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Human Molecular Genetics, 2003, Vol. 12, No. 10 1179-1185
DOI: 10.1093/hmg/ddg123
© 2003 Oxford University Press

FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome

Benjamin M. Kriederman1,*, Teressa L. Myloyde1, Marlys H. Witte1, Susan L. Dagenais2, Charles L. Witte1, Margaret Rennels1, Michael J. Bernas1, Michelle T. Lynch1, Robert P. Erickson1, Mark S. Caulder2, Naoyuki Miura3, David Jackson4, Brian P. Brooks5 and Thomas W. Glover2

1University of Arizona, Departments of Surgery, Pathology and Pediatrics, Tucson, Arizona, USA, 2University of Michigan, Departments of Human Genetics and Pediatrics, Ann Arbor, Michigan, USA, 3Department of Biochemistry, Hamamatsu University, Hamamatsu, Japan, 4Oxford University Department of Pathology, Oxford, UK and 5Medical Genetics Branch, NHGRI, Bethesda, Maryland, USA

Received January 23, 2003; Accepted March 11, 2003

Lymphedema-distichiasis (LD) (OMIM 153400) is a rare autosomal-dominant condition characterized by pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes arising from the meibomian glands. In some patients cardiac, skeletal and other defects coexist. We previously identified inactivating, nonsense and frameshift mutations in the forkhead transcription factor FOXC2 in affected members of LD families. To further delineate the relationship of FOXC2 deficiency to the clinical (and lymphangiodysplastic) phenotype in this syndrome, we performed dynamic lymphatic imaging and immunohistochemical examination of lymphatic tissues in mice heterozygous (+/-) for a targeted disruption of Foxc2. Adult heterozygote mice characteristically exhibited a generalized lymphatic vessel and lymph node hyper plasia and rarely exhibited hindlimb swelling. Retrograde lymph flow through apparently incompetent interlymphangion valves into the mesenteric nodes, intestinal wall and liver was also observed. In addition, Foxc2 +/- mice uniformly displayed distichiasis. We conclude that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of LD patients. Furthermore, the craniofacial, cardiovascular and skeletal abnormalities sometimes associated with LD have previously been shown to be fully penetrant in homozygous Foxc2 null mice. This Foxc2 mutant mouse thus provides an ideal model for exploring molecular mechanisms and physiologic events in mesenchymal differentiation associated with lymphatic growth and development and the clinical abnormalities seen in human LD syndrome.

* To whom correspondence should be addressed at: The University of Arizona College of Medicine, Department of Surgery, Lymphology Laboratories, 1501 N. Campbell Avenue, Room 4406, PO Box 245063, Tucson, AZ 85724-5063, USA. Tel: +1 5206266118; Fax: +1 5206260822; Email: lymph{at}u.arizona.edu


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