Alternative titles; symbols
HGNC Approved Gene Symbol: FOXC1
Cytogenetic location: 6p25.3 Genomic coordinates (GRCh38): 6:1,609,915-1,613,897 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p25.3 | Anterior segment dysgenesis 3, multiple subtypes | 601631 | Autosomal dominant | 3 |
| Axenfeld-Rieger syndrome, type 3 | 602482 | Autosomal dominant | 3 |
Forkhead transcription factors are distinguished by a characteristic 100-amino acid DNA-binding motif originally identified as a region of homology between Drosophila forkhead and rat Hnf3 (see 602294). Pierrou et al. (1994) identified 7 human genes containing forkhead domains, including FOXC1, which they called FREAC3. Northern blot analysis revealed that FOXC1 was expressed nearly ubiquitously as a 3.9-kb mRNA. Smaller mRNAs were detected in fetal colon and kidney and in leukocytes.
Pierrou et al. (1994) determined the DNA binding specificity of FOXC1 through selection of high-affinity binding sites from random sequence oligonucleotides.
Using an inducible FOXC1 construct, Berry et al. (2008) found that expression of several hundred genes was altered by FOXC1 in human nonpigmented ciliary epithelial cells. Northern blot analysis estimated that FOXC1 induced the expression of the stress response gene HSPA6 (140555) about 37-fold and the apoptosis regulator FOXO1A (136533) about 13-fold. The promoter regions of zebrafish and human FOXO1A contain consensus FOXC1 binding sites; chromatin immunoprecipitation and reporter gene assays confirmed that FOXC1 bound these sites and activated the FOXO1A promoter. Knockdown of FOXC1 in human trabecular meshwork cells reduced FOXO1A expression and increased cell death in response to oxidative stress. Morpholino-mediated knockdown of Foxo1a in zebrafish embryos resulted in increased cell death in the developing eye.
Omatsu et al. (2014) found that the transcription factor Foxc1 is preferentially expressed in the adipo-osteogenic progenitor Cxcl12 (600835)-abundant reticular (CAR) cells essential for hematopoietic stem and progenitor cell maintenance in vivo in the developing and adult bone marrow. When Foxc1 was deleted in all marrow mesenchymal cells or CAR cells, from embryogenesis onward, osteoblasts appeared normal, but hematopoietic stem and progenitor cells were markedly reduced and marrow cavities were occupied by adipocytes (yellow adipose marrow) with reduced CAR cells. Inducible deletion of Foxc1 in adult mice depleted hematopoietic stem and progenitor cells and reduced Cxcl12 and stem cell factor (SCF; 184745) expression in CAR cells, but did not induce a change in yellow marrow. Omatsu et al. (2014) concluded that their data suggested a role for FOXC1 in inhibiting adipogenic processes in CAR progenitors. FOXC1 might also promote CAR cell development, upregulating CXCL12 and stem cell factor expression.
Using bioinformatic analysis, Pan et al. (2014) identified a long noncoding RNA (lncRNA) gene, FOXCUT (615976), upstream of the FOXC1 gene promoter region. By real-time quantitative PCR analysis of 82 esophageal squamous cell carcinomas (ESCCs; see 133239), they found that expression of FOXCUT and FOXC1 were significantly upregulated in ESCCs compared with adjacent noncancerous tissues. Upregulation of FOXCUT and FOXC1 correlated with poor differentiation, advanced lymph node classification, metastasis, and poor prognosis. Knockdown of FOXCUT via small interfering RNA reduced expression of both FOXCUT and FOXC1, whereas knockdown of FOXC1 had no effect on FOXCUT expression. Knockdown of either FOXC1 or FOXCUT inhibited ESCC cell proliferation, colony formation, migration, and invasive potential. Pan et al. (2014) concluded that FOXCUT and FOXC1 may constitute a functional lncRNA-mRNA gene pair.
Wang et al. (2016) demonstrated that murine hair follicle stem cells (SCs) induce the Foxc1 transcription factor when activated. Deleting Foxc1 in activated, but not quiescent, SCs caused failure of the cells to reestablish quiescence and allowed premature activation. Deleting Foxc1 in the SC niche of gene-targeted mice led to loss of the old hair without impairing quiescence. In self-renewing SCs, Foxc1 activated Nfatc1 (600489) and bone morphogenetic protein (BMP; see 112264) signaling, 2 key mechanisms that govern quiescence. Wang et al. (2016) concluded that these findings revealed a dynamic, cell-intrinsic mechanism used by hair follicle SCs to reinforce quiescence upon self-renewal and suggested a unique ability of SCs to maintain cell identity.
Larsson et al. (1995) mapped the FOXC1 gene to chromosome 6p25 by fluorescence in situ hybridization and somatic cell hybrid analysis.
