Alternative titles; symbols
HGNC Approved Gene Symbol: SPARC
Cytogenetic location: 5q33.1 Genomic coordinates (GRCh38): 5:151,661,096-151,686,915 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q33.1 | Osteogenesis imperfecta, type XVII | 616507 | Autosomal recessive | 3 |
SPARC is a matrix-associated protein that elicits changes in cell shape, inhibits cell-cycle progression, and influences the synthesis of extracellular matrix (ECM) (Bradshaw et al., 2003).
Using Northern blot analysis, Mason et al. (1986) found variable Sparc expression in all adult mouse tissues examined and at all embryonic stages examined. During development, Sparc expression was higher in extraembryonic tissues than in embryos.
Using the mouse cDNA isolated by Mason et al. (1986), Swaroop et al. (1988) cloned human SPARC from a placenta cDNA library. The deduced 303-amino acid protein has an N-terminal signal peptide, followed by a putative calcium-binding domain rich in glutamic acid residues, a cysteine-rich domain, an alpha-helical domain, and a C-terminal calcium-binding domain containing an EF-hand motif. Human and mouse SPARC share 93% amino acid identity. Northern blot analysis revealed variable expression of a major 2.2-kb transcript in all fetal, newborn, and adult human tissues examined and in most human cell lines examined. A minor transcript of 3.0 kb was also observed that differed from the major transcript only in the use of downstream polyadenylation signals.
SPARC is identical to osteonectin (from Latin verb nectere, to bind, bridge, or link), a protein important to bone calcification that was identified in cow by Termine et al. (1981). It is a 32,000-dalton, bone-specific phosphoprotein that binds selectively to hydroxyapatite and to collagen fibrils at distinct sites. Osteonectin accounts for the unique property of bone collagen to undergo calcification; type I collagen of bone is identical to that of skin and tendon (see 120150). In bone, it is present in a concentration of 2.3 micrograms per 10 micrograms of protein. It is present also in dentin but absent from all other tissues. By comparison of protein sequences as well as investigation of the genes, Findlay et al. (1988) concluded that osteonectin is highly conserved among species.
Young et al. (1990) cloned human osteonectin from a bone cDNA library. The deduced protein is identical to the predicted placental form. Northern blot analysis detected a prominent 2.2-kb transcript that showed highest expression in cultured human bone, gingiva, periodontal ligament, and fetal skin cells. In placental tissues, predominant osteonectin expression was detected in expanding decidua during early pregnancy.
Using in situ hybridization and immunohistochemical analysis of human embryonic and fetal tissues, Mundlos et al. (1992) found widespread osteonectin expression, predominantly in tissues undergoing rapid proliferation. In mineralized tissues, high expression was detected in osteoblasts, odontoblasts, and chondrocytes of the upper hypertrophic and proliferative zones. High expression was also detected in odontoblasts of developing teeth, in steroid-producing cells of the adrenal gland and gonads, and in kidney glomeruli, lung bronchi, skin, megakaryocytes, and large vessels. Histochemical analysis detected extracellular osteonectin in bone and in the zone of mineralized cartilage only.
By Southern analysis of somatic cell hybrid DNA, Swaroop and Francke (1987) assigned the human SPARC gene to chromosome 5 and found RFLPs for the same. Swaroop et al. (1988) narrowed the assignment to chromosome 5q31-q33 by in situ chromosomal hybridization. By fluorescence in situ hybridization, Le Beau et al. (1993) mapped the SPARC gene to chromosome 5q31.3-q32.
Naylor et al. (1989) demonstrated RFLPs of the osteonectin gene that should be useful as markers on chromosome 5 and for investigating the possible role of osteonectin in bone diseases.
The mouse Sparc gene is located on chromosome 11 (Mason et al., 1986).
SPARC, which can be selectively expressed by the endothelium in response to certain types of injury, induces rounding in adherent endothelial cells in vitro. From the results of studies on the influence of SPARC on endothelial permeability, Goldblum et al. (1994) concluded that SPARC regulates endothelial barrier function through F-actin-dependent changes in cell shape, coincident with the appearance of intercellular gaps, that provide a paracellular pathway for extravasation of macromolecules.
By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Among the lung metastasis signature genes identified, several, including SPARC, were functionally validated. Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature.
