Further downstream in the VEGFR3 transduction cascade, a missense germline INPPL1 mutation affecting Sh2-domain-containing 5’-inositol phosphatase 2 (SHIP-2), an intracellular adapter protein that negatively regulates PI3K/Akt and MAPK/ERK activation, was isolated in some patients with primary lymphedema [73]. This evidence concerns the gene INPPL1 and primary lymphedema.