Anterior Segment Dysgenesis 3
Nishimura et al. (1998) demonstrated that patients with anterior segment dysgenesis (ASGD3; 601631), described as Rieger anomaly, Axenfeld anomaly, or iris hypoplasia, harbored heterozygous mutations in the FOXC1 gene (601090.0001-601090.0003, respectively).
By DNA sequencing of FOXC1 in 5 families and 16 sporadic patients with anterior segment defects, Mears et al. (1998) found 3 mutations: a 10-bp deletion predicted to cause a frameshift and premature protein truncation prior to the FOXC1 forkhead DNA-binding domain, as well as 2 missense mutations of conserved amino acids within the FOXC1 forkhead domain, one causing ASGD3 (601090.0009) and the other RIEG3 (601090.0008) (see below). However, mutation screening and genetic linkage analyses excluded FOXC1 from underlying the anterior segment disorders in 2 of the families with linkage to 6p25. The findings suggested that although mutations of FOXC1 result in anterior segment defects and glaucoma in some patients, it is probable that at least one more locus involved in the regulation of eye development is located at 6p25.
Nishimura et al. (2001) analyzed the coding region of the FOXC1 gene in 70 probands with congenital anterior chamber defects and detected 9 mutations, 8 of which were novel (see, e.g., 601090.0005-601090.0007). Affected members from 2 families, one with iris hypoplasia and the other with Peters anomaly, had 2 different partial duplications of 6p25, respectively, both encompassing the FOXC1 gene (see 601090.0006). These data suggested that both FOXC1 haploinsufficiency and increased gene dosage may cause anterior chamber defects of the eye.
Saleem et al. (2001) investigated 5 missense mutations of the FOXC1 transcription factor found in patients with Axenfeld-Rieger malformations to determine their effects on FOXC1 structure and function. Molecular modeling of the FOXC1 forkhead domain predicted that the missense mutations did not alter FOXC1 structure. Biochemical analyses indicated that whereas all mutant proteins correctly localized to the cell nucleus, the I87M (601090.0009) mutation reduced FOXC1 protein levels. DNA-binding experiments revealed that although the S82T (601090.0008) and S131L (601090.0002) mutations decreased DNA binding, the F112S (601090.0004) and I126M (601090.0003) mutations did not. However, the F112S and I126M mutations decreased the transactivation ability of FOXC1. All the FOXC1 mutations had the net effect of reducing FOXC1 transactivation ability. These results indicated that the FOXC1 forkhead domain contains separable DNA-binding and transactivation functions. In addition, these findings demonstrated that reduced stability, DNA binding, or transactivation, all causing a decrease in the ability of FOXC1 to transactivate genes, can underlie Axenfeld-Rieger malformations. Saleem et al. (2003) studied an additional 5 missense mutations in the FOXC1 gene. Biologic analyses indicated that all missense mutations studied caused various FOXC1 perturbations, including nuclear localization defects, reduced or abolished DNA binding capacity, and a reduction in the transactivation capacity of FOXC1.
Using genotyping and FISH to investigate a 9-generation Scottish family segregating autosomal dominant iridogoniodysgenesis, originally reported by Zorab (1932), Lehmann et al. (2002) demonstrated an interstitial duplication of chromosome 6p25 encompassing the FOXC1 gene (601090.0006).
In a mother and son with Axenfeld-Rieger syndrome, Ito et al. (2007) analyzed the FOXC1 gene and identified a missense mutation (601090.0010) that was de novo in the mother.
Axenfeld-Rieger Syndrome, Type 3
In 6 affected members of a 4-generation family originally reported by Gould et al. (1997) with Axenfeld-Rieger anomaly, in whom Mears et al. (1998) also found deafness and heart anomalies (RIEG3; 602482), Mears et al. (1998) identified a heterozygous mutation in the FOXC1 gene (601090.0008).
In 5 affected members of a 4-generation family segregating autosomal dominant anterior segment defects, including a patient who also had Peters anomaly, Honkanen et al. (2003) identified the F112S mutation (601090.0004) in the FOXC1 gene. Extraocular features were present in 4 of the 5 patients.
Maclean et al. (2005) stated that 12 cases had been reported of a distinctive clinical phenotype associated with deletion of distal chromosome 6p (612582), the features of which included Axenfeld-Rieger malformation, hearing loss, congenital heart disease, dental anomalies, developmental delay, and a characteristic facial appearance. They reported the case of a child in whom recognition of the specific ocular and facial phenotype led to identification of a 6p microdeletion arising from a de novo 6;18 translocation. Detailed analysis confirmed deletion of the FOXC1, FOXF2 (603250), FOXQ1 (612788) forkhead gene cluster at 6p25. CNS anomalies included hydrocephalus and hypoplasia of the cerebellum, brainstem, and corpus callosum with mild to moderate developmental delay. Unlike previous reports, hearing was normal.
