Alternative titles; symbols
HGNC Approved Gene Symbol: FOXI1
SNOMEDCT: 70348004; ICD10CM: E07.1;
Cytogenetic location: 5q35.1 Genomic coordinates (GRCh38): 5:170,105,897-170,109,737 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.1 | Enlarged vestibular aqueduct | 600791 | Autosomal recessive | 3 |
FKH10 is a member of the forkhead family of winged helix transcription regulators. The forkhead family is 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 a forkhead domain and designated them forkhead related activators (FREAC) 1 through 7. Northern blot analysis revealed that the FREAC6, or FKHL10, gene is expressed as a 2.3-kb mRNA only in kidney.
Larsson et al. (1995) showed that human FKHL10 is expressed in the adult and fetal kidney, whereas 15 other tissues (which did not include any inner ear-derived samples) were negative. Kidney-specific expression had been observed also in the mouse. Although Fkh10 may play a role in the kidney during later stages of development, it may be a minor, or perhaps redundant, role, as no kidney dysfunction was observed in homozygous knockout mice. On the contrary, Fkh10 appears to be unique in the sense that it is an early otic vesicle-specific gene necessary for the development of both cochlea and vestibulum. These findings implicated Fkh10 as an early regulator necessary for development of both cochlea and vestibulum and identified its human homolog, FKHL10, as a candidate deafness gene at 5q34. The phenotype described by Hulander et al. (1998) resembles a group of human congenital inner ear malformations called 'common cavity.' Hulander et al. (1998) proposed that mutations in FKH10 may cause a 'common cavity' phenotype in humans.
Yang et al. (2007) demonstrated that FOXI1 is a transcription factor for SLC26A4 (605646) and identified and characterized a key transcriptional regulatory element in the SLC26A4 promoter that binds FOXI1. The SLC26A4 cis element consists of 2 FOXI1 binding sites, FBS1 and FBS2, arranged head to head. Both binding sites and this specific orientation are required for FOXI1-mediated transcriptional activation.
Using single-cell RNA sequencing and in vivo lineage tracing to study the composition and hierarchy of the mouse tracheal epithelium, Montoro et al. (2018) identified a rare cell type, the Foxi1-positive pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that they termed 'hillocks'; and disease-relevant subsets of tuft and goblet cells. Montoro et al. (2018) developed 'pulse-seq,' combining single-cell RNA-seq and lineage tracing, to show that tuft, neuroendocrine, and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the CFTR (602421) in both mouse and human. Knockout of Foxi1 in mouse ionocytes caused loss of Cftr expression and disrupted airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis (219700). Montoro et al. (2018) concluded that by associating cell type-specific expression programs with key disease genes, they had established a new cellular narrative for airway disease.
Plasschaert et al. (2018) performed single-cell profiling of human bronchial epithelial cells and mouse tracheal epithelial cells to obtain a comprehensive census of cell types in the conducting airway and their behavior in homeostasis and regeneration. The analysis revealed cell states that represent known and novel cell populations, delineated their heterogeneity, and identified distinct differentiation trajectories during homeostasis and tissue repair. In addition, Plasschaert et al. (2018) identified a novel, rare cell type that they called the 'pulmonary ionocyte,' which coexpresses FOXI1, multiple subunits of the vacuolar-type H(+)-ATPase (V-ATPase), and CFTR. Using immunofluorescence, modulation of signaling pathways, and electrophysiology, Plasschaert et al. (2018) showed that Notch signaling (see 190198) is necessary and FOXI1 expression is sufficient to drive the production of the pulmonary ionocyte, and that the pulmonary ionocyte is a major source of CFTR activity in the conducting airway epithelium.
Larsson et al. (1995) mapped the FKHL10 gene to 5q34 by fluorescence in situ hybridization and somatic cell hybrid analysis.
Genes encoding forkhead proteins are instrumental during embryogenesis in mammals, in particular during development of the nervous system. Hulander et al. (1998) reported that mice with a targeted disruption of the Fkh10 locus exhibited circling behavior, poor swimming ability, and abnormal reaching response, all common findings in mice with vestibular dysfunction. These animals also failed to elicit a Preyer reflex in response to a suprathreshold auditory stimulation, as seen in mice with profound hearing impairment. Histologic examination of the inner ear revealed a gross structural malformation of the vestibulum as well as of the cochlea. These structures were replaced by a single irregular cavity in which neither proper semicircular ducts nor cochlea could be identified. Hulander et al. (1998) also showed that at 9.5 days postcoitum, Fkh10 was exclusively expressed in the otic vesicle.
Blomqvist et al. (2004) found that whereas macro- and microscopic kidney development appeared normal in Fkhl10-null mice, electron microscopy revealed an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrated complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts. The normal renal epithelium with its 2 major cell types, principal and intercalated cells, had been replaced by a single cell type positive for both principal and intercalated cell markers. The null mice were unable to acidify urine and had a lowered systemic buffer capacity and overt acidosis compared to their wildtype littermates. Blomqvist et al. (2004) concluded that Fkhl10-null mice develop distal renal tubular acidosis due to altered cellular composition of the distal nephron epithelium, which lacks the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.
