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Gene Review

FOXC2  -  forkhead box C2

Homo sapiens

Synonyms: FKHL14, Forkhead box protein C2, Forkhead-related protein FKHL14, LD, MFH-1, ...
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Disease relevance of FOXC2

  • Mutations in the FOXC2 transcription factor cause a major form of hereditary lymphedema, the lymphedema-distichiasis syndrome [1].
  • Increased FOXC2 levels, induced by high fat diet, seem to counteract most of the symptoms associated with obesity, including hypertriglyceridemia and diet-induced insulin resistance--a likely consequence hereof would be protection against type 2 diabetes [2].
  • FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance [2].
  • Our data indicate that variation in FOXC2 may have a minor role in body weight control and seems to be involved in the regulation of basal glucose turnover and plasma triglyceride levels in women, but this gene does not significantly contribute to the etiology of type 2 diabetes in Pima Indians [3].
  • The FOXC2 C-512T polymorphism is associated with obesity and dyslipidemia [4].
  • These observations indicate that FOXC2 plays a central role in promoting invasion and metastasis and that it may prove to be a highly specific molecular marker for human basal-like breast cancers [5].

Psychiatry related information on FOXC2

  • Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of rats in comparison with LD-treated animals [6].

High impact information on FOXC2

  • Increased FOXC2 expression, in adipocytes, has a pleiotropic effect on gene expression, which leads to a lean and insulin sensitive phenotype [2].
  • In lymphedema-distichiasis (LD), lymphatic vessel function fails because of mutations affecting the forkhead transcription factor FOXC2 [7].
  • Our data show that Foxc2 is essential for the morphogenesis of lymphatic valves and the establishment of a pericyte-free lymphatic capillary network and that it cooperates with Vegfr3 in the latter process [7].
  • Signals mediated by vascular endothelial growth factor-C, the homeodomain transcription factor PROX1 and the forkhead transcription factor FOXC2 have been implicated in the growth, morphogenesis and hierarchic organization of the lymphatic vascular network [8].
  • To search for the underlying gene in the 16q24.1 region, we investigated a novel functional and positional candidate gene, helix/forkhead transcription factor (FOXC2), by sequencing and by genotyping of two single-nucleotide polymorphisms in the families [9].

Chemical compound and disease context of FOXC2

  • Transgenic mice with adipocyte-specific overexpression of FOXC2 (forkhead transcription factor) have been generated and shown to be protected against diet-induced obesity and glucose intolerance [10].
  • METHODS: Paired transcranial magnetic stimulation (TMS) was used to assess cortico-cortical inhibition (CCI) and facilitation (CCF) in the opponens pollicis muscle of patients with atypical, non-L-dopa- (LD) responsive parkinsonism [11].
  • The main pharmacokinetic reason is considered to be the decreased capacity in LD activation to dopamine along with reduction of its storage ability in the nigrostriatal terminals, as a result of disease progression [12].

Biological context of FOXC2

  • Forkhead transcription factor FOXC2 is an important regulator of insulin resistance [13].
  • We analyzed the molecular consequences of two disease-causing missense mutations (R121H and S125L) occurring in the FHD of the FOXC2 gene that were identified in patients with hereditary lymphedema with distichiasis (LD) to test the predictive capacity of a FHD structure/function model [14].
  • We previously identified inactivating, nonsense and frameshift mutations in the forkhead transcription factor FOXC2 in affected members of LD families [15].
  • 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 [16].
  • Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians [3].

Anatomical context of FOXC2

  • We have identified the human winged helix/forkhead transcription factor gene FOXC2 as a key regulator of adipocyte metabolism [2].
  • 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 [15].
  • Also, the higher expression of FOXC2 in visceral than in subcutaneous fat was restricted to subjects homozygous for the T allele (P = 0.03 vs. P = 0.7) [17].
  • Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance [18].
  • Molecular analysis of the FOXC2 pathway may provide clues to developmental pathways shared by the lymphatic system and the other developmental abnormalities associated with this complex syndrome [19].