Berry et al. (2006) demonstrated that FOXC1 and the PITX2A isoform of PITX2 physically interact and that the interaction requires crucial functional domains on both proteins, e.g., the C-terminal activation domain of FOXC1 and the homeodomain of PITX2. Immunofluorescence studies revealed colocalization of FOXC1 and PITX2A within a common nuclear subcompartment, and transcription assay studies showed that PITX2A can function as a negative regulator of FOXC1 transactivity. The authors suggested that this negative regulation offers an explanation as to why increased FOXC1 gene dosage produces a phenotype resembling that of PITX2 deletions and mutations, and they concluded that functional interaction between FOXC1 and PITX2A underlies the sensitivity to FOXC1 gene dosage in Axenfeld-Rieger syndrome and related anterior segment dysgeneses.
In 5 affected members of a 3-generation family with Axenfeld-Rieger syndrome, who displayed a substantial degree of intrafamilial phenotypic variability including Peters anomaly in 1 patient, Weisschuh et al. (2008) identified heterozygosity for a nonsense mutation in the FOXC1 gene (601090.0011). The authors also screened the PITX2 (601542) and CYP1B1 (601771) genes in this family and identified no disease-causing mutations, although they did find that 2 known functional polymorphisms in CYP1B1, V432L and N453S, were carried in heterozygosity by all affected individuals except for the proband, who was homozygous for the common N453 allele, and her brother, who was homozygous for the minor L432 allele.
Aldinger et al. (2009) analyzed brain imaging studies in 18 individuals with chromosome 6p25 copy number variation involving the FOXC1 gene and 3 patients with intragenic mutations of FOXC1, all of whom had been previously reported (Pearce et al. (1982, 1983); Gould et al., 1997; Mears et al., 1998; Nishimura et al., 1998; Lehmann et al., 2000; DeScipio et al., 2005; Lin et al., 2005; Maclean et al., 2005; Chanda et al., 2008) with phenotypes of glaucoma, Axenfeld-Rieger anomaly or syndrome type 3, cardiac malformations, and/or brain anomalies, particularly Dandy-Walker malformation. All of the patients had abnormalities on MRI, showing classic or mild Dandy-Walker malformation (DWM), mega cisterna magna (MCM), or cerebellar vermis hypoplasia (CVH). The combined genotype and phenotype data showed consistently more severe phenotypes among individuals with large compared to small deletions, suggesting contributions from more than 1 causative gene in the region; in addition, all 12 deletions involved the FOXC1 gene plus at least 2 exons of the GMDS gene (602884), implicating 1 or both of these genes as having a previously unrecognized role in cerebellar development. In 3 patients from 2 families with missense mutations in FOXC1 resulting in Axenfeld anomaly (601090.0003) and Axenfeld-Rieger syndrome type 3 (601090.0008), respectively, Aldinger et al. (2009) observed mild CVH and an abnormal white matter signal corresponding to prominent perivascular spaces. Aldinger et al. (2009) concluded that alteration of FOXC1 function alone can cause CVH and contributes to MCM and DWM.
Reviews
Lines et al. (2002) reviewed the molecular genetics of Axenfeld-Rieger malformations, including the roles of PITX2 (601542) and FOXC1 in human disease and mouse models.
In 2 unrelated patients with iridogoniodysgenesis, Fetterman et al. (2009) identified heterozygosity for a FOXC1 missense mutation in the inhibitory domain (601090.0012) and stated that this was the first missense mutation to be reported outside of the forkhead domain. Noting that the iridogoniodysgenesis phenotype is more commonly associated with FOXC1 duplications than mutations, Fetterman et al. (2009) suggested that FOXC1 duplications and mutations that disrupt the inhibitory domain may lead to disease through similar mechanisms and thus have more similar phenotypes when compared to disease caused by missense mutations with reduced protein function.
The mouse gene Mf1, which encodes a forkhead/winged helix transcription factor expressed in many embryonic tissues, including prechondrogenic mesenchyme, periocular mesenchyme, meninges, endothelial cells, and kidney, is the mouse homolog of FOXC1. Homozygous null Mf1-lacZ mice die at birth with hydrocephalus, eye defects, and multiple skeletal abnormalities identical to those of the classic mutant, congenital hydrocephalus. Kume et al. (1998) showed that congenital hydrocephalus involves a point mutation in Mf1, generating a truncated protein lacking the DNA-binding domain. Mesenchyme cells from Mf1-lacZ embryos differentiated poorly into cartilage in micromass culture and did not respond to added BMP2 and TGF-beta-1. The differentiation of arachnoid cells in the mutant meninges was also abnormal.
