Alternative titles; symbols
HGNC Approved Gene Symbol: VEGFC
Cytogenetic location: 4q34.3 Genomic coordinates (GRCh38): 4:176,683,538-176,792,922 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q34.3 | Lymphatic malformation 4 | 615907 | Autosomal dominant | 3 |
The VEGFC gene encodes a ligand for vascular endothelial growth factor-3 (VEGFR3), also known as FLT4 (136352), a receptor tyrosine kinase expressed mainly in lymphatic endothelia (Joukov et al., 1996).
Joukov et al. (1996) used affinity chromatography to isolate the ligand of FLT4. They found it to be a polypeptide of 23 kD and determined its N-terminal protein sequence. Degenerate oligonucleotides based on this N-terminal sequence were used to clone the corresponding cDNA from a human PC-3 cell cDNA library. The resulting clone was named VEGFC. Lee et al. (1996) cloned VEGFC from a human glioma G61 cell cDNA library (GenBank HSC1WF111) using a probe based on a sequence from the EST library. Sequence analysis by Joukov et al. (1996) showed that the full-length clones contained an open reading frame of 419 amino acids with a VEGF-homologous region that is 30% identical to VEGF and 27% identical to VEGFB/VRF (601398). The N terminus contains a putative secretory signal sequence (prepro-VEGFC). Both Joukov et al. (1996) and Lee et al. (1996) noted that the C terminus of VEGFC has cysteine-rich repeat units characteristic of the Balbiani ring 3 protein (BR3P) of the midge Chironomus tentans. Transfection assays performed by Joukov et al. (1996) suggested that VEGFC forms disulfide-linked dimers and can activate both the FLT4 and KDR/FLK1 receptor tyrosine kinases. Lee et al. (1996) used competitive binding of purified components to show that VEGFC and FLT4 bind with a high affinity, suggesting that VEGFC is a biologically relevant ligand of FLT4. Joukov et al. (1996) also demonstrated that conditioned medium from cells expressing VEGFC could stimulate the growth of endothelial cells in a collagen gel matrix.
By somatic cell hybrid analysis and fluorescence in situ hybridization, Paavonen et al. (1996) mapped the VEGFC gene to chromosome 4q34.
Hung et al. (2003) investigated whether differential expression of VEGFC might explain the different propensity to lymph node metastasis in thyroid cancers. Using real-time quantitative PCR, they analyzed 111 normal and neoplastic thyroid tissues. Papillary thyroid cancers (see 188550) had a higher VEGFC expression than other thyroid malignancies (P less than 0.0005 ANOVA). Paired comparison of VEGFC expression between thyroid cancers and normal thyroid tissues from the same patients showed a significant increase of VEGFC expression in papillary thyroid cancer and a significant decrease of VEGFC expression in medullary thyroid cancer (155240). In contrast, there was no significant difference of VEGFC expression between cancer and normal tissues in other types of thyroid cancer.
Machnik et al. (2009) demonstrated that a high-salt diet in rats leads to interstitial hypertonic Na(+) accumulation in skin, resulting in increased density and hyperplasia of the lymphatic capillary network. The underlying mechanism was found to involve activation of tonicity-responsive enhancer-binding protein (TONEBP; 604708) in mononuclear phagocytes infiltrating the interstitium of the skin, which binds the VEGFC gene promoter and causes VEGFC secretion by macrophages. Depletion of mononuclear phagocytes or VEGFC trapping by soluble VEGFR3 (136352) blocks VEGFC signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase (NOS3; 163729) expression, and elevates blood pressure in response to a high-salt diet. Machnik et al. (2009) concluded that TONEBP-VEGFC signaling in mononuclear phagocytes is a major determinant of extracellular volume and blood pressure homeostasis, and that VEGFC is an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension (see 145500).
