A novel missense variant in the nuclear localization signal of POU4F3 causes autosomal dominant non-syndromic hearing loss

Lin, Yi-Hong; Lin, Yi‐Hsin; Lu, Yingchang; Liu, Tien‐Chen; Chen, Chien‐Yu; Hsu, Chuan‐Jen; Chen, Pei‐Lung

doi:10.1038/s41598-017-08236-y

Cited by 19 publications

(21 citation statements)

References 28 publications

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“…In 1998, POU4F3 was first described as a disease-causing gene within the DFNA15 locus in an Israeli Jewish family [11]. To date, 32 variants (including those in this study) and whole-gene deletion of POU4F3 have been reported to cause ADNSHL with variable ages of onset and degrees of severity in various ethnic groups, including Chinese, Japanese, Dutch, Korean, and Brazilian populations [12][13][14][15][16][17][18][19][20][21][22][23][24]. In 2017, Kitano et al reported that POU4F3 variants represent the third largest cause of ADNSHL (2.5%, 15/602) in Japan and the most prevalent configuration as midfrequency hearing loss type followed by high-frequency hearing loss [14].…”

Section: Introductionmentioning

confidence: 71%

“…Cytoplasmic localization of transcription factors obviously affects their ability to activate downstream targets. Mutant proteins showed greatly reduced capability for binding to DNA as well as transcriptionally activating reporter gene expression [ 10 , 16 , 20 , 21 , 23 ]. One possible mechanism is that the variant in the POU homeodomain of POU4F3 leads to a prematurely truncated protein with loss of the second and third helices, and the third helix is crucial for high-affinity binding to DNA; thus, the target gene cannot be induced, leading to impairment of inner ear hair cells [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although mice require only one copy of the functional POU4F3 to retain hearing [45,46], several previous studies supported that haploinsufficiency is the most likely molecular mechanism underlying the hearing loss caused by the POU4F3 variant [13,23,24]. Heterozygous deletion of the entire POU4F3 has been reported in a Brazilian family with ADNSHL [13].…”

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confidence: 95%

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Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Cui

Gao²,

Huang

et al. 2020

Neural Plasticity

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Hereditary hearing loss is one of the most common sensory disabilities worldwide. Mutation of POU domain class 4 transcription factor 3 (POU4F3) is considered the pathogenic cause of autosomal dominant nonsyndromic hearing loss (ADNSHL), designated as autosomal dominant nonsyndromic deafness 15. In this study, four novel variants in POU4F3, c.696G>T (p.Glu232Asp), c.325C>T (p.His109Tyr), c.635T>C (p.Leu212Pro), and c.183delG (p.Ala62Argfs∗22), were identified in four different Chinese families with ADNSHL by targeted next-generation sequencing and Sanger sequencing. Based on the American College of Medical Genetics and Genomics guidelines, c.183delG (p.Ala62Argfs∗22) is classified as a pathogenic variant, c.696G>T (p.Glu232Asp) and c.635T>C (p.Leu212Pro) are classified as likely pathogenic variants, and c.325C>T (p.His109Tyr) is classified as a variant of uncertain significance. Based on previous reports and the results of this study, we speculated that POU4F3 pathogenic variants are significant contributors to ADNSHL in the East Asian population. Therefore, screening of POU4F3 should be a routine examination for the diagnosis of hereditary hearing loss.

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Section: Introductionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Cui

Gao²,

Huang

et al. 2020

Neural Plasticity

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“…Data analyses were performed as previously described. 27,32 Briefly, the paired-end reads were aligned, sorted, and converted by BWA-MEM version 0.7.12 (Wellcome Trust Sanger Institute, Cambridge, UK) and Picard version 1.134 (Broad Institute, Cambridge, MA). Variants including singlenucleotide substitution and small deletions/insertions were called by GATK HaplotypeCaller version 3.4 (Broad Institute).…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing Facilitates Genetic Diagnosis and Provides Novel Pathogenetic Insights into Deafness with Enlarged Vestibular Aqueduct

Lin

et al. 2019

The Journal of Molecular Diagnostics

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Enlarged vestibular aqueduct (EVA) is an inner-ear malformation associated with sensorineural hearing impairment. Most EVAs are associated with Pendred syndrome and nonsyndromic autosomal recessive deafnesse4 (DFNB4), two autosomal-recessive disorders caused by mutations in SLC26A4. However, many EVA patients cannot have a confirmed diagnosis by screening common SLC26A4 mutations, constituting an enigma in genetic diagnosis. To enable comprehensive genetic examination and explore the etiologies of EVA, we designed a next-generation sequencing panel targeting the entire length of 3 Pendred syndrome/ DFNB4 genes (SLC26A4, FOXI1, and KCNJ10) and exons of 10 other genes related to EVA and performed genetic testing in 50 EVA families without confirmative results on screening for SLC26A4 hotspots (c.919-2A>G and p.H723R). Bi-allelic SLC26A4 mutations were identified in 34 families and EYA1 mutations in two families, yielding a diagnostic rate of 72% (36 of 50). In addition, two variants were identified in KCNJ10 and FOXI1, but findings did not support the previous hypothesis that mutations in these two genes are probable contributors to EVA through recessive inheritance or digenic inheritance with SLC26A4. Of note, a large SLC26A4 deletion was confirmed in one step using our panel. These results show the utility of a nextgeneration sequencingebased panel to address EVA families by identifying various types of gene mutations with satisfactory diagnostic yields and provide novel insights into the pathogenesis of EVA. (J Mol Diagn 2019, 21: 138e148; https://doi.

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“…In the present study, the earliest age of onset of hearing loss for affected family members was recorded at 11 years old (IV:1). Although the pathogenic mechanisms underlying hearing impairment of patients with POU4F3 variants remain unclear, the mechanism of haploinsufficiency has been supported by several studies [ 12 , 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

A Missense Mutation in POU4F3 Causes Midfrequency Hearing Loss in a Chinese ADNSHL Family

Gao

Wang

et al. 2018

BioMed Research International

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Hereditary nonsyndromic hearing loss is extremely heterogeneous. Mutations in the POU class 4 transcription factor 3 (POU4F3) are known to cause autosomal dominant nonsyndromic hearing loss linked to the loci of DFNA15. In this study, we describe a pathogenic missense mutation in POU4F3 in a four-generation Chinese family (6126) with midfrequency, progressive, and postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining targeted capture of 129 known deafness genes, next-generation sequencing, and bioinformatic analysis, we identified POU4F3 c.602T>C (p.Leu201Pro) as the disease-causing variant. This variant cosegregated with hearing loss in other family members but was not detected in 580 normal controls or the ExAC database and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. We conclude that POU4F3 c.602T>C (p.Leu201Pro) is related to midfrequency hearing loss in this family. Routine examination of POU4F3 is necessary for the genetic diagnosis of midfrequency hearing loss.

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A novel missense variant in the nuclear localization signal of POU4F3 causes autosomal dominant non-syndromic hearing loss

Cited by 19 publications

References 28 publications

Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Targeted Next-Generation Sequencing Facilitates Genetic Diagnosis and Provides Novel Pathogenetic Insights into Deafness with Enlarged Vestibular Aqueduct

A Missense Mutation in POU4F3 Causes Midfrequency Hearing Loss in a Chinese ADNSHL Family

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