Novel missense mutations in the FOXC2 gene alter transcriptional activity.

[lymphedemapeople]

Novel missense mutations in the FOXC2 gene alter transcriptional
activity.

Hum Mutat. 2009 Sep 16.

van Steensel MA, Damstra RJ, Heitink M, Bladergroen RS, Veraart J,
Steijlen PM, van Geel M.
Departments of dermatology, Maastricht University Medical Center,
Maastricht, the Netherlands.

Mutations in the FOXC2 gene that codes for a forkhead transcription
factor are associated with primary lymphedema that usually develops
around puberty. Associated abnormalities include distichiasis and,
very frequently, superficial and deep venous insufficiency. Most
mutations reported so far either truncate the protein or are missense
mutations in the forkhead domain causing a loss of function. The haplo-
insufficient state is associated with lymphatic hyperplasia in mice as
well as in humans. We analyzed the FOXC2 gene in 288 patients with
primary lymphedema and found 11 pathogenic mutations, of which 9 are
novel. Of those, 5 were novel missense mutations of which 4 were
located outside of the forkhead domain. To examine their pathogenic
potential we performed a transactivation assay using a luciferase
reporter construct driven by FOXC1 response elements. We found that
the mutations outside the forkhead domain cause a gain of function as
measured by luciferase activity. Patient characteristics conform to
previous reports with the exception of distichiasis, which was found
in only 2 patients out of 11. FOXC2 mutations causing lymphedema-
distichiasis syndrome reported thus far result in haplo-insufficiency
and lead to lymphatic hyperplasia. Our results suggest that gain-of-
function mutations may also cause lymphedema. One would expect that in
this case, lymphatic hypoplasia would be the underlying abnormality.
Patients with activating mutations might present with Meige disease. (

http://www3.interscience.wiley.com/journal/122599805/abstract?CRETRY=1&SRETRY=0