Alternative titles; symbols
HGNC Approved Gene Symbol: SYNRG
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:37,514,807-37,609,418 (from NCBI)
The AP1 complex is a heterotetramer consisting of 2 large subunits, gamma (see 603533) and beta-1 (600157), a medium subunit, mu-1 (603535), and a small subunit, sigma-1 (see 603531). The AP1 complex associates with the trans-Golgi network (TGN), where it links selected membrane proteins to the clathrin lattice, enabling these proteins to be concentrated in clathrin-coated vesicles (CCVs). AP1GBP1 is a protein that interacts with the gamma subunit of AP1.
By searching an EST database using rat Ap1gbp1 as the query, Page et al. (1999) obtained a cDNA encoding human AP1GBP1, which they called gamma-synergin. The deduced 1,314-amino acid protein contains an EH domain and a gamma-adaptin-binding domain. Page et al. (1999) also identified alternative splice sites. Northern blot analysis of multiple rat tissues revealed ubiquitous expression of Ap1gbp1 transcripts of 4.4 to 5.6 kb. Western blot analysis of rat tissues detected 110- and 150-kD bands in brain and a single 190-kD band in liver. Immunofluorescence localization in Madin-Darby bovine kidney (MDBK) cells showed colocalization of AP1GBP1 with gamma-adaptin within the TGN and in the cytosol.
Hirst et al. (2005) demonstrated that human aftiphilin (AFTPH; 619628), p200A (HEATR5B; 619627), and gamma-synergin formed a stable complex that was enriched in CCVs. Further analysis confirmed that the 3 proteins were bona fide components of the CCV machinery.
Page et al. (1999) determined that the SYNRG gene contains 9 exons.
Gross (2021) mapped the SYNRG gene to chromosome 17q12 based on an alignment of the SYNRG sequence (GenBank BC090930) with the genomic sequence (GRCh38).
Associations Pending Confirmation
For discussion of a possible association between variation in the SYNRG gene and autosomal recessive spastic paraplegia, see 607291.0001.
In a 6-year-old Turkish boy with autosomal recessive complicated spastic paraplegia, Ayaz et al. (2022) identified a homozygous nonsense variant in the SYNRG gene (G533X). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Segregation studies in the family were not reported and functional studies of the variant were not performed. The patient had onset of spastic paraplegia in infancy, seizures, impaired intellectual development, and brain imaging abnormalities.
This variant is classified as a variant of unknown significance because its contribution to autosomal recessive complicated spastic paraplegia has not been confirmed.
In 2 brothers, born of consanguineous Turkish parents (family 1), with an autosomal recessive form of complicated spastic paraplegia, Ayaz et al. (2022) identified a homozygous c.3605T-C transition in the SYNRG gene, resulting in a leu1202-to-pro (L1202P) substitution. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that variations in other AP family genes are associated with neurologic disorders, including spastic paraplegia (see, e.g., SPG47, 614066, caused by mutation in the AP4B1 gene, 607245). The patients, who were 18 and 6 years of age, had onset of unsteady gait due to spasticity of the lower limbs in early childhood around age 3 years. The older brother was diagnosed with cerebral palsy and lost the ability to walk. The disorder was progressive in both patients, but the older brother had a more severe course: he had spastic dysarthria, tremor, decreased muscle bulk, brisk reflexes, and abnormal plantar responses. Brain imaging in the older brother showed enlarged ventricles, cerebral white matter loss, and cerebellar atrophy. The younger brother was still able to walk with a spastic diplegic gait and had slowed speech. He did not have cerebellar signs or significant brain imaging abnormalities. Both patients also had mild intellectual disability.
Ayaz, A., Uzunhan, T. A., Aydin, K. Interacting with AP1 complex mutated synergin gamma (SYNRG) reveals a novel coatopathy in the form of complicated hereditary spastic paraplegia. Brain Dev. 44: 329-335, 2022. [PubMed: 35090779] [Full Text: https://doi.org/10.1016/j.braindev.2022.01.002]
Gross, M. B. Personal Communication. Baltimore, Md. 11/18/2021.
Hirst, J., Borner, G. H. H., Harbour, M., Robinson, M. S. The aftiphilin/p200/gamma-synergin complex. Molec. Biol. Cell 16: 2554-2565, 2005. [PubMed: 15758025] [Full Text: https://doi.org/10.1091/mbc.e04-12-1077]
Page, L. J., Sowerby, P. J., Lui, W. W. Y., Robinson, M. S. Gamma-synergin: an EH domain-containing protein that interacts with gamma-adaptin. J. Cell Biol. 146: 993-1004, 1999. [PubMed: 10477754] [Full Text: https://doi.org/10.1083/jcb.146.5.993]