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Human Molecular Genetics, 2001, Vol. 10, No. 11 1185-1189
© 2001 Oxford University Press

Truncating mutations in FOXC2 cause multiple lymphedema syndromes

David N. Finegold1,2,+, Mark A. Kimak1, Elizabeth C. Lawrence1, Kara L. Levinson1, Elizabeth M. Cherniske3, Barbara R. Pober3, Jean W. Dunlap1 and Robert E. Ferrell1

1Department of Human Genetics, Graduate School of Public Health and 2Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA and 3Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA

Hereditary lymphedemas are developmental disorders of the lymphatics resulting in edema of the extremities due to altered lymphatic flow. One such disorder, the lymphedema-distichiasis syndrome, has been reported to be caused by mutations in the forkhead transcription factor, FOXC2. We sequenced the FOXC2 gene in 86 lymphedema families to identify mutations. Eleven families were identified with mutations predicted to disrupt the DNA binding domain and/or C-terminal {alpha}-helices essential for transcription activation by FOXC2. Broad phenotypic heterogeneity was observed within these families. The phenotypes observed overlapped four phenotypically defined lymphedema syndromes. FOXC2 appears to be the primary cause of lymphedema-distichiasis syndrome and is also a cause of lymphedema in families displaying phenotypes attributed to other lymphedema syndromes. Our data demonstrates that the phenotypic classification of autosomal dominant lymphedema does not reflect the underlying genetic causation of these disorders.

+ To whom correspondence should be addressed. Tel: +1 412 624 3018; Fax: +1 412 624 3020; Email: dnf@mars.upmc.edu


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