Alternative titles; symbols
HGNC Approved Gene Symbol: ST3GAL5
SNOMEDCT: 722762005;
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38) : 2:85,837,120-85,889,034 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p11.2 | Salt and pepper developmental regression syndrome | 609056 | Autosomal recessive | 3 |
The ST3GAL5 gene encodes a sialyltransferase that synthesizes ganglioside GM3 synthase (EC 2.4.99.9), a glycosphingolipid enriched in neural tissue, by adding sialic acid to lactosylceramide (summary by Boccuto et al., 2014).
Sialic acid-containing glycosphingolipids, or gangliosides, have various important biologic functions. In vertebrates, almost all the ganglio-series gangliosides are synthesized from a common precursor, ganglioside GM3, which has the simplest structure among the major gangliosides. GM3, a plasma membrane glycosphingolipid, participates in induction of differentiation, modulation of proliferation, maintenance of fibroblast morphology, signal transduction, and integrin-mediated cell adhesion. ST3GAL5 is responsible for the synthesis of GM3 (Ishii et al., 1998).
Using a cDNA library prepared from a monocyte-differentiated human myelogenous leukemia cell line, Ishii et al. (1998) isolated a cDNA encoding SIAT9, which they called GM3 synthase, by a modified expression cloning strategy. The predicted 362-amino acid SIAT9 protein has features characteristic of the sialyltransferase family, including a type II transmembrane topology and the sialyl motifs L in the center and S in the C-terminal region. However, SIAT9 contains the nonconservative substitution of asp to his at a position in sialyl motif L that is invariant in all other known sialyltransferases. Hydropathy plot analysis suggested that SIAT9 may by anchored to the luminal side of the Golgi membrane. SIAT9 shares approximately 27 to 41% amino acid sequence similarity with other known sialyltransferases that catalyze formation of the alpha-2,3 and alpha-2,6 linkages of sialic acid to the acceptor galactose moiety, but not with enzymes that catalyze formation of the alpha-2,8 linkage to the nonreducing terminal sialic acid residue of glycosphingolipids and glycoproteins. Northern blot analysis detected a major 2.4-kb SIAT9 transcript in all tissues tested, with highest expression in brain, skeletal muscle, placenta, and testis. SIAT9 was widely distributed in human brain, with slightly elevated expression in the cerebral cortex, temporal lobe, and putamen.
By screening a fetal brain cDNA library, followed by 5-prime RACE, Kim et al. (2001) identified 4 ST3GAL5 variants that differed only in the 5-prime UTR. The variants resulted from a combination of alternative splicing and alternative promoter utilization. Northern blot analysis of adult and fetal tissue detected a 2.4-kb transcript expressed at highest levels in fetal brain and lung and in adult brain, placenta, and skeletal muscle. Lower expression was detected in fetal kidney.
Ishii et al. (1998) determined that the substrate specificity of SIAT9 was highly restricted to lactosylceramide as the acceptor.
Kim et al. (2001) determined that the ST3GAL5 gene contains 9 exons and spans about 44 kb. The coding region is located in exons 4 to 9. Kim et al. (2002) determined that the 5-prime flanking region of the ST3GAL5 gene lacks canonical TATA and CAAT boxes, but contains several putative transcription factor-binding sites, with both positive and negative regulatory elements.
By genomic sequence analysis, Zeng et al. (2003) determined that the SIAT9 gene contains 7 exons and spans more than 62 kb. They noted that the SIAT9 introns were larger in their analysis than those reported by Kim et al. (2001). Zeng et al. (2003) identified 2 transcription start sites upstream of exon 1. A 5-prime proximal fragment bound several transcription factors in a DNA-binding assay.
By genomic sequence analysis, Kim et al. (2001) mapped the SIAT9 gene to chromosome 2. Zeng et al. (2003) mapped the SAIT9 gene to chromosome 2p24.3-p24.1 by genomic sequence analysis.
Simpson et al. (2004) mapped an infantile-onset symptomatic epilepsy syndrome (609056) to 2p12-p11.2 by identification of a region of homozygosity and found a nonsense mutation in the SIAT9 gene, which was located in that region. Thus, the location of the gene appeared to be more proximal than had been thought.