By screening immunity-related proteins and their receptors for bacteria- or LPS-induced expression, Zhang et al. (2014) detected upregulation of VEGFR3 and VEGFC in macrophages. Serum VEGFC was also increased in patient and mouse models of septic shock. Ligation of VEGFR3 by VEGFC attenuated proinflammatory cytokine production. In the absence of either the ligand-binding domain or tyrosine kinase activity of Vegfr3, mice became more sensitive to septic shock. Vegfr3 restrained Tlr4 (603030)-NFKB (see 164011) activation by regulating the PI3K (see 601232)-Akt (see 164730) signaling pathway and Socs1 (603597) expression. Zhang et al. (2014) proposed that in addition to targeting lymphatic vessels, VEGFR3 signaling via VEGFC prevents microphagic overreaction to infections complicated by lymphedema.
Song et al. (2020) used a mouse model of glioblastoma to show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumors. The immunity that is mediated by CD8 T cells to the glioblastoma antigen was very limited when the tumor was confined to the central nervous system, resulting in uncontrolled tumor growth. However, ectopic expression of VEGFC promoted enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumor, rapid clearance of the glioblastoma, and a long-lasting antitumor memory response. Furthermore, transfection of an mRNA construct that expressed VEGFC worked synergistically with checkpoint blockade therapy to eradicate existing glioblastoma.
In affected members of a family with lymphatic malformation-4 (LMPHM4; 615907), Gordon et al. (2013) identified a heterozygous truncating mutation in the VEGFC gene (c.571insTT; 601528.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro functional cellular expression assays and studies in zebrafish showed that the mutation resulted in a loss of function without a dominant-negative effect, consistent with haploinsufficiency. Screening the VEGFC gene in 16 additional patients with a similar phenotype did not identify any mutations.
In 3 members of a 3-generation Caucasian family with LMPHM4, Balboa-Beltran et al. (2014) identified a heterozygous truncating mutation in the VEGFC gene (R210X; 601528.0002). The mutation, which was found by exome sequencing, segregated with the disorder in the family. Functional studies were not performed.
Karkkainen et al. (2004) observed edema at embryonic day 12.5 and lethality after embryonic day 15 in Vegfc -/- mice. Immunohistochemical analysis revealed that lymphatic vasculature failed to develop in Vegfc -/- mice, which showed no staining for lymphatic markers that were present in heterozygous and wildtype mice. Immunofluorescence microscopy demonstrated that endothelial cells expressing Prox1 (601546), a protein required for lymph sac formation, were present in Vegfc -/- mice at early time points in the wall of the cardinal vein, but they did not sprout out to form jugular lymph sacs. Karkkainen et al. (2004) concluded that VEGFC and VEGF, unlike VEGFB and VEGFD (FIGF; 300091), are essential for embryonic survival and lymphangiogenesis.
In 7 members of a 3-generation Caucasian family with autosomal dominant lymphatic malformation-4 (LMPHM4; 615907), Gordon et al. (2013) identified a heterozygous 2-bp insertion (c.571_572insTT) in exon 4 of the VEGFC gene, resulting in a frameshift and premature termination (Pro191LeufsTer10). The mutation, which was found by whole-exome sequencing of the proband and confirmed by Sanger sequencing, segregated with the disorder in the family. Transfection of the mutation into HEK293 cells showed that secretion of the mutant variant was strongly impaired compared to wildtype. Expression of the mutant protein in zebrafish indicated that it had significantly reduced or possibly absent angiogenic activity compared to wildtype, consistent with a loss of function. There was no evidence of a dominant-negative effect, and Gordon et al. (2013) postulated haploinsufficiency as a disease mechanism.
In 3 members of a 3-generation Caucasian family with lymphatic malformation-4 (LMPHM4; 615907), Balboa-Beltran et al. (2014) identified a heterozygous c.628C-T transition in exon 4 of the VEGFC gene, resulting in an arg210-to-ter (R210X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the dbSNP and 1000 Genomes Project databases and against internal exome data. Functional studies were not performed.
