Alternative titles; symbols
ORPHA: 90635; DO: 0110546;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q32 | Deafness, autosomal dominant 15/52 | 602459 | Autosomal dominant | 3 | POU4F3 | 602460 |
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-15 (DFNA15) is caused by heterozygous mutation in the POU4F3 gene (602460) on chromosome 5q32.
Autosomal dominant deafness-15 (DFNA15) is a form of progressive nonsyndromic sensorineural hearing loss with postlingual onset between the second and sixth decades of life (summary by Kim et al., 2013).
Vahava et al. (1998) studied progressive hearing loss in an Israeli Jewish family (family H) that traced its ancestry to Italy and to subsequent migrations through various North African and Middle Eastern countries, including Tunisia, Libya, and Egypt, with branches of the family now living in Israel, the United States, and Belgium. Five generations demonstrated autosomal dominant inheritance of progressive deafness. Earliest record of a hearing-impaired family member concerned an individual born in 1843 in Libya. He had 4 children, only 1 of whom was affected. Hearing loss in this kindred, referred to as family H, began between ages 18 and 30, with a moderate to severe defect in hearing by age 50.
Xia et al. (2002) described a Chinese family segregating bilateral, postlingual, progressive, and sensorineural nonsyndromic hearing impairment. High-frequency hearing loss began at the second or third decade and progressed to profound deafness involving all frequencies. No patients showed malformations of the inner ear by CT examination or abnormal function by vestibular testing.
Collin et al. (2008) reported a large Dutch family in which multiple members had hearing loss. The was large clinical variability in terms of age at onset, levels of progression, and shape of audiograms. For example, 1 patient reported subjective onset around puberty, whereas another had onset at 20 years of age.
Lee et al. (2010) reported a 44-year-old Korean woman with progressive sensorineural hearing loss beginning at age 20 years. Family history revealed affected family members spanning 4 generations.
Kim et al. (2013) reported a large 6-generation Korean family in which multiple individuals had postlingual onset of sensorineural hearing loss. The age at onset ranged from the early teens to late fifties, and no patients had additional syndromic features. Pure tone audiograms showed bilateral minimal to moderate sensorineural hearing loss with flat to gently downward-sloping audiograms.
Lee et al. (2023) reported probands from 4 unrelated Korean families with progressive nonsyndromic hearing loss with age of onset in the late teens or twenties. No patient complained of dizziness or vertigo. Hearing loss encompassed mainly mid and high frequencies, but 1 patient developed profound loss across all frequencies.
The transmission pattern of DFNA15 in the families reported by Vahava et al. (1998) and Kim et al. (2013) was consistent with autosomal dominant inheritance.
By linkage analysis of a large family (family H) with hearing loss, Vahava et al. (1998) identified a locus, termed DFNA15, on chromosome 5q31-q33. The candidate 25-cM region was bounded by D5S1979 and D5S422. Analysis of the maximum-likelihood genetic model for deafness in this family indicated a rare autosomal dominant allele with full penetrance by age 40 and 0.05 probability of deafness from other causes by age 40 (in other words, 5% phenocopies).
In a Chinese pedigree segregating autosomal dominant nonsyndromic hearing loss, Xia et al. (2002) mapped the disorder to chromosome 5q31.1-q32. Fine mapping indicated that the disease gene was located within an 8.8-cM region between markers D5S2056 and D5S638, with a maximum 2-point lod score of 6.89 at D5S2017.
Xia et al. (2002) referred to the deafness locus that they located on 5q as DFNA42; however, the HUGO Nomenclature Committee assigned this deafness locus DFNA52. The family reported by Xia et al. (2002) is incorporated into DFNA15 because mutation in the POU4F3 gene was later found to segregate with the disorder; see MOLECULAR GENETICS.
In searching for candidate genes in the DFNA15-linked region, Vahava et al. (1998) noted that the class 4 POU domain transcription factor-3 gene (POU4F3) may lie on 5q, on the basis of the localization of mouse Pou4f3 and the homology of human chromosomes 5 and 18 with mouse chromosome 18. POU4F3 was considered an excellent candidate for a gene causing human deafness because targeted deletion of both alleles of Pou4f3 caused complete deafness in mice. To map POU4F3 more precisely, they synthesized primers for the human POU4F3 cDNA sequence and used these to amplify pools of the CEPH3 yeast artificial chromosome (YAC) library. In this way, YACs containing markers linked to deafness in family H were found, indicating that POU4F3 must lie within the DFNA15-linked region. Using primers designed to amplify and sequence the entire coding region, they found an 8-bp deletion (602460.0001) in exon 2 of the POU4F3 gene. The predicted result of this deletion was a frameshift beginning at codon 295 and a premature translation stop at position 299. Deletion was not found in the POU4F3 gene of 114 unrelated individuals of various North African and Middle Eastern Jewish ancestry selected to represent the contribution of various ethnic Jewish populations to family H.