Associations of FOXC2 with chemical compounds

  • To understand the underlying mechanism, we examined the effects of chronic high-fat feeding on tissue-specific insulin action and glucose metabolism in the FOXC2 transgenic (Tg) mice [10].
  • Therefore, FOXC2 was analyzed as a candidate gene for susceptibility to type 2 diabetes in Pima Indians [3].
  • Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance [10].
  • 3. Here, we report the sequence of the FOXC2 gene in a German-Irish family with LD in six affected relatives over three generations and identify a single adenine base pair insertion at nt 1006--1007 [20].
  • A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with (R)-alpha-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating properties [6].

Other interactions of FOXC2

  • Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development [21].
  • Importantly, these results can also be applied to predict the consequences of the molecular effects of mutations of other FOX genes that have analogous missense mutations, including FOXP2, FOXE3 and FOXC2 [22].
  • RESULTS: Age of onset was typically congenital among FLT4 mutation families and pubertal among FOXC2 mutation families, with similar male and female penetrance in both groups [23].
  • We thus examined the possible relationships between a -512C --> T polymorphism of FOXC2 and a 1243C --> T polymorphism of PLIN to BMD in community-dwelling Japanese women and men [24].
  • Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs [25].

Analytical, diagnostic and therapeutic context of FOXC2


  1. Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome. Dagenais, S.L., Hartsough, R.L., Erickson, R.P., Witte, M.H., Butler, M.G., Glover, T.W. Gene Expr. Patterns (2004) [Pubmed]
  2. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cederberg, A., Grønning, L.M., Ahrén, B., Taskén, K., Carlsson, P., Enerbäck, S. Cell (2001) [Pubmed]
  3. Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians. Kovacs, P., Lehn-Stefan, A., Stumvoll, M., Bogardus, C., Baier, L.J. Diabetes (2003) [Pubmed]
  4. The FOXC2 C-512T polymorphism is associated with obesity and dyslipidemia. Carlsson, E., Almgren, P., Hoffstedt, J., Groop, L., Ridderstråle, M. Obes. Res. (2004) [Pubmed]
  5. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Mani, S.A., Yang, J., Brooks, M., Schwaninger, G., Zhou, A., Miura, N., Kutok, J.L., Hartwell, K., Richardson, A.L., Weinberg, R.A. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  6. L-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties. Di Stefano, A., Sozio, P., Cocco, A., Iannitelli, A., Santucci, E., Costa, M., Pecci, L., Nasuti, C., Cantalamessa, F., Pinnen, F. J. Med. Chem. (2006) [Pubmed]
  7. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Petrova, T.V., Karpanen, T., Norrmén, C., Mellor, R., Tamakoshi, T., Finegold, D., Ferrell, R., Kerjaschki, D., Mortimer, P., Ylä-Herttuala, S., Miura, N., Alitalo, K. Nat. Med. (2004) [Pubmed]
  8. Molecular lymphangiogenesis: new players. Tammela, T., Petrova, T.V., Alitalo, K. Trends Cell Biol. (2005) [Pubmed]
  9. Combined analysis of genome scans of dutch and finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q. Pajukanta, P., Allayee, H., Krass, K.L., Kuraishy, A., Soro, A., Lilja, H.E., Mar, R., Taskinen, M.R., Nuotio, I., Laakso, M., Rotter, J.I., de Bruin, T.W., Cantor, R.M., Lusis, A.J., Peltonen, L. Am. J. Hum. Genet. (2003) [Pubmed]
  10. Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance. Kim, J.K., Kim, H.J., Park, S.Y., Cederberg, A., Westergren, R., Nilsson, D., Higashimori, T., Cho, Y.R., Liu, Z.X., Dong, J., Cline, G.W., Enerback, S., Shulman, G.I. Diabetes (2005) [Pubmed]