In a large Old Order Amish pedigree in Geauga County, Ohio, Simpson et al. (2004) identified an autosomal recessive infantile-onset epilepsy syndrome associated with developmental stagnation and blindness (SPDRS; 609056). They sequenced genes in a region of homozygosity on 2p12-p11.2 and identified a nonsense mutation in SIAT9 (R288X; 604402.0001) that was predicted to result in a premature termination of the GM3 synthase enzyme (also called lactosylceramide alpha-2,3 sialyltransferase). GM3 synthase catalyzes the initial step in the biosynthesis of most complex gangliosides from lactosylceramide. Biochemical analysis of plasma glycosphingolipids confirmed that affected individuals lacked GM3 synthase activity, as marked by a complete lack of GM3 ganglioside and its biosynthetic derivatives and an increase in lactosylceramide and its alternative derivatives. Although the relationship between defects in ganglioside catabolism and a range of lysosomal storage diseases is well documented, this was, it seems, the first report of a disruption of ganglioside biosynthesis associated with human disease.
In 2 sibs, born of consanguineous French parents, with refractory epilepsy and delayed psychomotor development, Fragaki et al. (2013) identified a homozygous truncating mutation in the SIAT9 gene (604402.0001), which was the same mutation identified by Simpson et al. (2004) in Amish patients with a similar disorder. The mutation, which was identified by exome sequencing, segregated with the disorder in the family. Mass spectrometry analysis of patient fibroblasts showed complete absence of GM3 ganglioside and its biosynthetic derivatives and an upregulation of the alternative globoside pathway. Fibroblasts also showed a decrease in mitochondrial membrane potential, consistent with secondary dysfunction of the respiratory chain, as well as increased apoptosis. Fragaki et al. (2013) suggested that the accumulation of globosides may have had a role in the respiratory chain dysfunction.
Saul et al. (1983) reported sibs from an African American family with pigmentary disturbances, which they described as 'salt and pepper' pigmentary changes, and severe mental retardation. Boccuto et al. (2014) detected a homozygous mutation in the ST3GAL5 gene in affected family members (604402.0002).
Gangliosides are present on all mammalian plasma membranes, where they participate in recognition and signaling activities. Yamashita et al. (2003) generated mice lacking GM3 synthase which were unable to synthesize GM3 ganglioside. The mutant mice were viable and appeared to be without major abnormalities, but showed a heightened sensitivity to insulin, the basis of which was found to be enhanced insulin receptor phosphorylation in skeletal muscle. Importantly, the mutant mice were protected from high-fat diet-induced insulin resistance. The results showed that GM3 ganglioside is a negative regulator of insulin signaling, making it a potential therapeutic target in type II diabetes (125853).
Yoshikawa et al. (2009) found that Sati -/- mice exhibited no startle reflex in response to various acoustic stimulations, yet they demonstrated normal startle responses to air puffs. Electrophysiologic and histologic analyses of Sati -/- mice revealed that the organ of Corti in the inner ear was selectively degenerated and the spiral ganglion was scattered, but all other regions of the cochlea appeared normal. Scanning electron microscopy showed a significant deficit in hair bundles of outer hair cells, but not inner hair cells, in the organ of Corti of Sati -/- mice. Examination of brainstem auditory-evoked potentials revealed attenuated auditory responses in Sati -/- mice at postnatal day 14 (P14), when auditory responses were first observed in wildtype mice. No auditory responses were detected in Sati -/- mice by P17. Thin-layer chromatography revealed dramatic changes in several gangliosides during development in wildtype cochlea. At P13, GM3 was expressed in all regions of the cochlea, but at P14 and in adult mice, GM3 expression was limited to stria vascularis, spiral ganglion, and the organ of Corti. No GM3 was detected in the cochlea of Sati -/- mice. Yoshikawa et al. (2009) concluded that SATI-mediated synthesis of GM3 in the cochlea is essential for acquisition and maintenance of hearing.
Bharathi et al. (2022) demonstrated that, compared to wildtype mice, Gm3 synthase knockout mice (Gm3s -/-) had increased whole-body energy expenditure as evidenced by increased oxygen consumption and carbon dioxide production and a higher respiratory exchange rate, indicative of increased reliance on glucose for energy. PET scanning also demonstrated that the Gm3s -/- mice had greater brain glucose uptake compared to wildtype mice after short fasting. Complex I respiration and ADP-stimulated state 3 mitochondrial respiration was increased in brain homogenates from Gm3s -/- mice, which was attributed to increased expression of pyruvate dehydrogenase deficiency. Inhibition of glycolysis resulted in a decrease in kainate-induced seizures in the mutant mice.
In affected Amish individuals with autosomal recessive salt and pepper developmental regression syndrome (SPDRS; 609056), Simpson et al. (2004) demonstrated homozygosity for a c.694C-T transition in the SIAT9 gene, resulting in an arg232-to-ter (R232X) substitution. Heterozygosity was found in several carriers. The mutation was predicted to cause a loss of function of GM3 synthase. Affected children completely lacked GM3 and its downstream biosynthetic derivatives but they had increased levels of the immediate precursor to GM3, lactosylceramide, and evidence of increased flux through the globoside and paragloboside pathways.
