FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function.
Dominant mutations in the FOXC2 gene cause a form of lymphedema primarily of the limbs that usually develops at or after puberty. In 90-95% of patients, lymphedema is accompanied by distichiasis. FOXC2 is a member of the forkhead/winged-helix family of transcription factors and plays essential roles in different developmental pathways and physiological processes. We previously described six unrelated families with primary lymphedema-distichiasis in which patients showed different FOXC2 mutations located outside of the forkhead domain. Of those, four were missense mutations, one a frameshift mutation, and the last a stop mutation. To assess their pathogenic potential, we have now examined the subcellular localization and the transactivation activity of the mutated FOXC2 proteins. All six FOXC2 mutant proteins were able to localize into the nucleus; however, the frameshift truncated protein appeared to be sequestered into nuclear aggregates. A reduction in the ability to activate FOXC1/FOXC2 response elements was detected in 50% of mutations, while the remaining ones caused an increase of protein transactivation activity. Our data reveal that either a complete loss or a significant gain of FOXC2 function can cause a perturbation of lymphatic vessel formation leading to lymphedema.
Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Catholic University of The Sacred Heart, Milan, Italy.
Daniela
D
Tavian
Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Catholic University of The Sacred Heart, Milan, Italy.
Sara
S
Missaglia
MAGI Non-Profit Human Medical Genetics Institute, Rovereto (TN), Italy.
Paolo E
PE
Maltese
Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Rome, Italy.
Sandro
S
Michelini
Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Rome, Italy.
Alessandro
A
Fiorentino
Medicina Riabilitativa, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Torrette, Italy.
Maurizio
M
Ricci
Medicina Riabilitativa, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Torrette, Italy.
Roberta
R
Serrani
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.|Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta, Canada.
Michael A
MA
Walter
MAGI Non-Profit Human Medical Genetics Institute, Rovereto (TN), Italy.
Matteo
M
Bertelli
D000328:Adult; D000368:Aged; D005140:Eyelashes / Q000002:abnormalities*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008209:Lymphedema / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation
D051858:Forkhead Transcription Factors; C082078:mesenchyme fork head 1 protein
Foxc2 gene mutations; Pathology Section; distichiasis; gain of function; primary lymphedema; transcription factor