The autosomal recessive mouse mutation congenital hydrocephalus (ch) is characterized by congenital, lethal hydrocephalus in association with multiple developmental defects, notably skeletal defects, in tissues derived from the cephalic neural crest. Hong et al. (1999) used positional cloning methods to map ch in the vicinity of D13Mit294 and confirmed that the ch phenotype is caused by homozygosity for a nonsense mutation in the Mf1 gene. They found that ch heterozygotes have the glaucoma-related distinct phenotype of multiple anterior segment defects resembling Axenfeld-Rieger anomaly. They also localized a second member of this gene family (Hfh1), a candidate for other developmental defects, approximately 470 kb proximal to Mf1.
Smith et al. (2000) reported that Mf1 +/- mice have anterior segment abnormalities similar to those reported in humans: small or absent canal of Schlemm, aberrantly developed trabecular meshwork, iris hypoplasia, severely eccentric pupils, and displaced Schwalbe line, but with normal intraocular pressure. The penetrance of clinically obvious abnormalities varied with genetic background. In some affected eyes, collagen bundles were half normal diameter, or collagen and elastic tissue were very sparse, suggesting that abnormalities in extracellular matrix synthesis or organization may contribute to development of the ocular phenotypes. Similar abnormalities were found in Mfh1 +/- mice (FOXC2; 602402), but no disease-associated mutations were identified in the human homolog FOXC2 in 32 ARA patients.
Kume et al. (2001) found that Foxc1 -/- Foxc2 -/- compound homozygous mice died earlier with much more severe defects than single homozygotes alone. Compound homozygous mice had profound abnormalities in the first and second branchial arches and in early remodeling of blood vessels. They showed complete absence of segmented paraxial mesoderm, including anterior somites. In situ hybridization showed that both Foxc1 and Foxc2 were required for transcription in the anterior presomitic mesoderm of paraxis (TCF15; 601010), Mesp1 (608689), Mesp2 (605195), Hes5 (607348), and Notch1 (190198) and for formation of sharp boundaries of Dll1 (606582), Lfng (602576), and ephrin B2 (EFNB2; 600527) expression. Kume et al. (2001) proposed that FOXC1 and FOXC2 interact with the Notch signaling pathway and are required for prepatterning of anterior and posterior domains in the presumptive somites through a putative Notch/Delta/Mesp regulatory loop.
Libby et al. (2003) demonstrated that Tyr (606933) activity modifies the phenotype in Foxc1 +/- mice and also in mice deficient in Cyp1b1 (601771), which have ocular drainage structure abnormalities resembling those reported in human primary congenital glaucoma patients. The severe dysgenesis in eyes lacking both Cyp1b1 and Tyr was alleviated by administration of the tyrosinase product dihydroxyphenylalanine (L-DOPA). The authors concluded that their studies raised the possibility that a tyrosinase/L-DOPA pathway modifies human primary congenital glaucoma.
Using N-ethyl-N-nitrosourea mutagenesis, Zarbalis et al. (2007) produced 'hole-in-the-head' (hith) mice, which had cortical and skull defects but survived to adulthood. These mice had a phe107-to-leu mutation in Foxc1 that destabilized the protein without substantially altering transcriptional activity. Embryonic and postnatal histologic analysis showed that diminished Foxc1 expression in all 3 layers of meningeal cells in Foxc1(hith/hith) mice contributed to cortical and skull defects and that the prominent phenotypes appeared as the meninges differentiated into pia, arachnoid, and dura. Analysis of cortical phenotypes showed that Foxc1(hith/hith) mice displayed detachment of radial glial endfeet, marginal zone heterotopias, and cortical dyslamination. Zarbalis et al. (2007) concluded that the meninges regulate development of the skull and cerebral cortex by controlling aspects of the formation of these neighboring structures and that defects in meningeal differentiation can lead to severe cortical dysplasia.
Aldinger et al. (2009) generated Foxc1-null mice and observed embryonic abnormalities of the cerebellar rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 (601461) expression in the vermis. Foxc1 homozygous hypomorphs had cerebellar vermis hypoplasia with medial fusion and foliation defects.
Nishimura et al. (1998) found an 11-bp deletion upstream of the FKHL7 forkhead domain in 2 brothers diagnosed with different anterior segment defects (ASGD3; 601631): Rieger anomaly and iris hypoplasia, respectively. Both had glaucoma, and neither had the extraocular manifestations of Rieger syndrome. Their father, who had isolated posterior embryotoxon, was also found to carry the deletion.
In a mother and daughter with classic Rieger anomaly and glaucoma (ASGD3; 601631), Nishimura et al. (1998) identified a C-to-T transition within the forkhead domain of the FKHL7 gene, causing a ser131-to-leu (S131L) amino acid substitution.
In a patient with severe Axenfeld anomaly and glaucoma (ASGD3; 601631), Nishimura et al. (1998) found a C-to-G transversion within the forkhead domain of the FKHL7 gene. This change resulted in an ile126-to-met (I126M) amino acid substitution. The mutation was found also in the father who likewise was diagnosed with Axenfeld anomaly.
