Alternative titles; symbols
HGNC Approved Gene Symbol: FOXF1
SNOMEDCT: 233815004; ICD10CM: P29.3, P29.30; ICD9CM: 747.83;
Cytogenetic location: 16q24.1 Genomic coordinates (GRCh38): 16:86,510,527-86,515,422 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.1 | Alveolar capillary dysplasia with misalignment of pulmonary veins | 265380 | Autosomal dominant | 3 |
The forkhead genes are transcription factors distinguished by a characteristic 100-amino acid motif that was originally identified in Drosophila (see 164874).
Pierrou et al. (1994) identified 7 human genes containing forkhead domains and designated them forkhead-related activators (FREAC) 1 through 7. Northern blot analysis revealed that the FREAC1, or FKHL5, gene is expressed as a 2.6-kb mRNA in placenta and adult and fetal lung.
Hellqvist et al. (1996) reported the FREAC1 cDNA sequence. The predicted 354-amino acid protein is nearly identical to FREAC2 (FKHL6; 603250) within a 112-residue region containing the forkhead domain and adjacent sequences, and within the C-terminal region. Hellqvist et al. (1996) reported that the mouse HFH8 gene and FREAC1 share 90% nucleotide sequence identity. By resequencing of HFH8, these authors demonstrated that 5 frameshifts in the HFH8 sequence reported by Clevidence et al. (1994) were due to sequencing errors.
Madison et al. (2009) found that the upstream region of the FOXF1 gene contains 2 conserved GLI (see GLI1; 165220)-binding sites, as well as MEF2 (see 600660) and forkhead consensus sites.
Szafranski et al. (2013) reported that the 5.5-kb FOXF1 promoter region, which is located immediately upstream of the FOXF1 translation start site, contains several GLI-binding sites and partly overlaps a long noncoding RNA (lncRNA), FOXF1AS1 (614975), on the opposite strand. The promoter region is located within a large CpG island that extends into FOXF1 exon 1. Szafranski et al. (2013) also identified a 75-kb distant regulatory region located in a region lacking protein-coding genes between 332 and 257 kb upstream of the FOXF1 translation start site. This region contains several sequences conserved among vertebrates, including 2 lncRNAs, TCONS_00024764 (LINC01081; 614977) and TCONS_00024492 (LINC01082; 614978), a cluster of predicted binding sites for GLI1, GLI2 (165230), and GLI3 (165240), and a CpG island. Chromosome conformation capture analysis suggested chromatin looping between the distant regulatory region and the FOXF1 promoter.
Szafranski et al. (2014) presented evidence that LINC01081 and LINC01082 are distant enhancers of FOXF1. Knockdown of LINC01081 expression using 2 different siRNAs in fetal lung fibroblasts reduced FOXF1 transcript levels by 14% and 20%. Lung tissue from a patient with partial deletion of LINC01082 but intact FOXF1 showed a 70% reduction in FOXF1 expression.
Larsson et al. (1995) mapped the FKHL5 gene to chromosome 16q24 by fluorescence in situ hybridization and somatic cell hybrid analysis.
Madison et al. (2009) stated that mouse Foxf1 maps to a region of chromosome 8 containing several genes encoding forkhead transcription factors.
Using a reporter gene construct containing FREAC2 binding sequences in the promoter, Hellqvist et al. (1996) demonstrated that both FREAC1 and FREAC2 have C-terminal transcriptional activation domains. FREAC1/FREAC2 binding sequences are present in the promoters of several lung-specific genes, including CC10 (192020) and SPB (SFTPB; 178640). While both FREAC1 and FREAC2 transactivated an SPB promoter construct, CC10 was activated only by FREAC1. CC10 activation occurred specifically in a lung cell line with club cell-like characteristics.
Madison et al. (2009) found that expression of Foxf1 and Foxl1 (603252) in developing mouse stomach and intestine was dependent on Gli2 (165230) and Gli3 (165240) and was induced by an N-terminal fragment of Shh (600725). Several highly conserved Gli-binding sites appeared crucial for Gli-mediated binding and transcriptional activation of Foxf1 and Foxl1.
In 10 patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV; 265380) associated with multiple congenital anomalies, Stankiewicz et al. (2009) identified 6 overlapping microdeletions encompassing the FOX transcription factor gene cluster, all but 1 of which included the FOXF1 gene. By sequencing the FOXF1 gene in 18 additional patients with ACDMPV, Stankiewicz et al. (2009) identified heterozygosity for 1 nonsense, 1 no-stop, and 2 frameshift mutations in 4 unrelated patients (601089.0001-601089.0004, respectively). Stankiewicz et al. (2009) noted that in contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, which they suggested was due to haploinsufficiency for the neighboring FOXC2 (602402) and FOXL1 (603252) genes.