Using human pancreatic carcinoma cells and mouse fibroblasts, Seux et al. (2011) found that TP53INP1 (606185) inactivation increased cell migration in vivo and in vitro by reversing TP53INP1-mediated inhibition of SPARC expression. Knockdown of SPARC reduced migratory capacity of pancreatic cancer cells independent of TP53INP1 expression.
Osteogenesis Imperfecta, Type XVII
In 2 unrelated girls with osteogenesis imperfecta (OI17; 616507), Mendoza-Londono et al. (2015) performed whole-exome sequencing and identified homozygosity for missense variants in the SPARC gene, R166H (182120.0001) and E263K (182120.0002), respectively. The mutations, which segregated with disease in each family, were not found in in-house or public variant databases. The migration of collagen type I alpha chains (see COL1A1, 120150) produced by patient fibroblasts was mildly delayed, suggesting some overmodification of collagen during triple-helical formation. Mendoza-Londono et al. (2015) noted that the 2 residues involved had been shown (Sasaki et al., 1998) to interact directly with each other, forming an intramolecular salt bridge that is essential for SPARC binding to collagen type I.
Associations Pending Confirmation
For discussion of a possible association between variation in the SPARC gene and keratoconus, see KTCN1 (148300).
Gilmour et al. (1998) generated Sparc-deficient mice by targeted disruption. The mice appeared normal and fertile until around 6 months of age, when they developed severe eye pathology characterized by cataract formation and rupture of the lens capsule. The first sign of lens pathology occurred in the equatorial bow region where vacuoles gradually formed within differentiating epithelial cells and fiber cells. The lens capsule, however, showed no qualitative changes in the major basal lamina proteins laminin, collagen IV, perlecan, or entactin.
The absence of Sparc in mice gives rise to aberrations in the structure and composition of the extracellular matrix that result in generation of cataracts, development of severe osteopenia, and accelerated closure of dermal wounds. Bradshaw et al. (2003) showed that Sparc-null mice have greater deposits of subcutaneous fat and larger epididymal fat pads in comparison with wildtype mice. Similar to earlier studies of SPARC-null dermis, they observed a reduction in collagen I in Sparc-null fat pads in comparison with wildtype. Although elevated levels of serum leptin were observed in Sparc-null mice, their overall body weights were not significantly different from those of wildtype counterparts. The diameters of adipocytes in epididymal fat pads from Sparc-null versus wildtype mice were 252 +/- 61 and 161 +/- 33 microM, respectively, and there was an increase in adipocyte number within the Sparc-null fat pads in comparison with wildtype pads. Thus, the absence of Sparc appeared to result in an increase in the size of individual adipocytes as well as an increase in the number of adipocytes per fat pad. In fat pads isolated from wildtype mice, Sparc mRNA was associated with both the stromal/vascular and adipocyte fractions. Bradshaw et al. (2003) proposed that Sparc limits the accumulation of adipose tissue in mice in part through its demonstrated effects on the regulation of cell shape and production of the extracellular matrix.
Brekken et al. (2003) reported that implanted tumors grew more rapidly in Sparc-null mice than in wildtype mice and showed alterations in the production and organization of ECM components and a decrease in the infiltration of macrophages. There was no difference in the levels of angiogenic growth factors, although there was a statistically significant decrease in total vascular area in tumors grown in Sparc-null mice. Brekken et al. (2003) concluded that endogenous SPARC is important for the appropriate organization of the ECM in response to implanted tumors and that the ECM has a crucial role in regulating tumor growth.
In laser-injury studies in mice, Nozaki et al. (2006) observed that injury-induced choroidal neovascularization (CNV) was increased by excess Vegf (192240) before injury but was suppressed by Vegf after injury. This effect was mediated via Vegfr1 (FLT1; 165070) activation and Vegfr2 (KDR; 191306) deactivation: excess Vegf increased CNV before injury because Vegfr1 activation was silenced by Sparc, and a transient decline in Sparc after injury created a temporal window in which Vegf signaling was routed primarily through Vegfr1.
