Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.

[lymphedemapeople]

Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.

J Med Genet. 2009 Mar

Ghalamkarpour A, Holnthoner W, Saharinen P, Boon LM, Mulliken JB,
Alitalo K, Vikkula M.
Laboratory of Human Molecular Genetics, de Duve Institute, Université
catholique de Louvain, Belgium.

BACKGROUND: Heterozygous mutations in VEGFR3 have been identified in
some familial cases with dominantly inherited primary congenital
lymphoedema, known as Nonne-Milroy disease. Recessive cases of primary
lymphoedema with a genetic cause are not known, except for two
families with syndromic hypotrichosis-lymphoedema-telangiectasia, with
a SOX18 mutation.

RESULTS: In this study, we present the first case of isolated primary
congenital lymphoedema with recessive inheritance, caused by a
homozygous mutation in VEGFR3. The novel mutation is a transition from
alanine-to-threonine in amino acid 855, located in the ATP binding
domain of the VEGFR3 receptor. Assessment of receptor function showed
impaired ligand-induced internalization and ERK1/2 activity. Moreover,
receptor phosphorylation was reduced, although, less so than for a
kinase-dead VEGFR3 mutation, which causes Nonne-Milroy disease.

CONCLUSION: A hypomorphic VEGFR3 mutation, with moderate effect on
receptor function, in a homozygous state can result in insufficient
lymphatic functioning. Thus, in addition to Nonne-Milroy disease with
dominant inheritance, VEGFR3 alterations can cause isolated recessive
primary congenital lymphoedema. These data expand our understanding of
the aetiology of congenital lymphoedema and suggest that large sale
screening of VEGFR3 in all primary lymphoedema patients is necessary.

Journal of Medical Genetics / British Medical Journal

http://jmg.bmj.com/cgi/rapidpdf/jmg.2008.064469v1