Wang et al. (2016) reported 37 Amish patients, including 8 previously reported by Simpson et al. (2004), who were homozygous for the R288X mutation in exon 6 of the ST3GAL5 gene.
In 2 sibs, born of consanguineous French parents, with refractory epilepsy and delayed psychomotor development, Fragaki et al. (2013) identified a homozygous c.862C-T transition in exon 6 of the ST3GAL5 gene, resulting in an arg288-to-ter (R288X) substitution. The mutation was the same as that identified by Simpson et al. (2004) in Amish patients with a similar disorder; the numbering by Fragaki et al. (2013) was based on a later reference sequence. The mutation was identified by exome sequencing and segregated with the disorder in the family. Mass spectrometry analysis of patient fibroblasts showed complete absence of GM3 ganglioside and its biosynthetic derivatives and an upregulation of the alternative globoside pathway. Fibroblasts also showed a decrease in mitochondrial membrane potential, consistent with secondary dysfunction of the respiratory chain, as well as increased apoptosis. Fragaki et al. (2013) suggested that the accumulation of globosides may have had a role in the respiratory chain dysfunction.
In 2 sibs originally reported by Saul et al. (1983) as having 'salt and pepper' mental retardation syndrome (SPDRS; 609056), Boccuto et al. (2014) identified a homozygous c.994G-A transition in exon 7 of the ST3GAL5 gene, resulting in a glu332-to-lys (E332K) substitution in the S-motif of the protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 137) database or in 561 individuals from South Carolina, the geographic region of the family. Molecular modeling studies suggested that the E332K substitution would destabilize the protein. Patient fibroblasts showed no GM2 or GM3, consistent with a loss of ST3GAL5 function. Analysis of the glycolipid profile in patient cells and plasma showed a shift toward ceramides with longer fatty acid chain length. Microarray analysis of glycosyltransferase mRNAs detected modestly increased expression of ST3GAL5 as well as greater changes in transcripts encoding enzymes that lie downstream of ST3GAL5 and in other glycosphingolipid biosynthetic pathways. Comprehensive glycomic analysis of N-linked, O-linked, and glycosphingolipid glycans revealed collateral modulation of glycoprotein sialylation in response to the loss of complex gangliosides. Morpholino knockdown of st3gal5 in zebrafish embryos caused increased neuronal cell death that could be rescued by expression of the wildtype gene. The findings indicated that human neural cells are extremely sensitive to ST3GAL5 deficiency and altered glycosphingolipid synthesis.
In 2 Korean sisters with salt and pepper developmental regression syndrome (SPDRS; 609056), Lee et al. (2016) identified compound heterozygous missense mutations in the ST3GAL5 gene: a c.584G-C transversion (c.584G-C, NM_003896), resulting in a cys195-to-ser (C195S) substitution, and a c.601G-A transition, resulting in a gly201-to-arg (G201R; 604402.0004) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The C195S variant was not found in the 1000 Genomes Project or ExAC databases, whereas the G201R variant was found at a low frequency (8.3 x 10(-6)). Both mutations occurred at highly conserved residues in the L-motif of the protein. Plasma gangliosides in the 2 sibs were barely detectable, suggesting a loss of function. Functional studies of the variants and measurement of enzyme activity in patient cell were not performed.
For discussion of the c.601G-A transition (c.601G-A, NM_003896) in the ST3GAL5 gene, resulting in a gly201-to-arg (G201R) substitution, that was found in compound heterozygous state in 2 sibs with salt and pepper developmental regression syndrome (SPDRS; 609056) by Lee et al. (2016), see 604402.0003.