Sen et al. (2013) provided a comprehensive list of 42 identified FOXF1 variants in patients with ACDMPV. Twenty-five (60%) of the variants were located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. The majority of the ACDMPV cases were sporadic. Only 4 cases were familial, of which 3 showed maternal inheritance consistent with paternal imprinting of the gene.
In a male infant with a severe form of ACDMPV with imperforate anus and death at 13 days of age, Abu-El-Haija et al. (2018) identified heterozygosity for a de novo frameshift mutation in the FOXF1 gene (601089.0005). In a female infant with a more mild form of ACDMPV with a small omphalocele, Abu-El-Haija et al. (2018) identified a de novo heterozygous missense mutation in the FOXF1 gene (F85L; 601089.0006). The F85L mutation had previously been identified by Sen et al. (2013) in a patient with ACDMPV who had inherited the mutation from his mother.
Kalinichenko et al. (2002) reported that haploinsufficiency of the Foxf1 gene caused pulmonary abnormalities with perinatal lethality from lung hemorrhage in a subset of Foxf1 +/- newborn mice. They found that Foxf1 was expressed in embryonic septum transversum and gallbladder mesenchyme, and that gallbladders of Foxf1 +/- mice showed severe structural abnormalities. The Foxf1 +/- phenotype correlated with decreased expression of Vcam1 (192225), alpha-5 integrin (135620), Pdgf receptor-alpha (173490), and Hgf (142409), all of which are critical for cell adhesion, migration, and mesenchymal cell differentiation.
In a male infant with congenital alveolar capillary dysplasia and misalignment of the pulmonary veins (ACDMPV; 265380), previously reported by Sen et al. (2004), who died on day 10 of life and was also found to have a partial atrioventricular canal defect, patent ductus arteriosus, intestinal malrotation, annular pancreas and duodenal stenosis, bilateral hydronephrosis, hydroureter, and dilatation of the urinary bladder, Stankiewicz et al. (2009) identified heterozygosity for a 150C-A transversion in exon 1 of the FOXF1 gene, resulting in a tyr50-to-ter (Y50X) substitution in the forkhead box F1 domain.
In a male infant with congenital alveolar capillary dysplasia and misalignment of the pulmonary veins (ACDMPV; 265380), who died at 47 days of life and was also found to have intestinal malrotation and Meckel diverticulum, Stankiewicz et al. (2009) identified heterozygosity for a 1063T-C transition in exon 2 of the FOXF1 gene, resulting in a ter355-to-arg (X355R) substitution, predicted to lengthen the protein by 73 amino acids.
In a male infant with congenital alveolar capillary dysplasia and misalignment of the pulmonary veins (ACDMPV; 265380), who died 12 hours after birth and was also found to have obstructive renal dysplasia, Stankiewicz et al. (2009) identified heterozygosity for a 1-bp duplication in exon 1 of the FOXF1 gene, resulting in a frameshift and premature termination of the protein.
In a female infant with congenital alveolar capillary dysplasia and misalignment of the pulmonary veins (ACDMPV; 265380), who died at 1 day of life and who was also found to have partial anomalous pulmonary venous connection with absence of the left upper lobe pulmonary vein, congenital short bowel with malrotation, a small omphalocele, bilateral severe hydronephrosis, hydroureter, and bladder dilatation, as well as micrognathia and low-set ears, Stankiewicz et al. (2009) identified heterozygosity for a 2-bp deletion (956delTT) in exon 2 of the FOXF1 gene, predicted to add 29 amino acids to the protein.
In a male infant with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV; 265380), who died at 13 days of life, Abu-El-Haija et al. (2018) identified heterozygosity for a 22-bp duplication (c.1057_1078dup, NM_001451.2) in the FOXF1 gene, leading to a frameshift in the last exon and loss of a stop codon in the DNA-binding domain, predicted to lengthen the protein by 48 amino acids (Gly360ValfsTer58).
In a female infant with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV; 265380) with a small omphalocele, who was alive at 6 months of age, Abu-El-Haija et al. (2018) identified heterozygosity for a c.253T-C transition (c.253T-C, NM_001451.2) in the FOXF1 gene, resulting in a phe85-to-leu (F85L) substitution. The F85L mutation had previously been identified by Sen et al. (2013) in a patient (patient 35) with ACDMPV who had inherited the mutation from his mother.