Aldinger et al. (2009) analyzed brain imaging studies in 1 of the patients previously studied by Nishimura et al. (1998) and observed cerebellar vermis hypoplasia and abnormal white matter signal corresponding to prominent perivascular spaces.
Anterior Segment Dysgenesis 3
In a proband from an extended family with a spectrum of anterior segment defects, including Rieger and Axenfeld anomalies (ASGD3; 601631), Nishimura et al. (1998) identified a T-to-C transition in the FOXC1 gene that resulted in a phe112-to-ser (F112S) transition within the forkhead domain. The mutation was found to segregate with the disease in an extended pedigree and by sequence analysis was not present in an additional 12 individuals of European descent.
Axenfeld-Rieger Syndrome, Type 3
In 5 affected members of a 4-generation family segregating autosomal dominant Axenfeld-Rieger syndrome type 3 (602482), Honkanen et al. (2003) identified the F112S mutation in the FOXC1 gene. All affected individuals had posterior embryotoxon and iris processes; additional ocular findings in 2 patients included iris hypoplasia, corectopia, and glaucoma, and another patient also had Peters anomaly. Extraocular features were present in 4 patients, including 1 patient with hypodontia, flat maxillary processes, and a saddle nose defect, 1 patient with small teeth, 1 patient who had undergone aortic valve replacement, and 1 patient with cardiomegaly and congestive heart failure.
In a family with 9 affected individuals in 5 sibships in 3 generations, Mirzayans et al. (2000) found that Axenfeld-Rieger syndrome (RIEG3; 602482) was associated with a 67C-T transition in the FKHL7 gene, predicted to cause a gln23-to-ter (E23X) substitution upstream of the forkhead domain. The mutation was not found in more than 80 control chromosomes. Affected individuals presented with a variable degree of iris hypoplasia, displaced pupils (corectopia), and a prominent, anteriorly displaced Schwalbe line (posterior embryotoxon) to which peripheral iris strands were attached bridging the iridocorneal angle. Glaucoma was observed in 1 individual. Extraocular features included hypertelorism in 5 patients, microdontia in 4, flat midface in 4, umbilical abnormalities in 2, cardiac defect in 1, and hearing loss in 1.
Nishimura et al. (2001) found the same mutation in another case of Axenfeld-Rieger syndrome.
In a large pedigree with iris hypoplasia and glaucoma (ASGD3; 601631) mapping to chromosome 6p25, Lehmann et al. (2000) found no mutations in the FKHL7 gene by direct sequencing of the gene. However, genotyping with microsatellite repeat markers suggested the presence of a chromosomal duplication that segregated with the disease phenotype. The duplication was confirmed in affected individuals by FISH with markers encompassing FKHL7. These results provided evidence of gene duplication causing developmental disease in humans, with increased gene dosage of either FKHL7 or other, as yet unknown genes within the duplicated segment being the probable mechanism responsible for the phenotype. Aldinger et al. (2009) analyzed brain imaging studies in 2 of the patients previously studied by Lehmann et al. (2000) and observed enlarged cisterna magna and mild decrease in cerebellar vermis size.
In a parent and 3 sibs with iris hypoplasia, Nishimura et al. (2001) identified a partial duplication of chromosome 6p25, encompassing the FOXC1 gene, that was not found in the unaffected spouse or sole unaffected offspring. The authors found a different partial duplication of 6p25, also encompassing FOXC1, in a proband with Peters anomaly.
Using genotyping and FISH to investigate a 9-generation Scottish family segregating autosomal dominant iridogoniodysgenesis, originally reported by Zorab (1932), Lehmann et al. (2002) demonstrated an interstitial duplication of chromosome 6p25 encompassing the FOXC1 gene. Lehmann et al. (2002) stated that the iris hypoplasia phenotype in the Scottish family was 'identical' to that of the family previously found to have a 6p25 duplication by Lehmann et al. (2000).
In a patient with Axenfeld anomaly (ASGD3; 601631), Nishimura et al. (2001) found a 22-bp insertion from position 26 through 47 in the cDNA of the FKHL7 gene.
In 6 affected members of a 4-generation family originally reported by Gould et al. (1997) with Axenfeld-Rieger anomaly, in whom Mears et al. (1998) also reported deafness and heart anomalies (RIEG3; 602482), Mears et al. (1998) identified heterozygosity for a 245G-C transversion in the FOXC1 gene, predicted to result in a ser82-to-thr (S82T) substitution at the start of helix 1 of the forkhead domain. The mutation was not found in unaffected members of the family or in 140 control chromosomes.
Aldinger et al. (2009) analyzed brain imaging studies in 2 of the patients previously studied by Gould et al. (1997) and Mears et al. (1998), and observed cerebellar vermis hypoplasia and abnormal white matter signal corresponding to prominent perivascular spaces; 1 of the patients also showed meningeal defects.
