Forkhead Transcription Factors in Genetic Disease


Forkhead transcription factors represent an important family of proteins, for which more than 2000 family members have been identified so far, 26 of which can be found in humans. FOX genes exhibit many important functions in both development and adult life. Therefore, it is not surprising that alterations in these genes can cause of a broad range of developmental diseases and cancer. Today, 13 FOX genes are associated with developmental disorders. Mutations in five of them (FOXC1, FOXC2, FOXD3, FOXE3 and FOXL2) lead to an ocular phenotype, while mutations in three genes (FOXG1, FOXP1 and FOXP2) are a known cause for neurodevelopmental disorders, mutations in two (FOXL2 and FOXO3A) are associated with premature ovarian failure and mutation in other two genes (FOXN1 and FOXP3) are involved in immunodeficiency syndromes. Finally, FOXF1 mutations cause a lung development disorder. In this article, the different developmental disorders caused by mutations in FOX genes are reviewed. In addition, the article briefly touches cancers caused by genetic defects in FOX genes.

Key Concepts:

  • Forkhead transcription factor genes represent an important gene family, consisting out of more than 2000 members. In human, 26 family members have been identified and there are 8 FOX gene clusters.

  • The forkhead domain is built up by three α‐helices, two β‐sheets and two loops. These loops resemble wings of a butterfly, giving the family its nickname: winged helix transcription factors.

  • Forkhead transcription factors play important roles in a wide range of signalling pathways.

  • Mutations in FOX genes are known to cause hereditary developmental disorders. Five mutated FOX genes are associated with an ocular phenotype.

  • Forkhead transcription factors are also involved in cancer and ageing.

Keywords: forkhead transcription factors; forkhead domain; development; ocular phenotypes; cancer

Figure 1.

Overview of the forkhead gene clustering. In total, 21 of the 26 human forkhead genes are organised in 8 clusters.

Figure 2.

The FHD. (a) 3D‐structure of FOXO1 bound to DNA (Protein Database (PBD) accession: 3CO6). The DNA‐binding helix (H3) is coloured in blue. W1–W2 show the peculiar winged folding and are depicted in purple. The structure of FOXO1 was first resolved by Brent et al.. (b) 3D‐structure of FOXO3a (PDB accession: 2K86), with the 3 typical helices (H1–H3) and the 2 wings (W1–W2). This structure was first found by nuclear magnetic resonance by Wang et al..

Figure 3.

Ocular defects. (a–c) Ocular images from a patient carrying a partial FOXC1 deletion: (a) ectopic pupil, (b) right eye with iris strands and (c) peripheral polycoria and ectropion uveae.

Adapted from D'haene et al.2011. © Association for Research in Vision and Ophthalmology.
Figure 4.

Overview of copy number variations found in forkhead gene regions. Gene dosage is very important for forkhead transcription factor genes; this is underlined by the identification of copy number variations in several FOX genes, as demonstrated in panels (a–d). At the top of each panel, the chromosome ideogram is shown with a red box indicating the position of the corresponding FOX gene (marked with a blue box) region. (a) The FOXC1 region (chr 6:60 000–12 000 000, UCSC, Human Genome Browser, GRCh37/hg19) with custom tracks depicting FOXC1 deletions (red) and duplications (green) identified by Chanda et al.; D'haene et al.; Delahaye et al. and Reis et al.. (b) A regulatory duplication in the FOXC2 region (chr16: 86 533 617–86 669 777, UCSC, Human Genome Browser, GRCh37/hg19) described by Witte et al.. (c) The FOXF1 region (chr16:84 000 000–88 000 000, UCSC, Human Genome Browser, GRCh37/hg19) with custom tracks showing deletions of FOXF1 as described by Stankiewicz et al.. (d) The FOXL2 region (chr3:135 099 979–14 24 58 004, UCSC, Human Genome Browser, GRCh37/hg19) with custom tracks displaying the several FOXL2‐encompassing (light red) and FOXL2 regulatory (dark red) deletions found and delineated by Verdin et al.; D'haene et al.; D'haene et al. and Beysen et al..



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Further Reading

Katoh M, Igarashi M, Fukuda H, Nakagama H and Katoh M (2013) Cancer genetics and genomics of human FOX family genes. Cancer Letters 328: 198–206.

Lehmann OJ, Sowden JC, Carlsson P, Jordan T and Bhattacharya SS (2003) Fox's in Development and Disease. Trends in Genetics 19(6): 339–344.

Patridge L and Brüning JC (2008) Forkhead transcription factors and ageing. Oncogene 28: 2351–2363.

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Baetens, Dorien, Verdin, Hannah, Cools, Martine, and De Baere, Elfride(Sep 2013) Forkhead Transcription Factors in Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024256]