In a 14-year-old girl from a family of North African origin (individual 1) with osteogenesis imperfecta (OI17; 616507), Mendoza-Londono et al. (2015) identified homozygosity for a c.497G-A transition (c.497G-A, NM_003118.3) in exon 7 of the SPARC gene, resulting in an arg166-to-his (R166H) substitution at a highly conserved residue in the extracellular collagen-binding (EC) domain. The R166H mutation was present in heterozygosity in the unaffected parents, who came from the same geographically restricted area and were shown to share common ancestry; the variant was not found in an in-house exome database or the dbSNP, 1000 Genomes Project, NHLBI/NHGRI Exome Project, or ExAC databases. Patient fibroblasts secreted a reduced amount of SPARC compared to controls; SDS-PAGE showed a mild delay in the migration of collagen type I alpha chains (see COL1A1, 120150) produced by patient fibroblasts, and pulse-chase experiments indicated a delay in the secretion of procollagen type I.
In a 7-year-old girl (individual 2) with osteogenesis imperfecta (OI17; 616507), born of consanguineous Indian parents, Mendoza-Londono et al. (2015) identified homozygosity for a c.787G-A transition (c.787G-A, NM_003118.3) in exon 9 of the SPARC gene, resulting in a glu263-to-lys (E263K) substitution at a highly conserved residue in the extracellular collagen-binding (EC) domain. The mutation was present in heterozygosity in her unaffected parents, but was not found in an in-house exome database or the dbSNP, 1000 Genomes Project, NHLBI/NHGRI Exome Project, or ExAC databases. Patient fibroblasts secreted a normal amount of SPARC compared to controls; however, SDS-PAGE showed a mild delay in the migration of collagen type I alpha chains (see COL1A1, 120150) produced by patient fibroblasts, and pulse-chase experiments indicated a delay in the secretion of procollagen type I.
Bradshaw, A. D., Graves, D. C., Motamed, K., Sage, E. H. SPARC-null mice exhibit increased adiposity without significant differences in overall body weight. Proc. Nat. Acad. Sci. 100: 6045-6050, 2003. [PubMed: 12721366] [Full Text: https://doi.org/10.1073/pnas.1030790100]
Brekken, R. A., Puolakkainen, P., Graves, D. C., Workman, G., Lubkin, S. R., Sage, E. H. Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J. Clin. Invest. 111: 487-495, 2003. [PubMed: 12588887] [Full Text: https://doi.org/10.1172/JCI16804]
Findlay, D. M., Fisher, L. W., McQuillan, C. I., Termine, J. D., Young, M. F. Isolation of the osteonectin gene: evidence that a variable region of the osteonectin molecule is encoded within one exon. Biochemistry 27: 1483-1489, 1988. [PubMed: 2835093] [Full Text: https://doi.org/10.1021/bi00405a013]
Gilmour, D. T., Lyon, G. J., Carlton, M. B. L., Sanes, J. R., Cunningham, J. M., Anderson, J. R., Hogan, B. L. M., Evans, M. J., Colledge, W. H. Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age-onset cataract formation and disruption of the lens. EMBO J. 17: 1860-1870, 1998. [PubMed: 9524110] [Full Text: https://doi.org/10.1093/emboj/17.7.1860]
Goldblum, S. E., Ding, X., Funk, S. E., Sage, E. H. SPARC (secreted protein acidic and rich in cysteine) regulates endothelial cell shape and barrier function. Proc. Nat. Acad. Sci. 91: 3448-3452, 1994. [PubMed: 8159767] [Full Text: https://doi.org/10.1073/pnas.91.8.3448]
Le Beau, M. M., Espinosa, R., III, Neuman, W. L., Stock, W., Roulston, D., Larson, R. A., Keinanen, M., Westbrook, C. A. Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases. Proc. Nat. Acad. Sci. 90: 5484-5488, 1993. [PubMed: 8516290] [Full Text: https://doi.org/10.1073/pnas.90.12.5484]
Mason, I. J., Murphy, D., Munke, M., Francke, U., Elliott, R. W., Hogan, B. L. M. Developmental and transformation-sensitive expression of the SPARC gene on mouse chromosome 11. EMBO J. 5: 1831-1837, 1986. [PubMed: 3758028] [Full Text: https://doi.org/10.1002/j.1460-2075.1986.tb04434.x]
Mason, I. J., Taylor, A., Williams, J. G., Sage, H., Hogan, B. L. M. Evidence from molecular cloning that SPARC, a major product of mouse embryo parietal endoderm, is related to an endothelial cell 'culture shock' glycoprotein of Mr 43,000. EMBO J. 5: 1465-1472, 1986. [PubMed: 3755680] [Full Text: https://doi.org/10.1002/j.1460-2075.1986.tb04383.x]
Mendoza-Londono, R., Fahiminiya, S., Majewski, J., Care4Rare Canada Consortium, Tetreault, M., Nadaf, J., Kannu, P., Sochett, E., Howard, A., Stimec, J., Dupuis, L., Roschger, P., and 9 others. Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am. J. Hum. Genet. 96: 979-985, 2015. [PubMed: 26027498] [Full Text: https://doi.org/10.1016/j.ajhg.2015.04.021]
Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., Viale, A., Olshen, A. B., Gerald, W. L., Massague, J. Genes that mediate breast cancer metastasis to lung. Nature 436: 518-524, 2005. [PubMed: 16049480] [Full Text: https://doi.org/10.1038/nature03799]
Mundlos, S., Schwahn, B., Reichert, T., Zabel, B. Distribution of osteonectin mRNA and protein during human embryonic and fetal development. J. Histochem. Cytochem. 40: 283-291, 1992. [PubMed: 1552170] [Full Text: https://doi.org/10.1177/40.2.1552170]
Naylor, S. L., Helen-Davis, D., Villarreal, X. C., Long, G. L. The human osteonectin gene on chromosome 5 is polymorphic. (Abstract) Cytogenet. Cell Genet. 51: 1051 only, 1989.
