Alternative titles; symbols
HGNC Approved Gene Symbol: FOXE3
Cytogenetic location: 1p33 Genomic coordinates (GRCh38): 1:47,416,285-47,418,052 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p33 | {Aortic aneurysm, familial thoracic 11, susceptibility to} | 617349 | Autosomal dominant | 3 |
| Anterior segment dysgenesis 2, multiple subtypes | 610256 | Autosomal recessive | 3 | |
| Cataract 34, multiple types | 612968 | 3 |
The forkhead genes are transcription factors distinguished by a characteristic 100-amino acid motif that was originally identified in Drosophila; see 164874. Larsson et al. (1995) cloned a partial human cDNA corresponding to a novel forkhead gene, designated FOXE3. Blixt et al. (2000) isolated genomic clones of the mouse homolog, Foxe3, which encodes a 288-amino acid protein. By in situ hybridization, they detected Foxe3 expression in developing eye around embryonic day 9.5 at the start of lens placode induction. Expression increased as the lens placode was formed and was confined to the lens vesicle as it detached from the surface ectoderm. As the posterior cells of the lens fiber began to differentiate, expression was restricted to the undifferentiated cells covering the anterior surface of the lens. Other than lens, Blixt et al. (2000) detected Foxe3 expression only briefly in the neural folds in the cephalic region at about the same time as expression in the lateral head ectoderm. After closure of the anterior neuropore, expression was found in the most caudal, dorsolateral parts of the diencephalon. The expression peaked around embryonic days 9.5 to 10 and then disappeared.
Using RT-PCR, Wada et al. (2011) detected Foxe3 expression in adult mouse testis and eye, but not in brain or kidney.
The FOXE gene consists of a single coding exon (Valleix et al., 2006).
By fluorescence in situ hybridization and somatic cell hybrid analysis, Larsson et al. (1995) mapped the FOXE3 gene to chromosome 1p32.
By FISH, Blixt et al. (2000) mapped the mouse Foxe3 gene to chromosome 4C7, which is in agreement with the genetic mapping of the 'dysgenetic lens' (dyl) mutant to chromosome 4, in an area showing conserved synteny with human 1p32.
Anterior Segment Dysgenesis 2
Anterior segment dysgenesis is frequently associated with cataracts and glaucoma, resulting in visual disability in childhood. Semina et al. (2001) reported a single-nucleotide insertion in the coding region of the FOXE3 gene in a family with anterior segment ocular dysgenesis and cataracts (ASGD2; 610256). The mutation caused a frameshift that resulted in an abnormal sequence of 5 terminal amino acids and an addition of 111 amino acids to the predicted protein. The mutation was present in 2 affected individuals from this family and was not identified in 180 normal control chromosomes.
In a large 4-generation Newfoundland family segregating an autosomal dominant form of variable anterior segment dysgenesis, previously reported by Green and Johnson (1986), Doucette et al. (2011) analyzed 9 functional candidate genes and identified a heterozygous non-stop mutation in the FOXE3 gene (X320L; 601094.0003) that segregated with disease in the family and was not found in 141 ethnically matched controls.
Valleix et al. (2006) detected homozygosity for a nonsense mutation in the FOXE3 gene (601094.0002) in 3 sibs with congenital primary aphakia. The authors stated that the findings indicated a possible critical role for FOXE3 very early in the lens developmental program, perhaps earlier than any role recognized elsewhere for this gene.
In a large consanguineous Pakistani family with congenital primary aphakia, Anjum et al. (2010) identified homozygosity for the C240X mutation in the FOXE3 gene that segregated fully with disease.
In a large consanguineous family with ASGD mapping to chromosome 1p34.1-p32.3, Khan et al. (2016) sequenced the FOXE3 gene and identified homozygosity for a nonsense mutation (C240X; 601094.0004) that segregated with disease and was not found in 384 ethnically matched control chromosomes or in public variant databases. Through combined transcriptional and proteomic studies, the authors identified the DNAJB1 gene (604572) as a downstream target of FOXE3 and also showed that DNAJB1 plays a crucial role in the development and maintenance of lens transparency.
Cataract 34, Multiple Types
In 2 unrelated consanguineous Pakistani families segregating autosomal recessive congenital cataract mapping to chromosome 1p34.3-p32.2, Khan et al. (2016) sequenced the FOXE3 gene and identified 2 different homozygous missense mutations, N117K (601094.0005) and E103K (601094.0006), that segregated with disease and were not found in controls.
