Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase

Hereditary lymphedema is a chronic swelling of limbs due to dysfunction of lymphatic vessels. An autosomal dominant, congenital form of the disease, a lso known as "Milroy disease," has been mapped to the telomeric part of chr omosome 5q, in the region 5q34-q35. This region contains a good candidate g ene for the disease, VEGFR3 (FLT4), that encodes a receptor tyrosine kinase specific for lymphatic vessels. To clarify the role of VEGFR3 in the etiol ogy of the disease, we have analyzed a family with hereditary lymphedema. W e show linkage of the disease with markers in 5q34-q35, including a VEGFR3 intragenic polymorphism, and we describe an A-->G transition that cosegrega tes with the disease, corresponding to a histidine-to-arginine substitution in the catalytic loop of the protein. In addition, we show, by in vitro ex pression, that this mutation inhibits the autophosphorylation of the recept or. Thus, defective VEGFR3 signaling seems to be the cause of congenital he reditary lymphedema linked to 5q34-q35.