FOXC1 Gene

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1		Vivi Li	+ 593 word(s)	593	2020-12-15 07:53:35

This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/foxc1

Forkhead box C1

genes

1. Normal Function

The FOXC1 gene provides instructions for making a protein that attaches (binds) to specific regions of DNA and regulates the activity of other genes. On the basis of this action, the FOXC1 protein is called a transcription factor.

The FOXC1 protein plays a critical role in early development, particularly in the formation of structures in the front part of the eye (the anterior segment). These structures include the colored part of the eye (the iris), the lens of the eye, and the clear front covering of the eye (the cornea). Studies suggest that the FOXC1 protein may also have functions in the adult eye, such as helping cells respond to oxidative stress. Oxidative stress occurs when unstable molecules called free radicals accumulate to levels that can damage or kill cells.

The FOXC1 protein is also involved in the normal development of other parts of the body, including the heart, kidneys, and brain.

2. Health Conditions Related to Genetic Changes

2.1 Axenfeld-Rieger Syndrome

More than 50 mutations in the FOXC1 gene have been found to cause Axenfeld-Rieger syndrome type 3, a condition that primarily affects the development of the anterior segment of the eye but can also affect other parts of the body. Many FOXC1 gene mutations reduce the amount of functional FOXC1 protein that is produced or result in a defective protein that cannot regulate the activity of other genes. Other genetic changes (such as a duplication of the FOXC1 gene) likely increase the amount or function of the FOXC1 protein. Having either too little or too much activity of this protein disrupts the regulation of other genes needed for normal development.

Changes in the amount or function of the FOXC1 protein impairs the development of the anterior segment of the eye, leading to the eye abnormalities characteristic of Axenfeld-Rieger syndrome. In some cases, changes involving the FOXC1 protein also cause problems with development of other parts of the body.

2.2 Peters Anomaly

At least two mutations in the FOXC1 gene have been found to cause Peters anomaly. This condition is characterized by abnormal development of the anterior segment and clouding of the cornea. The mutations that cause Peters anomaly likely disrupt the protein's ability to regulate the expression of developmental genes, especially affecting the eye. Abnormal formation of the iris, cornea, and other structures of the anterior segment leads to the features of Peters anomaly. The FOXC1 gene mutations that cause Peters anomaly can cause other related eye disorders, such as Axenfeld-Rieger syndrome (described above), in members of the same family.

2.3 Dandy-Walker Malformation

2.4 Other Disorders

Mutations in the FOXC1 gene have also been identified in another eye disorder called iridogoniodysgenesis type 1. Like Axenfeld-Rieger syndrome and Peters anomaly, this condition primarily involves the anterior segment of the eye. Iridogoniodysgenesis type 1 is associated with underdevelopment of the iris and an elevated risk of increased pressure in the eye (glaucoma).

FOXC1 gene mutations have been reported in a few people with abnormalities of brain development. Mutations that change single protein building blocks (amino acids) in the FOXC1 protein have been associated with defects of the cerebellum, which is the part of the brain that is involved in coordinating movement. Additionally, deletions of genetic material from a region of chromosome 6 that includes the FOXC1 gene and several neighboring genes have been associated with a structural abnormality of the cerebellum known as Dandy-Walker malformation.

3. Other Names for This Gene

FKHL7
forkhead box protein C1
forkhead, drosophila, homolog-like 7
forkhead-related activator 3
forkhead-related protein FKHL7
forkhead-related transcription factor 3
forkhead/winged helix-like transcription factor 7
FOXC1_HUMAN
FREAC-3
FREAC3
myeloid factor-delta

References

Aldinger KA, Lehmann OJ, Hudgins L, Chizhikov VV, Bassuk AG, Ades LC, KrantzID, Dobyns WB, Millen KJ. FOXC1 is required for normal cerebellar development andis a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet.2009 Sep;41(9):1037-42. doi: 10.1038/ng.422.
Berry FB, Lines MA, Oas JM, Footz T, Underhill DA, Gage PJ, Walter MA.Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum MolGenet. 2006 Mar 15;15(6):905-19.
D'haene B, Meire F, Claerhout I, Kroes HY, Plomp A, Arens YH, de Ravel T,Casteels I, De Jaegere S, Hooghe S, Wuyts W, van den Ende J, Roulez F,Veenstra-Knol HE, Oldenburg RA, Giltay J, Verheij JB, de Faber JT, Menten B, DePaepe A, Kestelyn P, Leroy BP, De Baere E. Expanding the spectrum of FOXC1 andPITX2 mutations and copy number changes in patients with anterior segmentmalformations. Invest Ophthalmol Vis Sci. 2011 Jan 21;52(1):324-33. doi:10.1167/iovs.10-5309.
Honkanen RA, Nishimura DY, Swiderski RE, Bennett SR, Hong S, Kwon YH, StoneEM, Sheffield VC, Alward WL. A family with Axenfeld-Rieger syndrome and PetersAnomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene. Am JOphthalmol. 2003 Mar;135(3):368-75.
Lehmann OJ, Ebenezer ND, Ekong R, Ocaka L, Mungall AJ, Fraser S, McGill JI,Hitchings RA, Khaw PT, Sowden JC, Povey S, Walter MA, Bhattacharya SS, Jordan T. Ocular developmental abnormalities and glaucoma associated with interstitial 6p25duplications and deletions. Invest Ophthalmol Vis Sci. 2002 Jun;43(6):1843-9.
Nishimura DY, Searby CC, Alward WL, Walton D, Craig JE, Mackey DA, Kawase K,Kanis AB, Patil SR, Stone EM, Sheffield VC. A spectrum of FOXC1 mutationssuggests gene dosage as a mechanism for developmental defects of the anteriorchamber of the eye. Am J Hum Genet. 2001 Feb;68(2):364-72.
Reis LM, Tyler RC, Volkmann Kloss BA, Schilter KF, Levin AV, Lowry RB,Zwijnenburg PJ, Stroh E, Broeckel U, Murray JC, Semina EV. PITX2 and FOXC1spectrum of mutations in ocular syndromes. Eur J Hum Genet. 2012Dec;20(12):1224-33. doi: 10.1038/ejhg.2012.80.
Strungaru MH, Dinu I, Walter MA. Genotype-phenotype correlations inAxenfeld-Rieger malformation and glaucoma patients with FOXC1 and PITX2mutations. Invest Ophthalmol Vis Sci. 2007 Jan;48(1):228-37.
Tümer Z, Bach-Holm D. Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1mutations. Eur J Hum Genet. 2009 Dec;17(12):1527-39. doi: 10.1038/ejhg.2009.93.
Weisschuh N, Wolf C, Wissinger B, Gramer E. A novel mutation in the FOXC1 genein a family with Axenfeld-Rieger syndrome and Peters' anomaly. Clin Genet. 2008Nov;74(5):476-80. doi: 10.1111/j.1399-0004.2008.01025.x.

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Subjects: Genetics & Heredity

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Vivi Li

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Update Date: 25 Dec 2020

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