FOXC2

FOXC2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1D5V
Identifiers
Aliases	FOXC2, FKHL14, LD, MFH-1, MFH1, forkhead box C2
External IDs	OMIM: 602402; MGI: 1347481; HomoloGene: 21091; GeneCards: FOXC2; OMA:FOXC2 - orthologs
Gene location (Human) Chr. Chromosome 16 (human) Band 16q24.1 Start 86,566,829 bp End 86,569,728 bp
Gene location (Mouse) Chr. Chromosome 8 (mouse) Band 8 E1|8 70.33 cM Start 121,842,910 bp End 121,845,634 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in vena cava palpebral conjunctiva popliteal artery trigeminal ganglion tibial arteries urethra ascending aorta spinal ganglia Descending thoracic aorta cardiac muscle tissue of right atrium Top expressed in aortic arches ascending aorta fifth metatarsal bone renal corpuscle optic nerve aortic valve fourth metatarsal bone somite sclerotome lumbar spinal ganglion More reference expression data BioGPS n/a
Gene ontology Molecular function sequence-specific DNA binding DNA binding DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific protein binding identical protein binding transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding chromatin DNA binding promoter-specific chromatin binding DNA-binding transcription factor activity, RNA polymerase II-specific RNA polymerase II transcription regulatory region sequence-specific DNA binding RNA polymerase II cis-regulatory region sequence-specific DNA binding Cellular component nucleus nucleoplasm nuclear body Biological process Notch signaling pathway somitogenesis embryonic skeletal system morphogenesis skeletal system development insulin receptor signaling pathway ureteric bud development regulation of transcription, DNA-templated positive regulation of cell migration involved in sprouting angiogenesis neural crest cell development paraxial mesoderm formation paraxial mesodermal cell fate commitment ossification lymphangiogenesis collagen fibril organization kidney development glomerular mesangial cell development heart morphogenesis negative regulation of transcription by RNA polymerase II cardiac muscle cell proliferation lymph vessel development transcription, DNA-templated embryonic heart tube development positive regulation of endothelial cell migration positive regulation of transcription, DNA-templated multicellular organism development ventricular cardiac muscle tissue morphogenesis heart development blood vessel remodeling vascular endothelial growth factor receptor signaling pathway blood vessel development positive regulation of vascular wound healing artery morphogenesis branching involved in blood vessel morphogenesis glomerular visceral epithelial cell differentiation response to hormone embryonic viscerocranium morphogenesis embryonic cranial skeleton morphogenesis camera-type eye development glomerular endothelium development positive regulation of cell adhesion mediated by integrin mesoderm development regulation of organ growth metanephros development cell population proliferation positive regulation of transcription by RNA polymerase II negative regulation of apoptotic process involved in outflow tract morphogenesis transcription by RNA polymerase II cell differentiation regulation of transcription by RNA polymerase II anatomical structure morphogenesis negative regulation of cold-induced thermogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2303 14234 Ensembl ENSG00000176692 ENSMUSG00000046714 UniProt Q99958 Q61850 RefSeq (mRNA) NM_005251 NM_013519 RefSeq (protein) NP_005242 NP_038547 Location (UCSC) Chr 16: 86.57 – 86.57 Mb Chr 8: 121.84 – 121.85 Mb PubMed search
Wikidata
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Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene. FOXC2 is a member of the fork head box (FOX) family of transcription factors.

Structure and function

The protein is 501 amino acids in length. The gene has no introns; the single exon is approximately 1.5kb in size.

FOX transcription factors are expressed during development and are associated with a number of cellular and developmental differentiation processes. FOXC2 is required during early development of the kidneys, including differentiation of podocytes and maturation of the glomerular basement membrane. It is also involved in the early development of the heart.

An increased expression of FOXC2 in adipocytes can increase the amount of brown adipose tissue leading to lower weight and an increased sensitivity to insulin.

Role in disease

Absence of FOXC2 has been shown to lead to the failure of lymphatic valves to form and problems with lymphatic remodelling. A number of mutations in the FOXC2 gene have been associated with Lymphedema–distichiasis syndrome, It has also been suggested that there may be a link between polymorphisms in FOXC2 and varicose veins.

FOXC2 is also involved in cancer metastases. In particular, expression of FOXC2 is induced when epithelial cells undergo an epithelial-mesenchymal transition (EMT) and become mesenchymal looking cells. EMT can be induced by a number of genes including Snail, Twist, Goosecoid, and TGF-beta 1. Overexpression of FOXC2 has been noted in subtypes of breast cancer which are highly metastatic. Suppression of FOXC2 expression using shRNA in a highly metastatic breast cancer model blocks their metastatic ability.