Susceptibility to Familial Thoracic Aortic Aneurysm 11
In a large 4-generation family (TAA337) segregating autosomal dominant thoracic aortic aneurysm and dissection (AAT11; 617349) with reduced penetrance, Kuang et al. (2016) identified heterozygosity for a missense mutation in the FOXE3 gene (D153H; 601094.0007). Analysis of the FOXE3 gene in 564 unrelated probands with TAAD identified 3 additional likely pathogenic rare missense variants (see, e.g., G137D, 601094.0008), all located within the highly conserved forkhead DNA-binding domain.
Kuang et al. (2016) stated that FOXE3 mutations associated with thoracic aortic aneurysm and dissection involve amino acids at the C-terminal end of the forkhead DNA-binding domain, whereas mutations that cause ocular conditions are located at the N-terminal end of the forkhead domain or outside this domain.
Blixt et al. (2000) hypothesized that mutations in Foxe3 could be responsible for the phenotype observed in dysgenetic lens (dyl) mutant mice. In these mice, the lens vesicle fails to separate from the ectoderm, causing a fusion between the lens and the cornea. Blixt et al. (2000) identified 2 mutations within the DNA-binding domain of Foxe3 in dyl mice: phe93-to-leu and phe98-to-ser. These 2 phenylalanine residues are highly conserved in all forkhead proteins and Blixt et al. (2000) predicted the mutations would obliterate DNA binding.
Blixt et al. (2000) reported that in dyl mice, the posterior of the lens epithelium fails to divide and shows signs of premature differentiation, whereas the most anterior cells are eliminated by apoptosis. The normal separation of the lens vesicle from the ectoderm fails in dyl mice. However, lens fiber differentiation appears to be normal and is thought to be independent of Foxe3. Blixt et al. (2000) concluded that Foxe3 is essential for closure of the lens vesicle and is a factor that promotes survival and proliferation, while preventing differentiation, in the lens epithelium.
In the vacuolated lens (vl) mouse model resulting from a deletion in the mouse Gpr161 gene (612250), Matteson et al. (2008) mapped modifier quantitative trait loci and found the pro23 allele of Foxe3, which reduced the transcriptional activity of Foxe3, contributed to cataract development in vl/vl mice.
The Rinshoken cataract (rct) mutation is a recessive mutation in mice that causes mild microphthalmia and congenital cataracts with severe degeneration of lens fibers. Wada et al. (2011) determined that rct is caused by a 22-bp deletion within an upstream regulatory region of the Foxe3 gene that contains major and minor lens regulatory elements. The deletion includes a CTCTTTTCA motif that is highly conserved in vertebrates. RT-PCR detected reduced expression of Foxe3 in lens, but not testis, of rct mice compared with wildtype. Wada et al. (2011) concluded that rct is caused by reduced Foxe3 expression due to a deletion in a cis-acting regulatory element.
Kuang et al. (2016) knocked down foxe3 in zebrafish and observed that aortic arches were disrupted in 70% of morphants, without alterations in the cardiac outflow tract. Coinjection of a p53 (TP53; 191170) morpholino rescued the aortic arch defects on foxe3 morphants, suggesting that p53 might act downstream of FOXE3 in a pathway required for aortic development. Foxe3-deficient mice showed reduced smooth muscle cell (SMC) density and impaired SMC differentiation that was limited to the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity.
In a mother and daughter with anterior segment dysgenesis (ASGD2; 610256), Semina et al. (2001) identified a single G nucleotide insertion 15 bp upstream of the stop codon in the FOXE3 gene. The mutation resulted in a frameshift, which altered the sequence of the last 5 amino acids and added an additional 111 amino acids to the predicted protein.
In 3 sibs from a consanguineous family with anterior segment dysgenesis (ASGD2; 610256), described as congenital primary aphakia, Valleix et al. (2006) found homozygosity for a 720C-A transversion in the FOXE3 gene that predicted the substitution of a stop codon for cysteine at codon 240 (C240X). Each unaffected parent was heterozygous for the mutation.