Bharathi, S. S., Zhang, B. B., Paul, E., Zhang, Y., Schmidt, A. V., Fowler, B., Wu, Y., Tiemeyer, M., Inamori, K. I., Inokuchi, J. I., Goetzman, E. S. GM3 synthase deficiency increases brain glucose metabolism in mice. Molec. Genet. Metab. 137: 342-348, 2022. [PubMed: 36335793] [Full Text: https://doi.org/10.1016/j.ymgme.2022.10.006]
Boccuto, L., Aoki, K., Flanagan-Steet, H., Chen, C.-F., Fan, X., Bartel, F., Petukh, M., Pittman, A., Saul, R., Chaubey, A., Alexov, E., Tiemeyer, M., Steet, R., Schwartz, C. E. A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation. Hum. Molec. Genet. 23: 418-433, 2014. [PubMed: 24026681] [Full Text: https://doi.org/10.1093/hmg/ddt434]
Fragaki, K., Ait-El-Mkadem, S., Chaussenot, A., Gire, C., Mengual, R., Bonesso, L., Beneteau, M., Ricci, J.-E., Desquiret-Dumas, V., Procaccio, V., Rotig, A., Paquis-Flucklinger, V. Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency. Europ. J. Hum. Genet. 21: 528-534, 2013. [PubMed: 22990144] [Full Text: https://doi.org/10.1038/ejhg.2012.202]
Ishii, A., Ohta, M., Watanabe, Y., Matsuda, K., Ishiyama, K., Sakoe, K., Nakamura, M., Inokuchi, J., Sanai, Y., Saito, M. Expression cloning and functional characterization of human cDNA for ganglioside GM3 synthase. J. Biol. Chem. 273: 31652-31655, 1998. [PubMed: 9822625] [Full Text: https://doi.org/10.1074/jbc.273.48.31652]
Kim, K.-W., Kim, S.-W., Min, K.-S., Kim, C.-H., Lee, Y.-C. Genomic structure of human GM3 synthase gene (hST3Gal V) and identification of mRNA isoforms in the 5-prime-untranslated region. Gene 273: 163-171, 2001. [PubMed: 11595162] [Full Text: https://doi.org/10.1016/s0378-1119(01)00595-9]
Kim, S.-W., Lee, S.-H., Kim, K.-S., Kim, C.-H., Choo, Y.-K., Lee, Y.-C. Isolation and characterization of the promoter region of the human GM3 synthase gene. Biochim. Biophys. Acta 1578: 84-89, 2002. [PubMed: 12393190] [Full Text: https://doi.org/10.1016/s0167-4781(02)00505-5]
Lee, J. S., Yoo, Y., Lim, B. C., Kim, K. J., Song, J., Choi, M., Chae, J.-H. GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: masquerading as Rett syndrome-like phenotype. Am. J. Med. Genet. 170A: 2200-2205, 2016. [PubMed: 27232954] [Full Text: https://doi.org/10.1002/ajmg.a.37773]
Saul, R. A., Wilkes, G., Stevenson, R. E. 'Salt-and-pepper' pigmentary changes with severe mental retardation: a new neurocutaneous syndrome? Proc. Greenwood Genet. Center 2: 6-9, 1983.
Simpson, M. A., Cross, H., Proukakis, C., Priestman, D. A., Neville, D. C. A., Reinkensmeier, G., Wang, H., Wiznitzer, M., Gurtz, K., Verganelaki, A., Pryde, A., Patton, M. A., Dwek, R. A., Butters, T. D., Platt, F. M., Crosby, A. H. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nature Genet. 36: 1225-1229, 2004. [PubMed: 15502825] [Full Text: https://doi.org/10.1038/ng1460]
Wang, H., Wang, A., Wang, D., Bright, A., Sency, V., Zhou, A., Xin, B. Early growth and development impairments in patients with ganglioside GM3 synthase deficiency. Clin. Genet. 89: 625-629, 2016. [PubMed: 26649472] [Full Text: https://doi.org/10.1111/cge.12703]
Yamashita, T., Hashiramoto, A., Haluzik, M., Mizukami, H., Beck, S., Norton, A., Kono, M., Tsuji, S., Daniotti, J. L., Werth, N., Sandhoff, R., Sandhoff, K., Proia, R. L. Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc. Nat. Acad. Sci. 100: 3445-3449, 2003. [PubMed: 12629211] [Full Text: https://doi.org/10.1073/pnas.0635898100]
Yoshikawa, M., Go, S., Takasaki, K., Kakazu, Y., Ohashi, M., Nagafuku, M., Kabayama, K., Sekimoto, J., Suzuki, S., Takaiwa, K., Kimitsuki, T., Matsumoto, N., Komune, S., Kamei, D., Saito, M., Fujiwara, M., Iwasaki, K., Inokuchi, J. Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti. Proc. Nat. Acad. Sci. 106: 9483-9488, 2009. [PubMed: 19470479] [Full Text: https://doi.org/10.1073/pnas.0903279106]
Zeng, G., Gao, L., Xia, T., Tencomnao, T., Yu, R. K. Characterization of the 5-prime-flanking fragment of the human GM3-synthase gene. Biochim. Biophys. Acta 1625: 30-35, 2003. [PubMed: 12527423] [Full Text: https://doi.org/10.1016/s0167-4781(02)00573-0]