In a patient with Axenfeld-Rieger anomaly (ASGD3; 601631), Mears et al. (1998) identified a 261C-G transversion in the FOXC1 gene, resulting in an ile87-to-met (I87M) substitution in helix 1 of the forkhead domain. The mutation was not found in 144 control chromosomes.
In a mother and son with Axenfeld-Rieger syndrome (RIEG3; 602482), Ito et al. (2007) identified a heterozygous 388C-T transition in the FOXC1 gene, resulting in a leu130-to-phe (L130F) substitution in helix 3, the so-called 'recognition helix' of the forkhead domain. The L130F mutant was expressed at levels similar to those of wildtype FOXC1, but migrated at an apparent reduced molecular weight, suggesting that the mutant and wildtype proteins might be differentially phosphorylated. Functional studies showed that the L130F protein also had a significantly impaired capacity to localize to the nucleus, bind DNA, and transactivate reporter genes. The mutation was not found in the maternal grandparents, indicating a de novo mutation in the mother, and was not found in 100 control chromosomes.
In 5 affected members of a 3-generation family with Axenfeld-Rieger syndrome (602482), who displayed a substantial degree of intrafamilial phenotypic variability including Peters anomaly in 1 patient, Weisschuh et al. (2008) identified heterozygosity for a 358C-T transition in the FOXC1 gene, resulting in a gln120-to-ter (Q120X) substitution causing truncation of part of the forkhead domain. All 5 affected individuals had extraocular features, including maxillary hypoplasia in 3, protuberant umbilical skin in 2, ureteral stenosis in 2, hypertelorism in 1, and atrial septal defect in 1.
In 2 unrelated patients with iridogoniodysgenesis (ASAD3; 601631), Fetterman et al. (2009) identified heterozygosity for an 889C-T transition in the FOXC1 gene, resulting in a pro297-to-ser (P297S) substitution in the inhibitory domain. Both patients were myopic, and primary open angle glaucoma had been diagnosed at ages 25 years and 48 years, respectively. Functional studies in transfected cells showed that the P297S mutant did not affect localization to the nucleus or DNA binding, and P297S mutant expression levels and molecular mass were not altered compared to wildtype; the P297S mutant was, however, found to have a half-life that was 45% longer than wildtype. In addition, transactivation ability of P297S was consistently less than 75% of wildtype.
Aldinger, K. A., Lehmann, O. J., Hudgins, L., Chizhikov, V. V., Bassuk, A. G., Ades, L. C., Krantz, I. D., Dobyns, W. B., Millen, K. J. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nature Genet. 41: 1037-1042, 2009. [PubMed: 19668217] [Full Text: https://doi.org/10.1038/ng.422]
Berry, F. B., Lines, M. A., Oas, J. M., Footz, T., Underhill, D. A., Gage, P. J., Walter, M. A. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum. Molec. Genet. 15: 905-919, 2006. [PubMed: 16449236] [Full Text: https://doi.org/10.1093/hmg/ddl008]
Berry, F. B., Skarie, J. M., Mirzayans, F., Fortin, Y., Hudson, T. J., Raymond, V., Link, B. A., Walter, M. A. FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A. Hum. Molec. Genet. 17: 490-505, 2008. [PubMed: 17993506] [Full Text: https://doi.org/10.1093/hmg/ddm326]
Chanda, B., Asai-Coakwell, M., Ye, M., Mungall, A. J., Barrow, M., Dobyns, W. B., Behesti, H., Sowden, J. C., Carter, N. P., Walter, M. A., Lehmann, O. J. A novel mechanistic spectrum underlies glaucoma-associated chromosome 6p25 copy number variation. Hum. Molec. Genet. 17: 3446-3458, 2008. [PubMed: 18694899] [Full Text: https://doi.org/10.1093/hmg/ddn238]
DeScipio, C., Schneider, L., Young, T. L., Wasserman, N., Yaeger, D., Lu, F., Wheeler, P. G., Williams, M. S., Bason, L., Jukofsky, L., Menon, A., Geschwindt, R., Chudley, A. E., Saraiva, J., Schinzel, A. A. G. L., Guichet, A., Dobyns, W. E., Toutain, A., Spinner, N. B., Krantz, I. D. Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome. Am. J. Med. Genet. 134A: 3-11, 2005. [PubMed: 15704124] [Full Text: https://doi.org/10.1002/ajmg.a.30573]
