Alternative titles; symbols
HGNC Approved Gene Symbol: POU4F3
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:146,338,839-146,341,728 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | Deafness, autosomal dominant 15 | 602459 | Autosomal dominant | 3 |
The POU4F3 gene encodes a member of the POU family of transcription factors and is critical for the maintenance of inner ear hair cells (summary by Weiss et al., 2003).
Xiang et al. (1995) cloned human cDNAs and genomic DNAs encoding the POU4F3 protein, termed BRN3C, based on its sequence similarity to BRN3A (601632) and BRN3B (113725). The BRN3C gene encodes a 338-amino acid polypeptide that contains several identifiable motifs, including a POU domain. Although its splicing pattern is identical to that of BRN3A and BRN3B, the 3 members of the BRN3 family are unlinked.
Vahava et al. (1998) found that POU4F3 is not expressed in human brain, heart, placenta, skeletal muscle, lung, liver, kidney, pancreas, or lymphoblast tissues evaluated by Northern RNA blot analysis. Nor were any POUF43 expressed sequenced tags identified in human libraries found in public databases. Studying POU4F3 RNA expression in human fetal tissues by means of RT-PCR, cDNA was detected only in fetal cochlea. Its expression pattern corresponded to that observed in the mouse; Pou4f3 is highly expressed in inner ear hair cells, but only in very defined regions of the brain and not in nonneural tissues, including liver, kidney, heart, and skeletal muscle.
Xiang et al. (1995) determined that the BRN3C gene contains 2 exons.
The POU4F3 was suspected to be located on 5q on the basis of the localization of mouse pou4f3 to mouse chromosome 18 and the homology of human chromosomes 5 and 18 to mouse chromosome 18. Vahava et al. (1998) mapped the POU4F3 gene more precisely to chromosome 5q31 using hybridization using primers to amplify pools of the CEPH3 YAC library.
In a large Israeli Jewish family, Vahava et al. (1998) mapped an autosomal dominant form of progressive hearing loss (DFNA15; 602459) to 5q31 and showed that it was distinct from DFNA1, which also maps to that region. The authors noted that POU4F3 was an excellent candidate for a gene causing human deafness, because targeted deletion of both alleles of pouf43 caused complete deafness in mice (Erkman et al., 1996; Xiang et al., 1997). In affected members of a family with DFNA15, Vahava et al. (1998) identified a heterozygous deletion in the POU4F3 gene (602460.0001).
In affected members of 2 unrelated Dutch families with autosomal dominant hearing loss, Collin et al. (2008) identified 2 different heterozygous mutations in the POU4F3 gene (602460.0002 and 602460.0003, respectively).
Using a combination of linkage analysis and whole-exome sequencing, Kim et al. (2013) identified a heterozygous missense mutation in the POU4F3 gene (R326K; 602460) in affected members of a large Korean family with DFNA15.
Xiang et al. (1995) analyzed the expression patterns of Brn3a, Brn3b, and Brn3c in fetal and adult mouse retina and brain. Antibodies to Brn3c identify a small fraction of retinal ganglion cells. The 3 Brn3 factors identify overlapping subsets of retinal ganglion cells and of neurons in the dorsal root and trigeminal ganglia, suggesting that primary somatosensory neurons and retinal ganglion cells share genetic regulatory hierarchies.
By comparing inner ear gene expression profiles of embryonic day 16.5 wildtype and Pou4f3-mutant deaf mice, Hertzano et al. (2004) identified the GFI1 gene (600871) as a target gene regulated by Pou4f3. Deficiency of Pou4f3 led to a reduction in Gfi1 expression levels, and the dynamics of Gfi1 mRNA abundance closely followed the pattern of expression for Pou4f3. Immunohistochemical and ultrastructural analyses revealed that loss of Gfi1 resulted in outer hair cell degeneration, which appeared comparable to that observed in Pou4f3 mutants. Hertzano et al. (2004) concluded that Gfi1 is the first downstream target of a hair cell-specific transcription factor, and they suggested that outer hair cell degeneration in Pou4f3 mutants may be largely or entirely a result of the loss of expression of Gfi1.
In an Israeli Jewish kindred with autosomal dominant progressive hearing loss (DFNA15; 602459) through at least 5 generations, Vahava et al. (1998) demonstrated that affected individuals had an 8-bp deletion in exon 2 of the POU4F3 gene, predicted to result in a frameshift beginning at codon 295 and a premature translation stop at position 299. The first amino acid lost as a result of the 8-bp deletion in family H was an isoleucine.
In in vitro cellular studies, including a cell line of mouse embryonic inner ear sensory epithelium, Weiss et al. (2003) demonstrated that the 8-bp deletion in POU4F3 identified by Vahava et al. (1998) interfered with normal DNA-binding activity and caused decreased transcriptional activity of POU4F3 compared to wildtype. There was no dominant-negative effect. The mutant truncated protein was expressed and had increased stability compared to the wildtype protein. The mutation caused a severe defect in trafficking, and the mutant protein was found in both the cytoplasm and nucleus of transfected cells. Two nuclear localization signals of the protein were identified, one of which was lost due to the 8-bp deletion. Weiss et al. (2003) suggested that this spectrum of defects in the function of POU4F3 eventually leads to death of inner ear hair cells.