Nozaki, M., Sakurai, E., Raisler, B. J., Baffi, J. Z., Witta, J., Ogura, Y., Brekken, R. A., Sage, E. H., Ambati, B. K., Ambati, J. Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. J. Clin. Invest. 116: 422-429, 2006. [PubMed: 16453023] [Full Text: https://doi.org/10.1172/JCI26316]
Sasaki, T., Hohenester, E., Goehring, W., Timpl, R. Crystal structure and mapping by site-directed mutagenesis of the collagen-binding epitope of an activated form of BM-40/SPARC/osteonectin. EMBO J. 17: 1625-1634, 1998. [PubMed: 9501084] [Full Text: https://doi.org/10.1093/emboj/17.6.1625]
Schwartz, R. C., Young, M. F., Tsipouras, P. Two RFLPs in the 5-prime end of the human osteonectin (ON) gene. Nucleic Acids Res. 16: 9076 only, 1988. [PubMed: 2902577] [Full Text: https://doi.org/10.1093/nar/16.18.9076]
Seux, M., Peuget, S., Montero, M. P., Siret, C., Rigot, V., Clerc, P., Gigoux, V., Pellegrino, E., Pouyet, L., N'Guessan, P., Garcia, S., Dufresne, M., Iovanna, J. L., Carrier, A., Andre, F., Dusetti, N. J. TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression. Oncogene 30: 3049-3061, 2011. [PubMed: 21339733] [Full Text: https://doi.org/10.1038/onc.2011.25]
Stenner, D. D., Tracy, R. P., Riggs, B. L., Mann, K. G. Human platelets contain and secrete osteonectin, a major protein of mineralized bone. Proc. Nat. Acad. Sci. 83: 6892-6896, 1986. [PubMed: 3489235] [Full Text: https://doi.org/10.1073/pnas.83.18.6892]
Swaroop, A., Francke, U. Molecular cloning, cDNA sequence, and expression of human SPARC (osteonectin). (Abstract) Am. J. Hum. Genet. 41: A240 only, 1987.
Swaroop, A., Hogan, B. L. M., Francke, U. Molecular analysis of the cDNA for human SPARC/osteonectin/BM-40: sequence, expression, and localization of the gene to chromosome 5q31-q33. Genomics 2: 37-47, 1988. [PubMed: 2838412] [Full Text: https://doi.org/10.1016/0888-7543(88)90107-3]
Termine, J. D., Kleinman, H. K., Whitson, S. W., Conn, K. M., McGarvey, M. L., Martin, G. R. Osteonectin, a bone-specific protein linking mineral to collagen. Cell 26: 99-105, 1981. [PubMed: 7034958] [Full Text: https://doi.org/10.1016/0092-8674(81)90037-4]
Young, M. F., Day, A. A., Dominquez, P., McQuillan, C. I., Fisher, L. W., Termine, J. D. Structure and expression of osteonectin mRNA in human tissue. Connect. Tissue Res. 24: 17-28, 1990. [PubMed: 2338025] [Full Text: https://doi.org/10.3109/03008209009152419]