Table 1.
Important genes for lymphatic development and/or VEGF-C activation, which are involved in human hereditary disorders. Mutations in the VEGF-C-activating proteases are not associated with any lymphatic phenotype except for ADAMTS3, arguing that only ADAMTS3 is essential for lymphatic development.
| Gene | Protein | Human Disease (OMIM) | Remarks |
|---|---|---|---|
| Genes within the VEGF-C/VEGFR-3 signaling pathway; for clinical details see [130], and for molecular details [141] | |||
| VEGFC | Vascular Endothelial Growth Factor-C (VEGF-C) | Hereditary lymphedema type 1D (615907) | VEGF-C is the primary growth factor for lymphatic endothelial cells. |
| FLT4 | Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) | Hereditary lymphedema type 1A (Milroy disease, 153100) | VEGFR-3 is the primary receptor of VEGF-C. |
| CCBE1 | Collagen and calcium-binding EGF domain-containing protein 1 | Hennekam lymphangiectasia-lymphedema syndrome type 1 (235510) | Enhances the processing of VEGF-C by ADAMTS3 and KLK3. |
| ADAMTS3 | A disintegrin and metalloproteinase with thrombospondin motifs 3 | Hennekam lymphangiectasia-lymphedema syndrome type 3 (618154) | ADAMTS3 catalyzes the final step in the activation of VEGF-C. |
| Genes coding for proteases that can activate VEGF-C and/or VEGF-D (no lymphatic phenotype reported) | |||
| ADAMTS14 | A disintegrin and metalloproteinase with thrombospondin motifs 14 | Association with age of onset in tendinopathy [142] | ADAMTS14 can activate VEGF-C in vitro [65]. |
| KLK3 | Kallikrein-like peptidase 3, Prostate-specific antigen (PSA) | Association with human fertility [91] | KLK3/PSA is most commonly known as a prostate cancer marker [143]. |
| CTSD | Cathepsin D | Neuronal Ceroid Lipofuscinosis type 10 (610127) | CTSD deficiency causes a neurodegenerative disorder [144]. |
| F2 | Prothrombin/Thrombin | Hereditary thrombophilia type 1 (188050) | Specific F2 mutations increase the risk of venous thromboembolism [145]. Thrombin potentiates vascular endothelial growth factor- (VEGF-) induced endothelial cell proliferation [146]. |
| PLG | Plasminogen/Plasmin | Plasminogen deficiency type 1 (217090) | PLG deficiency leads to pathological fibrin deposition but no increased risk of thrombosis [147]. |
| Selected other “lymphedema” genes; for a comprehensive listing, see [130] | |||
| FOXC2 | Forkhead box protein C2 | Lymphedema distichiasis syndrome (153400) | The maturation of lymphatic vessels and the formation of lymphatic valves requires FOXC2 [148,149]. |
| GJC2 | Connexin 47 | Hereditary lymphedema type 1C (613480) | CJC2 is a gap junction protein that enables communication between lymphatic endothelial cells [150]. |
| FAT4 | Protocadherin Fat 4 | Hennekam lymphangiectasia-lymphedema syndrome type 2 (616006) | FAT4 is required for lymphatic endothelial cell polarity and might influence VEGFR-3 signaling [139]. |
| Van Maldergem syndrome type 2 (615546) | Van Maldergem syndrome 2 has overlapping features with Hennekam syndrome type 2 but none or only infrequent lymphatic involvement [151]. | ||