Balboa-Beltran, E., Fernandez-Seara, M. J., Perez-Munuzuri, A., Lago, R., Garcia-Magan, C., Couce, M. L., Sobrino, B., Amigo, J., Carracedo, A., Barros, F. A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. J. Med. Genet. 51: 475-478, 2014. Note: Erratum: J. Med. Genet. 52: 216 only, 2015. [PubMed: 24744435] [Full Text: https://doi.org/10.1136/jmedgenet-2013-102020]
Gordon, K., Schulte, D., Brice, G., Simpson, M. A., Roukens, M. G., van Impel, A., Connell, F., Kalidas, K., Jeffery, S., Mortimer, P. S., Mansour, S., Schulte-Merker, S., Ostergaard, P. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant Milroy-like primary lymphedema. Circ. Res. 112: 956-960, 2013. [PubMed: 23410910] [Full Text: https://doi.org/10.1161/CIRCRESAHA.113.300350]
Hung, C. J., Ginzinger, D. G., Zarnegar, R., Kanauchi, H., Wong, M. G., Kebebew, E., Clark, O. H., Duh, Q.-Y. Expression of vascular endothelial growth factor-C in benign and malignant thyroid tumors. J. Clin. Endocr. Metab. 88: 3694-3699, 2003. [PubMed: 12915657] [Full Text: https://doi.org/10.1210/jc.2003-030080]
Joukov, V., Pajusola, K., Kaipainen, A., Chilov, D., Lantinen, I., Kukk, E., Saksela, O., Kalkkinen, N., Alitalo, K. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 15: 290-298, 1996. Note: Erratum: EMBO J. 15: 1751 only, 1996. [PubMed: 8617204]
Karkkainen, M. J., Haiko, P., Sainio, K., Partanen, J., Taipale, J., Petrova, T. V., Jeltsch, M., Jackson, D. G., Talikka, M., Rauvala, H., Betsholtz, C., Alitalo, K. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immun. 5: 74-80, 2004. [PubMed: 14634646] [Full Text: https://doi.org/10.1038/ni1013]
Lee, J., Gray, A., Yuan, J., Luoh, S.-M., Avraham, H., Wood, W. I. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc. Nat. Acad. Sci. 93: 1988-1992, 1996. [PubMed: 8700872] [Full Text: https://doi.org/10.1073/pnas.93.5.1988]
Machnik, A., Neuhofer, W., Jantsch, J., Dahlmann, A., Tammela, T., Machura, K., Park, J.-K., Beck, F.-X., Muller, D. N., Derer, W., Goss, J., Ziomber, A., and 10 others. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nature Med. 15: 545-552, 2009. [PubMed: 19412173] [Full Text: https://doi.org/10.1038/nm.1960]
Paavonen, K., Horelli-Kuitunen, N., Chilov, D., Kukk, E., Pennanen, S., Kallioniemi, O.-P., Pajusola, K., Olafsson, B., Eriksson, U., Joukov, V., Palotie, A., Alitalo, K. Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q13 and 4q34, respectively. Circulation 93: 1079-1082, 1996. [PubMed: 8653826] [Full Text: https://doi.org/10.1161/01.cir.93.6.1079]
Song, E., Mao, T., Dong, H., Boisserand, L. S. B., Antila, S., Bosenberg, M., Alitalo, K., Thomas, J.-L., Iwasaki, A. VEGF-C-driven lymphatic drainage enables immunosurveillance of brain tumours. Nature 577: 689-694, 2020. Note: Erratum: Nature 590: E34, 2021. [PubMed: 31942068] [Full Text: https://doi.org/10.1038/s41586-019-1912-x]
Zhang, Y., Lu, Y., Ma, L., Cao, X., Xiao, J., Chen, J., Jiao, S., Gao, Y., Liu, C., Duan, Z., Li, D., He, Y., Wei, B., Wang, H. Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-kappa-beta signaling and protects against endotoxin shock. Immunity 40: 501-514, 2014. [PubMed: 24656836] [Full Text: https://doi.org/10.1016/j.immuni.2014.01.013]