In 5 affected individuals from a large consanguineous Pakistani family with aphakia, Anjum et al. (2010) identified homozygosity for the C240X mutation in the FOXE3 gene. The unaffected parents and an unaffected sib were heterozygous for the mutation. Haplotype analysis indicated that the mutation likely arose independently in this family and in the family reported by Valleix et al. (2006).
In 8 affected members of a large 4-generation Newfoundland family with variable anterior segment dysgenesis (ASGD2; 610256), previously reported by Green and Johnson (1986), Doucette et al. (2011) identified heterozygosity for a 959G-T transversion in the FOXE3 gene, resulting in the elimination of the functional opal stop codon (ter320-to-leu; X320L) and predicting the addition of 72 amino acid residues to the C terminus. The mutation was not found in 17 unaffected family members or in 141 ethnically matched controls. Direct sequencing of an affected individual's cDNA demonstrated the absence of the 959G-T mutation, suggesting that the mRNA transcribed from the 'non-stop' allele might be degraded before being translated, or that the mRNA might not be transcribed at all.
In 4 affected individuals from a consanguineous family with anterior segment dysgenesis (ASGD2; 610256), Khan et al. (2016) identified homozygosity for a c.720C-A transversion in the FOXE3 gene, resulting in a cys240-to-ter (C240X) substitution. The mutation segregated fully with disease in the family and was not found in 384 ethnically matched control chromosomes or in the 1000 Genomes Project or NHLBI Exome Variant Server databases. Analysis of HEK293 cells transfected with wildtype FOXE3 the C240X mutant revealed only 1 gene, DNAJB1 (604572), that was differentially expressed in both transcriptome and proteome screens, showing downregulation with the C240X mutant compared to wildtype FOXE3. In addition, overexpression of FOXE3 in HEK293 cells showed 3-fold higher expression of DNAJB1 in cells transfected with wildtype FOXE3 compared to cells expressing the C240X mutant.
In 5 affected sibs from a consanguineous Pakistani family (PKCC009) with congenital cataract of the membranous type (CTRCT34; 612968), originally studied by Butt et al. (2007), Khan et al. (2016) identified homozygosity for a c.351C-G transversion in the FOXE3 gene, resulting in an asn117-to-lys (N117K) substitution at a highly conserved residue within the putative DNA-binding domain. The mutation segregated fully with disease in the family and was not found in 144 Pakistani or 24 Saudi Arabian control chromosomes or in the 1000 Genomes Project, NHLBI Exome Sequencing Project, or dbSNP databases. In addition to cataract, the affected sibs also displayed other ocular abnormalities, including corneal opacity, microcornea,and nystagmus.
In 7 affected sibs from a consanguineous Pakistani family (PKCC039) with congenital cataract of the posterior subcapsular type (CTRCT34; 612968), originally studied by Butt et al. (2007), Khan et al. (2016) identified homozygosity for a c.307G-A transition in the FOXE3 gene, resulting in a glu103-to-lys (E103K) substitution at a highly conserved residue within the putative DNA-binding domain. The mutation segregated fully with disease in the family and was not found in 144 Pakistani or 24 Saudi Arabian control chromosomes or in the 1000 Genomes Project, NHLBI Exome Sequencing Project, or dbSNP databases.
In a large 4-generation family (family TAA337) segregating autosomal dominant thoracic aortic aneurysm and dissection (AAT11; 617349) with reduced penetrance, Kuang et al. (2016) identified heterozygosity for a c.457G-C transversion (c.457G-C, NM_012186.2) in the FOXE3 gene, resulting in an asp153-to-his (D153H) substitution at a highly conserved residue within the forkhead DNA-binding domain. The mutation, which was found in 1/13,000 chromosomes in the ESP database and with a minor allele frequency of 0.0008 in the ExAC database, was present in 3 affected male members of the family, but was also detected in 2 asymptomatic female members, aged 61 and 23 years; in addition, a female obligate carrier who died at age 87 had no evidence of aortic disease. Coinjection of FOXE3 mRNA harboring the D153H mutation rescued the aortic arch disruption phenotype in significantly fewer foxe3 morphants compared with wildtype mRNA.
In a father and 2 sons (family MS300) with aortic root dilation (AAT11; 617349), Kuang et al. (2016) identified heterozygosity for a c.410G-A transition (c.410G-A, NM_012186.2) in the FOXE3 gene, resulting in a gly137-to-asp (G137D) substitution at a highly conserved residue within the forkhead DNA-binding domain. The mutation had a minor allele frequency of 0.0017 in the ExAC database.