Abu-El-Haija, A., Fineman, J., Connolly, A. J., Murali, P., Judge, L. M., Slavotinek, A. M. Two patients with FOXF1 mutations with alveolar capillary dysplasia with misalignment of pulmonary veins and other malformations: two different presentations and outcomes. Am. J. Med. Genet. 176A: 2877-2881, 2018. [PubMed: 30380203] [Full Text: https://doi.org/10.1002/ajmg.a.40641]
Clevidence, D. E., Overdier, D. G., Peterson, R. S., Porcella, A., Ye, H., Paulson, K. E., Costa, R. H. Members of the HNF-3/forkhead family of transcription factors exhibit distinct cellular expression patterns in lung and regulate the surfactant protein B promoter. Dev. Biol. 166: 195-209, 1994. [PubMed: 7958446] [Full Text: https://doi.org/10.1006/dbio.1994.1307]
Hellqvist, M., Mahlapuu, M., Blixt, A., Enerback, S., Carlsson, P. The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. J. Biol. Chem. 273: 23335-23343, 1998. [PubMed: 9722567] [Full Text: https://doi.org/10.1074/jbc.273.36.23335]
Hellqvist, M., Mahlapuu, M., Samuelsson, L., Enerback, S., Carlsson, P. Differential activation of lung-specific genes by two forkhead proteins, FREAC-1 and FREAC-2. J. Biol. Chem. 271: 4482-4490, 1996. [PubMed: 8626802] [Full Text: https://doi.org/10.1074/jbc.271.8.4482]
Kalinichenko, V. V., Zhou, Y., Bhattacharyya, D., Kim, W., Shin, B., Bambal, K., Costa, R. H. Haploinsufficiency of the mouse forkhead box f1 gene causes defects in gall bladder development. J. Biol. Chem. 277: 12369-12374, 2002. [PubMed: 11809759] [Full Text: https://doi.org/10.1074/jbc.M112162200]
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]
Madison, B. B., McKenna, L. B., Dolson, D., Epstein, D. J., Kaestner, K. H. FoxF1 and FoxL1 link hedgehog signaling and the control of epithelial proliferation in the developing stomach and intestine. J. Biol. Chem. 284: 5936-5944, 2009. [PubMed: 19049965] [Full Text: https://doi.org/10.1074/jbc.M808103200]
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]
Sen, P., Thakur, N., Stockton, D. W., Langston, C., Bejjani, B. A. Expanding the phenotype of alveolar capillary dysplasia (ACD). J. Pediat. 145: 646-651, 2004. [PubMed: 15520767] [Full Text: https://doi.org/10.1016/j.jpeds.2004.06.081]
Sen, P., Yang, Y., Navarro, C., Silva, I., Szafranski, P., Kolodziejska, K. E., Dharmadhikari, A. V., Mostafa, H., Kozakewich, H., Kearney, D., Cahill, J. B., Whitt, M., and 70 others. Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. Hum. Mutat. 34: 801-811, 2013. [PubMed: 23505205] [Full Text: https://doi.org/10.1002/humu.22313]
Stankiewicz, P., Sen, P., Bhatt, S. S., Storer, M., Xia, Z., Bejjani, B. A., Ou, Z., Wiszniewska, J., Driscoll, D. J., Maisenbacher, M. K., Bolivar, J., Bauer, M., and 32 others. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am. J. Hum. Genet. 84: 780-791, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 537 only, 2009. [PubMed: 19500772] [Full Text: https://doi.org/10.1016/j.ajhg.2009.05.005]
Szafranski, P., Dharmadhikari, A. V., Brosens, E., Gurha, P., Kolodziejska, K. E., Zhishuo, O., Dittwald, P., Majewski, T., Mohan, K. N., Chen, B., Person, R. E., Tibboel, D., and 17 others. Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder. Genome Res. 23: 23-33, 2013. [PubMed: 23034409] [Full Text: https://doi.org/10.1101/gr.141887.112]
Szafranski, P., Dharmadhikari, A. V., Wambach, J. A., Towe, C. T., White, F. V., Grady, R. M., Eghtesady, P., Cole, F. S., Deutsch, G., Sen, P., Stankiewicz, P. Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins. Am. J. Med. Genet. 164A: 2013-2019, 2014. [PubMed: 24842713] [Full Text: https://doi.org/10.1002/ajmg.a.36606]