Mutations in FOXC2 (MFH-1), a Forkhead Family Transcription Factor, Are Responsible for the Hereditary Lymphedema-Distichiasis Syndrome

Abstract

Lymphedema-distichiasis (LD) is an autosomal dominant disorder that classically presents as lymphedema of the limbs, with variable age at onset, and double rows of eyelashes (distichiasis). Other complications may include cardiac defects, cleft palate, extradural cysts, and photophobia, suggesting a defect in a gene with pleiotrophic effects acting during development. We previously reported neonatal lymphedema, similar to that in Turner syndrome, associated with a t(Y;16)(q12;q24.3) translocation. A candidate gene was not found on the Y chromosome, and we directed our efforts toward the chromosome 16 breakpoint. Subsequently, a gene for LD was mapped, by linkage studies, to a 16-cM region at 16q24.3. By FISH, we determined that the translocation breakpoint was within this critical region and further narrowed the breakpoint to a 20-kb interval. Because the translocation did not appear to interrupt a gene, we considered candidate genes in the immediate region that might be inactivated by position effect. In two additional unrelated families with LD, we identified inactivating mutations-a nonsense mutation and a frameshift mutation-in the FOXC2 (MFH-1) gene. FOXC2 is a member of the forkhead/winged-helix family of transcription factors, whose members are involved in diverse developmental pathways. FOXC2 knockout mice display cardiovascular, craniofacial, and vertebral abnormalities similar to those seen in LD syndrome. Our findings show that FOXC2 haploinsufficiency results in LD. FOXC2 represents the second known gene to result in hereditary lymphedema, and LD is only the second hereditary disorder known to be caused by a mutation in a forkhead-family gene.

Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency

“…Interestingly, previous research in Foxc2 −/− mice also showed an abnormal amount of SMCs surrounding enlarged lymph vessels (Petrova et al, 2004). Mutations in the human FOXC2 gene are associated with congenital lymphedema and defective lymph valves (Fang et al, 2000). FOXC2 normally suppresses the expression of plateletderived growth factor (PDGF)-B in lymphatic endothelial cells, thereby inhibiting SMC attraction and proliferation, as these processes are positively influenced by PDGF-B (Lindahl et al, 1997;Petrova et al, 2004).…”

CJD and intraocular surgery

“…The gene for LD, located on the long arm of chromosome 16, is that encoding FOXC2, a forkhead family transcription factor involved in numerous developmental pathways. 13 In all three members of the family presented in this report, a 19 bp insertion in the FOXC2 gene was identified. To our knowledge this mutation has not been previously reported.…”

Developmental and pathological lymphangiogenesis: from models to human disease

“…Mice heterozygous for both Foxc2 and Vegfr3 display a phenotype very similar to Foxc2 ¡/-mice, suggesting that FOXC2 and VEGFR-3 act through a common genetic pathway to establish some of the distinct properties of the lymphatic vasculature. The human disease lymphedema-distichiasis (LD), an autosomal dominant disease, is caused by heterozygousloss-of-function mutations of Foxc2 (Fang et al 2000). Unlike in congenital lymphedema, the lymphatic vasculature in LD is normal or hyperplastic, but there is lymph backXow, presumably due to abnormal lymphatic valves, defective patterning and the presence of ectopic SMCs (Brice et al 2002;Petrova et al 2004).…”

“…This model has been used to test VEGF-C gene therapy, which promoted the formation of functional lymphatic vessels in these mice. In the case of lymphedema-distichiasis (LD, OMIM 153400), mutations in the forkhead transcription factor FOXC2 have been identiWed (Fang et al 2000;Finegold et al 2001). This disorder is characterized by distichiasis (a double row of eyelashes) at birth and bilateral lower limb lymphedema at puberty.…”