Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: SORT1
Cytogenetic location: 1p13.3 Genomic coordinates (GRCh38): 1:109,309,575-109,397,918 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.3 | [Low density lipoprotein cholesterol level QTL6] | 613589 | Autosomal dominant | 3 |
Sortilin is a VPS10-containing receptor that binds neuropeptides. It derives its name from the yeast vacuolar protein sorting protein-10, which is involved in sorting of carboxy-peptidase Y from the Golgi apparatus to the vacuole (Marcusson et al., 1994).
Petersen et al. (1997) used RAP (104225) affinity chromatography of membrane protein extracts to isolate the RAP-binding protein sortilin. By cDNA library screening, they cloned the corresponding gene, which encodes an 833-amino acid polypeptide with a predicted molecular mass of 89 kD. The sequence includes a putative secretory signal peptide, a furin cleavage site, and a single transmembrane domain. It is homologous to the yeast protein Vps10p and the human sortilin-related receptor (602005). The C terminus of the protein contains a lysosomal sorting motif shared by the mannose-6-phosphate receptors. Expression of the sortilin gene in COS-1 cells results in the appearance of a 95-kD protein in the endoplasmic reticulum and Golgi. By Northern blotting, Petersen et al. (1997) showed that the gene is expressed as 8- and 3.5-kb transcripts at high levels in brain, spinal cord, heart, skeletal muscle, thyroid, placenta, and testis.
Mazella et al. (1998) demonstrated that the 100-kD neurotensin receptor (NT3) is identical to sortilin (Petersen et al., 1997). They stated that NT3 does not belong to the superfamily of G protein-coupled receptors.
Rat adipocyte vesicles containing the glucose transporter Glut4 (SLC2A4; 138190) also contain a major 110-kD protein. Morris et al. (1998) found that this 110-kD protein is sortilin. Subcellular fractionation of rat and 3T3-L1 adipocytes, together with Glut4 vesicle isolation, showed that sortilin is primarily located in the low density microsomes of vesicles containing Glut4. Insulin (INS; 176730) caused an increase in the amount of sortilin at the plasma membranes of 3T3-L1 adipocytes, as assessed by cell surface biotinylation. The expression of sortilin in 3T3-L1 cells occurred only upon differentiation.
Nykjaer et al. (2004) demonstrated that the precursor of nerve growth factor (NGF; 162030), proNGF, creates a signaling complex by simultaneously binding to p75(NTR) (162010) and sortilin. Sortilin acts as a coreceptor and molecular switch governing the p75(NTR)-mediated proapoptotic signal induced by proNGF. Together with p75(NTR), sortilin facilitates the formation of a composite high-affinity binding site for proNGF. Thus, sortilin serves as a coreceptor and molecular switch, enabling neurons expressing TRK (191315) and p75(NTR) to respond to a proneurotrophin and to initiate proapoptotic rather than prosurvival actions. In the absence of sortilin, regulated activity of extracellular proteases may cleave proNGF to mature NGF, promoting TRK-mediated survival signals. Nykjaer et al. (2004) concluded that NGF-induced neuronal survival and death is far more complicated than previously appreciated, as it depends on an intricate balance between proNGF and mature NGF, as well as on the spatial and temporal expression of 3 distinct receptors: TRKA, p75(NTR), and sortilin.
Shi and Kandror (2005) found that expression of sortilin in mouse preadipocytes increased the formation of Glut4-containing storage vesicles and stimulated insulin-regulated glucose uptake, whereas partial knockdown of sortilin using RNA interference had the opposite effect.
Hu et al. (2010) found in cellular studies that SORT1 is a cell surface binding site for PGRN (138945). PGRN binds to SORT1 on cortical neurons via its C terminus, and the complex undergoes endocytosis, with delivery of PGRN to lysosomes. PGRN was induced in activated microglia cells surrounding motor neurons after murine spinal cord injury. Sort1-null mice had 5-fold increased levels of Pgrn in brain and serum, suggesting that SORT1 can control PGRN levels in vivo. Hu et al. (2010) suggested a role for the endosomal/autophagosomal/lysosomal pathway in the pathogenesis of GRN-related FTLD (607485).
By in silico genomics, Hampe et al. (2001) elucidated the exon-intron structures of the human VPS10-receptor genes, including sortilin, sortilin-related receptor (602005), SORCS1 (606283), SORCS2 (606284), and SORCS3 (606285). They contain many short exons, separated by introns, several of which extend over more than 50 kb.
SORT1 Transcription Factor Binding Site 1
Musunuru et al. (2010) demonstrated that a common noncoding polymorphism at chromosome 1p13, rs12740374, creates a CEBP (116897) transcription factor binding site and alters hepatic expression of the SORT1 gene. The SNP rs12740374 lies in a 6.1-kb noncoding region between the CELSR2 (604265) and PSRC1 (613126) genes. The minor allele (T) creates the binding site and the major allele (G) disrupts it. Electrophoretic mobility shift assays and chromatin immunoprecipitation confirmed that CEBP bound to the predicted consensus site. Quantitative RT-PCR demonstrated that CEBP proteins influence SORT1 expression via rs12740374, with the minor allele at rs12740374 resulting in increased SORT1 expression. Results of experiments in mice were concordant with the genetic findings in human cohorts, in whom the 1p13 minor haplotype was associated with increased liver SORT1 expression and decreased LDL-C and, especially, very small LDL particles.
