Milroy's Disease (lymphedema) and the VEGFR3 (FLT3)

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Milroy's Disease (lymphedema) and the VEGFR3 (FLT3)

Postby patoco » Wed Sep 20, 2006 1:24 pm

Congenital hereditary lymphedema (Milroy's Disease) and the VEGFR3 (FLT3)

August 2006

Wide clinical spectrum in a family with hereditary lymphedema type I
due to a novel missense mutation in VEGFR3.

Spiegel R, Ghalamkarpour A, Daniel-Spiegel E, Vikkula M, A Shalev S.
Genetic Institute, Ha'Emek Medical Center, Afula, 18101, Israel.

Hereditary lymphedema type I (HL-I), also known as Milroy disease, is
an autosomal dominant disorder characterized by typical phenotype of
infantile onset lower-limb lymphedema accompanied by variable
expression of recurrent episodes of cellulites, toenail changes, and
papillomatosis. Mutations in the vascular endothelial growth factor
receptor 3 (VEGFR3), also known as FLT4 gene, which encodes a lymphatic endothelial-specific tyrosine kinase receptor, have been identified as a genetic cause of HL-I. We report a large Muslim Arab family residing in northern Israel with 14 individuals presenting clinical features of HL-I. Genetic analysis revealed novel missense mutation E1106K in the tyrosine kinase domain II of VEGFR3 that cosegregates with the disorder in the family. Most affected individuals presented with bilateral congenital lower-limb lymphedema. Wide intrafamilial phenotypic
variability included two asymptomatic individuals, a case of prenatal
hydrothorax evolving to hydrops fetalis, and a late-onset complication,
yet unreported, of chronic degenerative joint disease of the knees.
This report broadens the known "classic" phenotype of HL-I.

PMID: 16924388 [PubMed - as supplied by publisher] ... etrieve&...


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

Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M.
Laboratory of Human Molecular Genetics, Christian de Duve Institute of
Cellular Pathology and Universite catholique de Louvain, B-1200
Brussels, Belgium.

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

Full text article: ... ed&pubme...


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