Anjum, I., Eiberg, H., Baig, S. M., Tommerup, N., Hansen, L. A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family. Molec. Vision 16: 549-555, 2010. [PubMed: 20361012]
Blixt, A., Mahlapuu, M., Aitola, M., Pelto-Huikko, M., Enerback, S., Carlsson, P. A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev. 14: 245-254, 2000. [PubMed: 10652278]
Butt, T., Yao, W., Kaul, H., Xiaodong, J., Gradstein, L., Zhang, Y., Husnain, T., Riazuddin, S., Hejtmancik, J. F., Riazuddin, S. A. Localization of autosomal recessive congenital cataracts in consanguineous Pakistani families to a new locus on chromosome 1p. Molec. Vis. 13: 1635-1640, 2007. [PubMed: 17893665]
Doucette, L., Green, J., Fernandez, B., Johnson, G. J., Parfrey, P., Young, T.-L. A novel, non-stop mutation in FOXE3 causes an autosomal dominant form of variable anterior segment dysgenesis including Peters anomaly. Europ. J. Hum. Genet. 19: 293-299, 2011. [PubMed: 21150893] [Full Text: https://doi.org/10.1038/ejhg.2010.210]
Green, J. S., Johnson, G. J. Congenital cataract with microcornea and Peters' anomaly as expressions of one autosomal dominant gene. Ophthalmic Paediat. Genet. 7: 187-194, 1986. [PubMed: 3550563] [Full Text: https://doi.org/10.3109/13816818609004137]
Khan, S. Y., Vasanth, S., Kabir, F., Gottsch, J. D., Khan, A. O., Chaerkady, R., Lee, M.-C. W., Leitch, C. C., Ma, Z., Laux, J., Villasmil, R., Khan, S. N., Riazuddin, S., Akram, J., Cole, R. N., Talbot, C. C., Pourmand, N., Zaghloul, N. A., Hejtmancik, J. F., Riazuddin, S. A. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nature Commun. 7: 10953, 2016. Note: Electronic Article. [PubMed: 27218149] [Full Text: https://doi.org/10.1038/ncomms10953]
Kuang, S.-Q., Medina-Martinez, O., Guo, D., Gong, L., Regalado, E. S., Reynolds, C. L., Boileau, C., Jondeau, G., Prakash, S. K., Kwartler, C. S., Zhu, L. Y., Peters, A. M., and 13 others. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J. Clin. Invest. 126: 948-961, 2016. [PubMed: 26854927] [Full Text: https://doi.org/10.1172/JCI83778]
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]
Matteson, P. G., Desai, J., Korstanje, R., Lazar, G., Borsuk, T. E., Rollins, J., Kadambi, S., Joseph, J., Rahman, T., Wink, J., Benayed, R., Paigen, B., Millonig, J. H. The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. Proc. Nat. Acad. Sci. 105: 2088-2093, 2008. [PubMed: 18250320] [Full Text: https://doi.org/10.1073/pnas.0705657105]
Semina, E. V., Brownell, I., Mintz-Hittner, H. A., Murray, J. C., Jamrich, M. Mutations in the human forkhead transcription factor FOXE3 associated with anterior segment ocular dysgenesis and cataracts. Hum. Molec. Genet. 10: 231-236, 2001. [PubMed: 11159941] [Full Text: https://doi.org/10.1093/hmg/10.3.231]
Valleix, S., Niel, F., Nedelec, B., Algros, M.-P., Schwartz, C., Delbosc, B., Delpech, M., Kantelip, B. Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans. Am. J. Hum. Genet. 79: 358-364, 2006. [PubMed: 16826526] [Full Text: https://doi.org/10.1086/505654]
Wada, K., Maeda, Y. Y., Watanabe, K., Oshio, T., Ueda, T., Takahashi, G., Yokohama, M., Saito, J., Seki, Y., Takahama, S., Ishii, R., Shitara, H., Taya, C., Yonekawa, H., Kikkawa, Y. A deletion in a cis element of Foxe3 causes cataracts and microphthalmia in rct mice. Mammalian Genome 22: 693-702, 2011. [PubMed: 22002806] [Full Text: https://doi.org/10.1007/s00335-011-9358-y]