Petersen et al. (1997) used fluorescence in situ hybridization to map the SORT1 gene to chromosome 1p21.3-p13.1.
Through a series of studies in human cohorts, mice, and hepatocytes, Musunuru et al. (2010) provided evidence that a single noncoding DNA variant at chromosome 1p13, rs12740374, influences LDL cholesterol and myocardial infarction (MI) risk (LDLCQ6; 613589) via liver-specific transcriptional regulation of the SORT1 gene by CEBP transcription factors. Whereas the minor allele (T) of rs12740374 creates a transcription factor binding site, the major allele (G) disrupts it. Binding of CEBP transcription factors to the site results in increased SORT1 expression and decreased LDL-C and, especially, very small LDL particles. The clinical importance of this pathway is defined by the approximately 40% difference in MI risk between alternative 1p13 homozygotes, an effect comparable to those of common variants of LDLR (606945) and PCSK9 (607786) and larger than the effects of common variants in HMGCR (142910), the target of statin drugs (Samani et al., 2007; Myocardial Infarction Genetics Consortium, 2009). As the 1p13 minor allele frequency is about 30% in Europeans and is also common in other ethnicities including African Americans, Hispanics, Asian Indians, and Chinese, this locus is an important global determinant of MI risk.
Hampe, W., Rezgaoui, M., Hermans-Borgmeyer, I., Schaller, H. C. The genes for the human VPS10 domain-containing receptors are large and contain many small exons. Hum. Genet. 108: 529-536, 2001. [PubMed: 11499680] [Full Text: https://doi.org/10.1007/s004390100504]
Hu, F., Padukkavidana, T., Vaegter, C. B., Brady, O. A., Zheng, Y., Mackenzie, I. R., Feldman, H. H., Nykjaer, A., Strittmatter, S. M. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68: 654-667, 2010. [PubMed: 21092856] [Full Text: https://doi.org/10.1016/j.neuron.2010.09.034]
Marcusson, E. G., Horazdovsky, B. F., Cereghino, J. L., Gharakhanian, E., Emr, S. D. The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene. Cell 77: 579-586, 1994. [PubMed: 8187177] [Full Text: https://doi.org/10.1016/0092-8674(94)90219-4]
Mazella, J., Zsurger, N., Navarro, V., Chabry, J., Kaghad, M., Caput, D., Ferrara, P., Vita, M., Gully, D., Maffrand, J.-P., Vincent, J.-P. The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor. J. Biol. Chem. 273: 26273-26276, 1998. [PubMed: 9756851] [Full Text: https://doi.org/10.1074/jbc.273.41.26273]
Morris, N. J., Ross, S. A., Lane, W. S., Moestrup, S. K., Petersen, C. M., Keller, S. R., Lienhard, G. E. Sortilin is the major 110-kDa protein in GLUT4 vesicles from adipocytes. J. Biol. Chem. 273: 3582-3587, 1998. [PubMed: 9452485] [Full Text: https://doi.org/10.1074/jbc.273.6.3582]
Musunuru, K., Strong, A., Frank-Kamenetsky, M., Lee, N. E., Ahfeldt, T., Sachs, K. V., Li, X., Li, H., Kuperwasser, N., Ruda, V. M., Pirruccello, J. P., Muchmore, B., and 18 others. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466: 714-719, 2010. [PubMed: 20686566] [Full Text: https://doi.org/10.1038/nature09266]
Myocardial Infarction Genetics Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nature Genet. 41: 334-341, 2009. Erratum: Nature Genet. 41: 762 only, 2009. [PubMed: 19198609] [Full Text: https://doi.org/10.1038/ng.327]
Nykjaer, A., Lee, R., Teng, K. K., Jansen, P., Madsen, P., Nielsen, M. S., Jacobsen, C., Kliemannel, M., Schwarz, E., Willnow, T. E., Hempstead, B. L., Petersen, C. M. Sortilin is essential for proNGF-induced neuronal cell death. Nature 427: 843-848, 2004. [PubMed: 14985763] [Full Text: https://doi.org/10.1038/nature02319]
Petersen, C. M., Nielsen, M. S., Nykjaer, A., Jacobsen, L., Tommerup, N., Rasmussen, H. H., Roigaard, H., Gliemann, J., Madsen, P., Moestrup, S. K. Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. J. Biol. Chem. 272: 3599-3605, 1997. [PubMed: 9013611] [Full Text: https://doi.org/10.1074/jbc.272.6.3599]
Samani, N. J., Erdmann, J., Hall, A. S., Hengstenberg, C., Mangino, M., Mayer, B., Dixon, R. J., Meitinger, T., Braund, P., Wichmann, H.-E., Barrett, J. H., Konig, I. R., and 23 others. Genomewide association analysis of coronary artery disease. New Eng. J. Med. 357: 443-453, 2007. [PubMed: 17634449] [Full Text: https://doi.org/10.1056/NEJMoa072366]
Shi, J., Kandror, K. V. Sortilin is essential and sufficient for the formation of Glut4 storage vesicles in 3T3-L1 adipocytes. Dev. Cell 9: 99-108, 2005. [PubMed: 15992544] [Full Text: https://doi.org/10.1016/j.devcel.2005.04.004]