Fetterman, C. D., Mirzayans, F., Walter, M. A. Characterization of a novel FOXC1 mutation, P297S, identified in two individuals with anterior segment dysgenesis. (Letter) Clin. Genet. 76: 296-299, 2009. [PubMed: 19793056] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01210.x]
Gould, D. B., Mears, A. J., Pearce, W. G., Walter, M. A. Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25. (Letter) Am. J. Hum. Genet. 61: 765-768, 1997. [PubMed: 9326342]
Hong, H.-K., Lass, J. H., Chakravarti, A. Pleiotropic skeletal and ocular phenotypes of the mouse mutation congenital hydrocephalus (ch/Mf1) arise from a winged helix/forkhead transcription factor gene. Hum. Molec. Genet. 8: 625-637, 1999. [PubMed: 10072431] [Full Text: https://doi.org/10.1093/hmg/8.4.625]
Honkanen, R. A., Nishimura, D. Y., Swiderski, R. E., Bennett, S. R., Hong, S., Kwon, Y. H., Stone, E. M., Sheffield, V. C., Alward, W. L. M. A family with Axenfeld-Rieger syndrome and Peters anomaly caused by a point mutation (phe112ser) in the FOXC1 gene. Am. J. Ophthal. 135: 368-375, 2003. [PubMed: 12614756] [Full Text: https://doi.org/10.1016/s0002-9394(02)02061-5]
Ito, Y. A., Footz, T. K., Murphy, T. C., Courtens, W., Walter, M. A. Analyses of a novel L130F missense mutation in FOXC1. Arch. Ophthal. 125: 128-135, 2007. [PubMed: 17210863] [Full Text: https://doi.org/10.1001/archopht.125.1.128]
Kume, T., Deng, K.-Y., Winfrey, V., Gould, D. B., Walter, M. A., Hogan, B. L. M. The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell 93: 985-996, 1998. [PubMed: 9635428] [Full Text: https://doi.org/10.1016/s0092-8674(00)81204-0]
Kume, T., Jiang, H. Y., Topczewska, J. M., Hogan, B. L. M. The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis. Genes Dev. 15: 2470-2482, 2001. [PubMed: 11562355] [Full Text: https://doi.org/10.1101/gad.907301]
Larsson, C., Hellqvist, M., Pierrou, S., White, I., Enerback, S., Carlsson, P. Chromosomal localization of six human forkhead genes, freac-1 (FKHL5), -3 (FKHL7), -4 (FKHL8), -5 (FKHL9), -6 (FKHL10), and -8 (FKHL12). Genomics 30: 464-469, 1995. [PubMed: 8825632] [Full Text: https://doi.org/10.1006/geno.1995.1266]
Lehmann, O. J., Ebenezer, N. D., Ekong, R., Ocaka, L., Mungall, A. J., Fraser, S., McGill, J. I., Hitchings, R. A., Khaw, P. T., Sowden, J. C., Povey, S., Walter, M. A., Bhattacharya, S. S., Jordan, T. Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions. Invest. Ophthal. Vis. Sci. 43: 1843-1849, 2002. [PubMed: 12036988]
Lehmann, O. J., Ebenezer, N. D., Jordan, T., Fox, M., Ocaka, L., Payne, A., Leroy, B. P., Clark, B. J., Hitchings, R. A., Povey, S., Khaw, P. T., Bhattacharya, S. S. Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma. Am. J. Hum. Genet. 67: 1129-1135, 2000. [PubMed: 11007653] [Full Text: https://doi.org/10.1016/S0002-9297(07)62943-7]
Libby, R. T., Smith, R. S., Savinova, O. V., Zabaleta, A., Martin, J. E., Gonzalez, F. J., John, S. W. M. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 299: 1578-1581, 2003. [PubMed: 12624268] [Full Text: https://doi.org/10.1126/science.1080095]
Lin, R. J., Cherry, A. M., Chen, K. C., Lyons, M., Hoyme, H. E., Hudgins, L. Terminal deletion of 6p results in a recognizable phenotype. Am. J. Med. Genet. 136A: 162-168, 2005. [PubMed: 15940702] [Full Text: https://doi.org/10.1002/ajmg.a.30784]
Lines, M. A., Kozlowski, K., Walter, M. A. Molecular genetics of Axenfeld-Rieger malformations. Hum. Molec. Genet. 11: 1177-1184, 2002. [PubMed: 12015277] [Full Text: https://doi.org/10.1093/hmg/11.10.1177]
Maclean, K., Smith, J., St. Heaps, L., Chia, N., Williams, R., Peters, G. B., Onikul, E., McCrossin, T., Lehmann, O. J., Ades, L. C. Axenfeld-Rieger malformation and distinctive facial features: clues to a recognizable 6p25 microdeletion syndrome. Am. J. Med. Genet. 132A: 381-385, 2005. [PubMed: 15654696] [Full Text: https://doi.org/10.1002/ajmg.a.30274]