  11. Abnormalities of motor cortical excitability are not correlated with clinical features in atypical parkinsonism. Marchese, R., Trompetto, C., Buccolieri, A., Abbruzzese, G. Mov. Disord. (2000) [Pubmed]
  12. Monitoring of L-dopa concentrations in Parkinson's disease. Furlanut, M., Furlanut , M., Benetello, P. Pharmacol. Res. (2001) [Pubmed]
  13. Foxc2 is a common mediator of insulin and transforming growth factor beta signaling to regulate plasminogen activator inhibitor type I gene expression. Fujita, H., Kang, M., Eren, M., Gleaves, L.A., Vaughan, D.E., Kume, T. Circ. Res. (2006) [Pubmed]
  14. The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Berry, F.B., Tamimi, Y., Carle, M.V., Lehmann, O.J., Walter, M.A. Hum. Mol. Genet. (2005) [Pubmed]
  15. FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Kriederman, B.M., Myloyde, T.L., Witte, M.H., Dagenais, S.L., Witte, C.L., Rennels, M., Bernas, M.J., Lynch, M.T., Erickson, R.P., Caulder, M.S., Miura, N., Jackson, D., Brooks, B.P., Glover, T.W. Hum. Mol. Genet. (2003) [Pubmed]
  16. Truncating mutations in FOXC2 cause multiple lymphedema syndromes. Finegold, D.N., Kimak, M.A., Lawrence, E.C., Levinson, K.L., Cherniske, E.M., Pober, B.R., Dunlap, J.W., Ferrell, R.E. Hum. Mol. Genet. (2001) [Pubmed]
  17. FOXC2 mRNA Expression and a 5' untranslated region polymorphism of the gene are associated with insulin resistance. Ridderstråle, M., Carlsson, E., Klannemark, M., Cederberg, A., Kösters, C., Tornqvist, H., Storgaard, H., Vaag, A., Enerbäck, S., Groop, L. Diabetes (2002) [Pubmed]
  18. Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity. Di Gregorio, G.B., Westergren, R., Enerback, S., Lu, T., Kern, P.A. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  19. Research perspectives in inherited lymphatic disease. Ferrell, R.E. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  20. A novel frameshift mutation of FOXC2 gene in a family with hereditary lymphedema-distichiasis syndrome associated with renal disease and diabetes mellitus. Yildirim-Toruner, C., Subramanian, K., El Manjra, L., Chen, E., Goldstein, S., Vitale, E. Am. J. Med. Genet. A (2004) [Pubmed]
  21. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Smith, R.S., Zabaleta, A., Kume, T., Savinova, O.V., Kidson, S.H., Martin, J.E., Nishimura, D.Y., Alward, W.L., Hogan, B.L., John, S.W. Hum. Mol. Genet. (2000) [Pubmed]
  22. Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1. Saleem, R.A., Banerjee-Basu, S., Berry, F.B., Baxevanis, A.D., Walter, M.A. Hum. Mol. Genet. (2003) [Pubmed]
  23. Age of onset in hereditary lymphedema. Levinson, K.L., Feingold, E., Ferrell, R.E., Glover, T.W., Traboulsi, E.I., Finegold, D.N. J. Pediatr. (2003) [Pubmed]
  24. Association of polymorphisms in forkhead box C2 and perilipin genes with bone mineral density in community-dwelling Japanese individuals. Yamada, Y., Ando, F., Shimokata, H. Int. J. Mol. Med. (2006) [Pubmed]
  25. Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs. Ng, M.Y., Andrew, T., Spector, T.D., Jeffery, S. J. Med. Genet. (2005) [Pubmed]
  26. Role of the FOXC2 -512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome. Carlsson, E., Groop, L., Ridderstråle, M. International journal of obesity (2005) (2005) [Pubmed]
  27. FOXC2 truncating mutation in distichiasis, lymphedema, and cleft palate. Bahuau, M., Houdayer, C., Tredano, M., Soupre, V., Couderc, R., Vazquez, M.P. Clin. Genet. (2002) [Pubmed]
  28. Formal genetics of the HL-A region. Dausset, J., Degos, L., Fellous, M., Legrand, L. Genetics (1975) [Pubmed]
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