In affected members of a large Dutch family with autosomal dominant hearing loss (DFNA15; 602459), Collin et al. (2008) identified a heterozygous 865C-T transition in exon 2 of the POU4F3 gene, resulting in a leu298-to-phe (L298F) substitution in the POU homeodomain of the protein. The phenotype was highly variable, with different audiometric profiles, different levels of progression, and different ages of onset.
In affected members of a small Dutch family with autosomal dominant hearing loss (DFNA15; 602459), Collin et al. (2008) identified a heterozygous 668T-C transition in the POU4F3 gene, resulting in a leu223-to-pro (L223P) substitution in the DNA-binding domain of the protein.
In affected members of a large Korean family with autosomal dominant hearing loss (DFNA15; 602459) spanning 6 generations, Kim et al. (2013) identified a heterozygous c.977G-A transition in the POUF4 gene, resulting in an arg326-to-lys (R326K) substitution at a conserved residue in the third alpha-helix of the homeodomain, predicted to reduce the proper protein-DNA interactions. The mutation, which was found using a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. The variant was present in less than 1% of samples from the 1000 Genomes Project and Exome Sequencing Project 6500 databases and was not observed in 100 control chromosomes. Functional studies were not performed.
In a 44-year-old Korean woman with autosomal dominant hearing loss (DFNA15; 602459), Lee et al. (2010) identified a heterozygous 14-bp deletion (c.662del14) in exon 2 of the POU4F3 gene, resulting in a frameshift and premature termination (Glu221fs) and a protein lacking both functional POU domains. The patient developed progressive sensorineural hearing loss beginning at age 20 years. In vitro expression studies showed that the mutant protein lost most of its nuclear localization as well as transcriptional activity. Family history revealed affected family members spanning 4 generations. The proband was 1 of 42 unrelated Korean patients with autosomal dominant nonsyndromic hearing loss who were sequenced for POU4F3 mutations.
Collin, R. W. J., Chellappa, R., Pauw, R.-J., Vriend, G., Oostrik, J., van Drunen, W., Huygen, P. L., Admiraal, R., Hoefsloot, L. H., Cremers, F. P. M., Xiang, M., Cremers, C. W. R. J., Kremer, H. Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding. Hum. Mutat. 29: 545-554, 2008. [PubMed: 18228599] [Full Text: https://doi.org/10.1002/humu.20693]
Erkman, L., McEvilly, R. J., Luo, L., Ryan, A. K., Hooshmand, F., O'Connell, S. M., Keithley, E. M., Rapaport, D. H., Ryan, A. F., Rosenfeld, M. G. Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature 381: 603-606, 1996. [PubMed: 8637595] [Full Text: https://doi.org/10.1038/381603a0]
Hertzano, R., Montcouquiol, M., Rashi-Elkeles, S., Elkon, R., Yucel, R., Frankel, W. N., Rechavi, G., Moroy, T., Friedman, T. B., Kelley, M. W., Avraham, K. B. Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. Hum. Molec. Genet. 13: 2143-2153, 2004. [PubMed: 15254021] [Full Text: https://doi.org/10.1093/hmg/ddh218]
Kim, H.-J., Won, H.-H., Park, K.-J., Hong, S. H., Ki, C.-S., Cho, S. S., Venselaar, H., Vriend, G., Kim, J.-W. SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15). PLos One 8: e79063, 2013. Note: Electronic Article. [PubMed: 24260153] [Full Text: https://doi.org/10.1371/journal.pone.0079063]
Lee, H. K., Park, H.-J., Lee, K.-Y., Park, R., Kim, U.-K. A novel frameshift mutation of POU4F3 gene associated with autosomal dominant non-syndromic hearing loss. Biochem. Biophys. Res. Commun. 396: 626-630, 2010. Note: Erratum: Biochem. Biophys. Res. Commun. 398: 790 only, 2010. [PubMed: 20434433] [Full Text: https://doi.org/10.1016/j.bbrc.2010.04.132]
Vahava, O., Morell, R., Lynch, E. D., Weiss, S., Kagan, M. E., Ahituv, N., Morrow, J. E., Lee, M. K., Skvorak, A. B., Morton, C. C., Blumenfeld, A., Frydman, M., Friedman, T. B., King, M.-C., Avraham, K. B. Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science 279: 1950-1954, 1998. [PubMed: 9506947] [Full Text: https://doi.org/10.1126/science.279.5358.1950]
Weiss, S., Gottfried, I., Mayrose, I., Khare, S. L., Xiang, M., Dawson, S. J., Avraham, K. B. The DFNA15 deafness mutation affects POU4F3 protein stability, localization, and transcriptional activity. Molec. Cell. Biol. 23: 7957-7964, 2003. [PubMed: 14585957] [Full Text: https://doi.org/10.1128/MCB.23.22.7957-7964.2003]
Xiang, M., Gan, L., Li, D., Chen, Z. Y., Zhou, L., O'Malley, B. W. Jr., Klein W., Nathans, J. Essential role of POU-domain factor Brn-3c in auditory and vestibular hair cell development. Proc. Nat. Acad. Sci. 94: 9445-9450, 1997. [PubMed: 9256502] [Full Text: https://doi.org/10.1073/pnas.94.17.9445]
Xiang, M., Zhou, L., Macke, J. P., Yoshioka, T., Hendry, S. H. C., Eddy, R. L., Shows, T. B., Nathans, J. The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J. Neurosci. 15: 4762-4785, 1995. [PubMed: 7623109] [Full Text: https://doi.org/10.1523/JNEUROSCI.15-07-04762.1995]