Mears, A. J., Jordan, T., Mirzayans, F., Dubois, S., Kume, T., Parlee, M., Ritch, R., Koop, B., Kuo, W.-L., Collins, C., Marshall, J., Gould, D. B., Pearce, W., Carlsson, P., Enerback, S., Morissette, J., Bhattacharya, S., Hogan, B., Raymond, V., Walter, M. A. Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am. J. Hum. Genet. 63: 1316-1328, 1998. [PubMed: 9792859] [Full Text: https://doi.org/10.1086/302109]
Mirzayans, F., Gould, D. B., Heon, E., Billingsley, G. D., Cheung, J. C., Mears, A. J., Walter, M. A. Axenfeld-Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25. Europ. J. Hum. Genet. 8: 71-74, 2000. [PubMed: 10713890] [Full Text: https://doi.org/10.1038/sj.ejhg.5200354]
Nishimura, D. Y., Searby, C. C., Alward, W. L., Walton, D., Craig, J. E., Mackey, D. A., Kawase, K., Kanis, A. B., Patil, S. R., Stone, E. M., Sheffield, V. C. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am. J. Hum. Genet. 68: 364-372, 2001. [PubMed: 11170889] [Full Text: https://doi.org/10.1086/318183]
Nishimura, D. Y., Swiderski, R. E., Alward, W. L. M., Searby, C. C., Patil, S. R., Bennet, S. R., Kanis, A. B., Gastier, J. M., Stone, E. M., Sheffield, V. C. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nature Genet. 19: 140-147, 1998. [PubMed: 9620769] [Full Text: https://doi.org/10.1038/493]
Omatsu, Y., Seike, M., Sugiyama, T., Kume, T., Nagasawa, T. Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation. Nature 508: 536-540, 2014. [PubMed: 24590069] [Full Text: https://doi.org/10.1038/nature13071]
Pan, F., Yao, J., Chen, Y., Zhou, C., Geng, P., Mao, H., Fang, X. A novel long non-coding RNA FOXCUT and mRNA FOXC1 pair promote progression and predict poor prognosis in esophageal squamous cell carcinoma. Int. J. Clin. Exp. Path. 7: 2838-2849, 2014. [PubMed: 25031703]
Pearce, W. G., Wyatt, H. T., Boyd, T. A., Ombres, R. S., Salter, A. B. Autosomal dominant iridogoniodysgenesis: genetic features. Canad. J. Ophthal. 18: 7-10, 1983. [PubMed: 6839205]
Pearce, W. G., Wyatt, H. T., Boyd, T. A. S., Ombres, R. S., Salter, A. B. Autosomal dominant iridogoniodysgenesis: a genetic and clinical study. Birth Defects Orig. Art. Ser. 18(6): 561-569, 1982. [PubMed: 7171775]
Pierrou, S., Hellqvist, M., Samuelsson, L., Enerback, S., Carlsson, P. Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending. EMBO J. 13: 5002-5012, 1994. [PubMed: 7957066] [Full Text: https://doi.org/10.1002/j.1460-2075.1994.tb06827.x]
Saleem, R. A., Banerjee-Basu, S., Berry, F. B., Baxevanis, A. D., Walter, M. A. Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1. Am. J. Hum. Genet. 68: 627-641, 2001. [PubMed: 11179011] [Full Text: https://doi.org/10.1086/318792]
Saleem, R. A., Banerjee-Basu, S., Berry, F. B., Baxevanis, A. D., Walter, M. A. Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1. Hum. Molec. Genet. 12: 2993-3005, 2003. [PubMed: 14506133] [Full Text: https://doi.org/10.1093/hmg/ddg324]
Smith, R. S., Zabaleta, A., Kume, T., Savinova, O. V., Kidson, S. H., Martin, J. E., Nishimura, D. Y., Alward, W. L. M., Hogan, B. L. M., John, S. W. M. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum. Molec. Genet. 9: 1021-1032, 2000. [PubMed: 10767326] [Full Text: https://doi.org/10.1093/hmg/9.7.1021]
Wang, L., Siegenthaler, J. A., Dowell, R. D., Yi, R. Foxcl reinforces quiescence in self-renewing hair follicle stem cells. Science 351: 613-617, 2016. [PubMed: 26912704] [Full Text: https://doi.org/10.1126/science.aad5440]
Weisschuh, N., Wolf, C., Wissinger, B., Gramer, E. A novel mutation in the FOXC1 gene in a family with Axenfeld-Rieger syndrome and Peters' anomaly. Clin. Genet. 74: 476-480, 2008. [PubMed: 18498376] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01025.x]
Zarbalis, K., Siegenthaler, J. A., Choe, Y., May, S. R., Peterson, A. S., Pleasure, S. J. Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development. Proc. Nat. Acad. Sci. 104: 14002-14007, 2007. [PubMed: 17715063] [Full Text: https://doi.org/10.1073/pnas.0702618104]
Zorab, A. Glaucoma simplex familialis. Trans. Ophthal. Soc. U.K. 52: 446-460, 1932.