Further reading

• Fauret AL, Tuleja E, Jeunemaitre X, Vignes S (2010). "A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasis syndrome". Lymphology. 43 (1): 14–8. PMID 20552815.
• Witte MH, Erickson RP, Khalil M, et al. (2009). "Lymphedema-distichiasis syndrome without FOXC2 mutation: evidence for chromosome 16 duplication upstream of FOXC2". Lymphology. 42 (4): 152–60. PMID 20218083.
• de Mooij YM, van den Akker NM, Bekker MN, et al. (2009). "Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency". Prenat. Diagn. 29 (9): 840–6. doi:10.1002/pd.2316. PMID 19548265. S2CID 2293233.
• Sano H, Leboeuf JP, Novitskiy SV, et al. (2010). "The Foxc2 transcription factor regulates tumor angiogenesis". Biochem. Biophys. Res. Commun. 392 (2): 201–6. doi:10.1016/j.bbrc.2010.01.015. PMC 2822046. PMID 20060810.
• Vreeburg M, Heitink MV, Damstra RJ, et al. (2008). "Lymphedema-distichiasis syndrome: a distinct type of primary lymphedema caused by mutations in the FOXC2 gene". Int. J. Dermatol. 47 (Suppl 1): 52–5. doi:10.1111/j.1365-4632.2008.03962.x. PMID 18986489. S2CID 10265549.
• Kume T (2008). "Foxc2 transcription factor: a newly described regulator of angiogenesis". Trends Cardiovasc. Med. 18 (6): 224–8. doi:10.1016/j.tcm.2008.11.003. PMC 2674371. PMID 19185813.
• Yoshida T, Kato K, Fujimaki T, et al. (2009). "Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome". Genomics. 93 (3): 221–6. doi:10.1016/j.ygeno.2008.11.001. PMID 19056482.
• Ma GC, Liu CS, Chang SP, et al. (2008). "A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy". Prenat. Diagn. 28 (11): 1057–63. doi:10.1002/pd.2130. PMID 18973153. S2CID 206346009.
• Yerges LM, Klei L, Cauley JA, et al. (2009). "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men". J. Bone Miner. Res. 24 (12): 2039–49. doi:10.1359/jbmr.090524. PMC 2791518. PMID 19453261.
• Lu Y, Dollé ME, Imholz S, et al. (2008). "Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations". J. Lipid Res. 49 (12): 2582–9. doi:10.1194/jlr.M800232-JLR200. PMID 18660489.
• van Steensel MA, Damstra RJ, Heitink MV, et al. (2009). "Novel missense mutations in the FOXC2 gene alter transcriptional activity". Hum. Mutat. 30 (12): E1002–9. doi:10.1002/humu.21127. PMID 19760751. S2CID 7674502.
• Pappa KI, Gazouli M, Economou K, et al. (2010). "Gestational diabetes mellitus shares polymorphisms of genes associated with insulin resistance and type 2 diabetes in the Greek population". Gynecological Endocrinology. 27 (4): 267–272. doi:10.3109/09513590.2010.490609. PMID 20540670. S2CID 28980963.
• Joslyn G, Ravindranathan A, Brush G, et al. (2010). "Human variation in alcohol response is influenced by variation in neuronal signaling genes". Alcohol. Clin. Exp. Res. 34 (5): 800–12. doi:10.1111/j.1530-0277.2010.01152.x. PMID 20201926.
• Fabretto A, Shardlow A, Faletra F, et al. (2010). "A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation". Ophthalmic Genet. 31 (2): 98–100. doi:10.3109/13816811003620517. hdl:11368/2935146. PMID 20450314. S2CID 22263077.
• Ghalamkarpour A, Debauche C, Haan E, et al. (2009). "Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2". J. Pediatr. 155 (1): 90–3. doi:10.1016/j.jpeds.2009.02.023. PMID 19394045.
• Silander K, Alanne M, Kristiansson K, et al. (2008). Janssens AC (ed.). "Gender differences in genetic risk profiles for cardiovascular disease". PLOS ONE. 3 (10): e3615. Bibcode:2008PLoSO...3.3615S. doi:10.1371/journal.pone.0003615. PMC 2574036. PMID 18974842.
• Dellinger MT, Thome K, Bernas MJ, et al. (2008). "Novel FOXC2 missense mutation identified in patient with lymphedema-distichiasis syndrome and review". Lymphology. 41 (3): 98–102. PMID 19013876.
• Corpeleijn E, Petersen L, Holst C, et al. (2010). "Obesity-related polymorphisms and their associations with the ability to regulate fat oxidation in obese Europeans: the NUGENOB study". Obesity (Silver Spring). 18 (7): 1369–77. doi:10.1038/oby.2009.377. PMID 19876004. S2CID 205527246.
• Horra A, Salazar J, Ferré R, et al. (2009). "Prox-1 and FOXC2 gene expression in adipose tissue: A potential contributory role of the lymphatic system to familial combined hyperlipidaemia". Atherosclerosis. 206 (2): 343–5. doi:10.1016/j.atherosclerosis.2009.02.026. PMID 19339011.

External links

• GeneReviews/NCBI/NIH/UW entry on Lymphedema-Distichiasis Syndrome