Mice homozygous for the targeted deletion of Foxi1 have a phenotype that includes cochlear dysplasia and enlarged vestibular aqueduct (Hulander et al., 2003). Also included in the Foxi1 -/- mouse phenotype are male infertility and distal renal tubular acidosis (Blomqvist et al. (2004, 2006)), 2 abnormalities that had not been reported in humans with Pendred syndrome or enlarged vestibular aqueduct.
Recessive mutations in the anion transporter gene SLC26A4 (605646) are known to be responsible for Pendred syndrome (274600) and for nonsyndromic hearing loss associated with enlarged vestibular aqueduct (DFNB4; 600791). However, a large percentage of patients with these phenotypes lack mutations in the SLC26A4 coding region in one or both alleles. Yang et al. (2007) identified and characterized a key transcriptional regulatory element in the SLC26A4 promoter that binds FOXI1, which is a transcriptional activator of SLC26A4. They found 9 patients with Pendred syndrome or nonsyndromic EVA who were heterozygous for a novel -103T-C mutation (605646.0027) in this regulatory element, which interfered with FOXI1 binding and completely abolished FOXI1-mediated transcriptional activation. They also identified 2 Pendred and 4 EVA patients with heterozygous mutations in FOXI1 that compromised its ability to activate SLC26A4 transcription; 1 of the EVA patients was a double heterozygote who also carried a heterozygous mutation in the SLC26A4 gene (see 605646.0028 and 601093.0001). This finding was consistent with their observation that EVA occurs in the mouse mutant doubly heterozygous for mutations in these 2 genes, and the results supported a dosage-dependent model for the molecular pathogenesis of Pendred syndrome and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery. Mutations in many transcription factors had been shown to lead to nonsyndromic or syndromic hearing impairment, but the FOXI1/SLC26A4 connection was the first identification of a specific downstream target gene; Yang et al. (2007) stated the this was the first example of digenic inheritance to be verified as a cause of human deafness.
Yang et al. (2007) described a patient with enlarged vestibular aqueduct as the basis of nonsyndromic hearing loss (DFNB4; 600791) in whom the combination of a heterozygous glu29-to-gln (E29Q) mutation of SLC26A4 (605646.0028) and a gly258-to-glu (G258E) mutation of FOXI1 was responsible. Each unaffected parent was heterozygous for 1 of the mutations, and her unaffected sister carried only the E29Q mutation in SLC26A4. Yang et al. (2007) concluded that this was the first example of digenic inheritance to be verified as a cause of human deafness.
In 2 families given a diagnosis of DFNB4 with EVA (600791), Yang et al. (2007) found heterozygosity for an arg267-to-gln change (R267Q) in the FOXI1 protein. Although both of these families were classified by the authors as 'nonsyndromic EVA,' in one of them goiter reminiscent of Pendred syndrome (274600) was noted. Both alleles of the SLC26A4 gene (605646) were wildtype. The R267Q mutation showed significantly decreased luciferase activation in promoter-reporter assays, suggesting that this variant compromised FOXI1 transactivation ability of SLC26A4 expression and was causally related to disease.
Blomqvist, S. R., Vidarsson, H., Fitzgerald, S., Johansson, B. R., Ollerstam, A., Brown, R., Persson, A. E. G., Bergstrom, G., Enerback, S. Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1. J. Clin. Invest. 113: 1560-1570, 2004. [PubMed: 15173882] [Full Text: https://doi.org/10.1172/JCI20665]
Blomqvist, S. R., Vidarsson, H., Soder, O., Enerback, S. Epididymal expression of the forkhead transcription factor Foxi1 is required for male fertility. EMBO J. 25: 4131-4141, 2006. [PubMed: 16932748] [Full Text: https://doi.org/10.1038/sj.emboj.7601272]
Hulander, M., Kiernan, A. E., Blomqvist, S. R., Carlsson, P., Samuelsson, E. J., Johansson, B. R., Steel, K. P., Enerback, S. Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice. Development 130: 2013-2025, 2003. [PubMed: 12642503] [Full Text: https://doi.org/10.1242/dev.00376]
Hulander, M., Wurst, W., Carlsson, P., Enerback, S. The winged helix transcription factor Fkh10 is required for normal development of the inner ear. Nature Genet. 20: 374-376, 1998. [PubMed: 9843211] [Full Text: https://doi.org/10.1038/3850]
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]
Montoro, D. T., Haber, A. L., Biton, M., Vinarsky, V., Lin, B., Birket, S. E., Yuan, F., Chen, S., Leung, H. M., Villoria, J., Rogel, N., Burgin, G., and 17 others. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560: 319-324, 2018. [PubMed: 30069044] [Full Text: https://doi.org/10.1038/s41586-018-0393-7]
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]
Plasschaert, L. W., Zilionis, R., Choo-Wing, R., Savova, V., Knehr, J., Roma, G., Klein, A. M., Jaffe, A. B. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature 560: 377-381, 2018. [PubMed: 30069046] [Full Text: https://doi.org/10.1038/s41586-018-0394-6]
Yang, T., Vidarsson, H., Rodrigo-Blomqvist, S., Rosengren, S. S., Enerback, S., Smith, R. J. H. Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4). Am. J. Hum. Genet. 80: 1055-1063, 2007. Note: Erratum: Am. J. Hum. Genet. 81: 634 only, 2007. [PubMed: 17503324] [Full Text: https://doi.org/10.1086/518314]