Alternative titles; symbols
HGNC Approved Gene Symbol: STX5
Cytogenetic location: 11q12.3 Genomic coordinates (GRCh38) : 11:62,806,860-62,832,051 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.3 | ?Congenital disorder of glycosylation, type IIaa | 620454 | Autosomal recessive | 3 |
In eukaryotic cells, vesicle docking is thought to be regulated in part by the specific interactions of a vesicle-associated membrane protein (VAMP), or synaptobrevin (e.g., 185880), with the presynaptic plasma membrane proteins syntaxin and SNAP25 (600322). By PCR using oligonucleotides based on the sequence of rat syntaxin-5, Ravichandran and Roche (1997) isolated a partial cDNA encoding human syntaxin-5. They used the partial cDNA to clone a full-length human syntaxin-5 cDNA from an EBV-transformed lymphocyte cell cDNA library. The predicted 301-amino acid human protein is 96% identical to rat syntaxin-5. In vitro, human syntaxin-5 bound efficiently to rat VAMP2 (see SYB2; 185881) but not to human SNAP25.
To fuse transport vesicles with target membranes, proteins of the SNARE complex must be located on both the vesicle and the target membrane. In yeast, 4 integral membrane proteins, Sed5, Bos1, Sec22 (see 604029), and Bet1 (605456), are each believed to contribute a single helix to form the SNARE complex that is needed for transport from endoplasmic reticulum to Golgi. This generates a 4-helix bundle, which ultimately mediates the actual fusion event. Parlati et al. (2000) explored how the anchoring arrangement of the 4 helices affects their ability to mediate fusion. Parlati et al. (2000) reconstituted 2 populations of phospholipid bilayer vesicles, with the individual SNARE proteins distributed in all possible combinations between them. Of the 8 nonredundant permutations of 4 subunits distributed over 2 vesicle populations, only 1 resulted in membrane fusion. Fusion occurred only when the v-SNARE Bet1 is on 1 membrane and the syntaxin heavy chain Sed5 and its 2 light chains, Bos1 and Sec22, are on the other membrane, where they form a functional t-SNARE. Thus, each SNARE protein is topologically restricted by design to function either as a v-SNARE or as part of a t-SNARE complex.
Gross (2014) mapped the STX5 gene to chromosome 11q12.3 based on an alignment of the STX5 sequence (GenBank BC002645) with the genomic sequence (GRCh37).
In 3 sibs, the offspring of consanguineous parents, with congenital disorder of glycosylation type IIaa (CDG2AA; 620454), Linders et al. (2021) identified a homozygous mutation in the STX5 gene (M55V; 603189.0001). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the mother; the father was not available for testing. The mutation affected the methionine start site of the STX5 short isoform (STX5S), and immunoblotting in patient fibroblasts demonstrated the presence of the STX5 long isoform (STX5L) but absence of the short isoform. Immunofluorescence labeling in patient fibroblasts demonstrated that loss of STX5S resulted in irregular localization of glycosyltransferases to the Golgi apparatus. Linders et al. (2021) concluded that loss of an alternative start site in STX5 resulted in loss of the STX5 short isoform, which affected intracellular membrane trafficking and led to congenital disorder of glycosylation.
In 3 sibs, offspring of consanguineous parents, with congenital disorder of glycosylation type IIaa (CDG2AA; 620454), Linders et al. (2021) identified homozygosity for a c.163A-G transition (c.163A-G, NM_003164.4) in the STX5 gene, resulting in a met55-to-val (M55V) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the mother; the father was not available for testing. The mutation affects the methionine start site of the STX5 short isoform (STX5S), and immunoblotting in patient fibroblasts demonstrated the presence of the STX5 long isoform but absence of the short isoform. Glycosylation was shown to be impaired in patient fibroblasts, with a specific defect in mucin-type O-glycosylation.
Gross, M. B. Personal Communication. Baltimore, Md. 4/25/2014.
Linders, P. T. A., Gerretsen, E. C. F., Ashikov, A., Vals, M. A., de Boer, R., Revelo, N. H., Arts, R., Baerenfaenger, M., Zijlstra, F., Huijben, K., Raymond, K., Muru, K., Fjodorova, O., Pajusalu, S., Ounap, K., Ter Beest, M., Lefeber, D., van den Bogaart, G. Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5. Nature Commun. 12: 6227, 2021. [PubMed: 34711829] [Full Text: https://doi.org/10.1038/s41467-021-26534-y]
Parlati, F., McNew, J. A., Fukuda, R., Miller, R., Sollner, T. H., Rothman, J. E. Topological restriction of SNARE-dependent membrane fusion. Nature 407: 194-198, 2000. [PubMed: 11001058] [Full Text: https://doi.org/10.1038/35025076]
Ravichandran, V., Roche, P. A. Cloning and identification of human syntaxin 5 as a synaptobrevin/VAMP binding protein. J. Molec. Neurosci. 8: 159-161, 1997. [PubMed: 9188044] [Full Text: https://doi.org/10.1007/BF02736780]