene, resulting in frameshift and premature termination (Thr92fsTer45). This mutation was not found in 272 control chromosomes and was not found in unaffected family members.
In a 3-generation pedigree segregating X-linked intellectual developmental disorder-96 (XLID96; 300802), Tarpey et al. (2009) identified a 2-bp substitution in the SYP gene resulting in premature protein termination (177_178CA-GT, N59_K60-KX).
In a family segregating X-linked intellectual developmental disorder-96 (XLID96; 300802), Tarpey et al. (2009) identified a 4-bp deletion in the SYP gene beginning at nucleotide 829, resulting in frameshift and premature termination of the protein (Asp277fsTer59).
In a large 4-generation pedigree segregating X-linked intellectual developmental disorder-96 (XLID96; 300802), Tarpey et al. (2009) identified a G-to-C transversion at nucleotide 649 of the SYP gene, resulting in a gly-to-arg substitution at codon 217 (G217R). The mutation segregated with the phenotype and was not detected in any unaffected male family members. In addition to X-linked mental retardation, some affected individuals manifested epilepsy.
Cremin, S. M., Greer, W. L., Bodok-Nutzati, R., Schwartz, M., Peacocke, M., Siminovitch, K. A. Linkage of Wiskott-Aldrich syndrome with three marker loci, DXS426, SYP and TFE3, which map to the Xp11.3-p11.22 region. Hum. Genet. 92: 250-253, 1993. [PubMed: 8104859] [Full Text: https://doi.org/10.1007/BF00244467]
Janz, R., Sudhof, T. C., Hammer, R. E., Unni, V., Siegelbaum, S. A., Bolshakov, V. Y. Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron 24: 687-700, 1999. [PubMed: 10595519] [Full Text: https://doi.org/10.1016/s0896-6273(00)81122-8]
Kwon, S. E., Chapman, E. R. Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons. Neuron 70: 847-854, 2011. [PubMed: 21658579] [Full Text: https://doi.org/10.1016/j.neuron.2011.04.001]
McMahon, H. T., Bolshakov, V. Y., Janz, R., Hammer, R. E., Siegelbaum, S. A., Sudhof, T. C. Synaptophysin, a major synaptic vesicle protein, is not essential for neurotransmitter release. Proc. Nat. Acad. Sci. 93: 4760-4764, 1996. [PubMed: 8643476] [Full Text: https://doi.org/10.1073/pnas.93.10.4760]
Ozcelik, T., Lafreniere, R. G., Archer, B. T., III, Johnston, P. A., Willard, H. F., Francke, U., Sudhof, T. C. Synaptophysin: structure of the human gene and assignment to the X chromosome in man and mouse. Am. J. Hum. Genet. 47: 551-561, 1990. [PubMed: 1975480]
Sudhof, T. C., Lottspeich, F., Greengard, P., Mehl, E., Jahn, R. The cDNA and derived amino acid sequences for rat and human synaptophysin. Nucleic Acids Res. 15: 9607 only, 1987. [PubMed: 3120152] [Full Text: https://doi.org/10.1093/nar/15.22.9607]
Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genet. 41: 535-543, 2009. [PubMed: 19377476] [Full Text: https://doi.org/10.1038/ng.367]