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).
In a 44-year-old Korean woman with DFNA15, Lee et al. (2010) identified a heterozygous truncating mutation in the POU4F3 gene (602460.0005). In vitro expression studies showed that the mutant protein lost most of its nuclear localization as well as transcriptional activity. The proband was 1 of 42 unrelated Korean patients with autosomal dominant nonsyndromic hearing loss who were sequenced for POU4F3 mutations.
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.
In affected members of a 5-generation Chinese family with autosomal dominant bilateral progressive nonsyndromic hearing loss, Cai et al. (2017) identified a heterozygous 1-bp deletion in the POU4F3 gene (602460.0006). Xia et al. (2002) had previously reported this family and had mapped the disorder to chromosome 5q31, but did not identify mutations in POU4F3 at that time.
In individuals with progressive hearing loss 4 unrelated Korean families Lee et al. (2023) identified 4 different mutations in the POU4F3 gene (602460.0007-602460.0010) by whole-exome sequencing.
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.
Singh et al. (2024) generated a conditional knockout mouse model in which Pou4f3 could be deleted in cochlear hair cells at various stages of development. They observed that Pou4f3 deletion produced a delayed loss of spiral ganglion neurons at 4 months after deletion and somewhat earlier if immature hair cells were targeted. They concluded that Pou4f3 indirectly alters the survival of spiral ganglion neurons.
In a Chinese pedigree segregating autosomal dominant nonsyndromic hearing loss, Xia et al. (2002) mapped the disorder to chromosome 5q31.1-q32. At that time, the authors did not identify any causative mutations in the POU4F3 (602460) or DIAPH1 (602121) genes, both of which map to 5q31. Cai et al. (2017) identified a heterozygous mutation in the POU4F3 gene in affected members of this family; see MOLECULAR GENETICS.
Qiong et al. (2008) sequenced the exons and intron-exon boundaries of 52 candidate genes in the 5q31 region in the patients described by Xia et al. (2002). Qiong et al. (2008) found 108 SNPs; however, none was identified as disease-causing.
Cai, X. Z., Li, Y., Xia, L., Peng, Y., He, C. F., Jiang, L., Feng, Y., Xia, K., Liu, X. Z., Mei, L. Y., Hu, Z. M. Exome sequencing identifies POU4F3 as the causative gene for a large Chinese family with non-syndromic hearing loss. J. Hum. Genet. 62: 317-320, 2017. [PubMed: 27535032] [Full Text: https://doi.org/10.1038/jhg.2016.102]
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]
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]
Lee, S.-Y., Kim, M. Y., Han, J. H., Park, S. S., Yun, Y., Jee, S.-C., Han, J. J., Lee, J. H., Seok, H., Choi, B. Y. Ramifications of POU4F3 variants associated with autosomal dominant hearing loss in various molecular aspects. Sci. Rep. 13: 12584, 2023. [PubMed: 37537203] [Full Text: https://doi.org/10.1038/s41598-023-38272-w]
Qiong, P., Hu, Z., Feng, Y., Pan, Q., Xia, J., Xia, K. Bioinformatics analysis of candidate genes and mutations in a congenital sensorineural hearing loss pedigree: detection of 52 genes for the DFNA52 locus. J. Laryng. Otol. 122: 1029-1036, 2008. [PubMed: 18312703] [Full Text: https://doi.org/10.1017/S0022215107001582]
Singh, J., Randle, M. R., Walters, B. J., Cox, B. C. The transcription factor Pou4f3 is essential for the survival of postnatal and adult mouse cochlear hair cells and normal hearing. Front. Cell. Neurosci. 18: 1369282, 2024. [PubMed: 38566840] [Full Text: https://doi.org/10.3389/fncel.2024.1369282]
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]
Xia, J., Deng, H., Feng, Y., Zhang, H., Pan, Q., Dai, H., Long, Z., Tang, B., Deng, H., Chen, Y., Zhang, R., Zheng, D., He, Y., Xia, K. A novel locus for autosomal dominant nonsyndromic hearing loss identified at 5q31.1-32 in a Chinese pedigree. J. Hum. Genet. 47: 635-640, 2002. [PubMed: 12522684] [Full Text: https://doi.org/10.1007/s100380200098]