Four Novel Variants in <i>POU4F3</i> Cause Autosomal Dominant Nonsyndromic Hearing Loss

Cui, Tianyi; Gao, Xue; Huang, Shasha; Sun, Yanyan; Zhang, Siqi; Xinxia, Jiang; Yan-zhong, Yang; Kang, Dongyang; Zhu, Qi; Yuan, Yongyi

doi:10.1155/2020/6137083

Cited by 6 publications

(7 citation statements)

References 52 publications

(83 reference statements)

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“…POU4F3 , a member of the POU family of TFs, is encoded by a gene located on chromosome 5q32 [ 30 ] and comprises two highly conserved POU domains: a POU-specific domain and a POU homeodomain [ 31 ]. POU4F3 is expressed in cochlear hair cells and plays a pivotal role in their differentiation, maturation, and maintenance by regulating downstream transcripts [ 32 ]. In humans, POU4F3 defects commonly cause autosomal dominant deafness, with variants associated with progressive non-syndromic deafness of postlingual onset [ 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Load of Alternations of Transcription Factor Genes in Non-Syndromic Deafness and the Associated Clinical Phenotypes: Experience from Two Tertiary Referral Centers

Han

Lee

et al. 2022

Biomedicines

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Sensorineural hearing loss is one of the most common inherited sensory disorders. Functional classifications of deafness genes have shed light on genotype- and mechanism-based pharmacological approaches and on gene therapy strategies. In this study, we characterized the clinical phenotypes and genotypes of non-syndromic deafness caused by transcription factor (TF) gene variants, one of the functional classifications of genetic hearing loss. Of 1280 probands whose genomic DNA was subjected to molecular genetic testing, TF genes were responsible for hearing loss in 2.6%. Thirty-three pathogenic variants, including nine novel variants, accounting for non-syndromic deafness were clustered in only four TF genes (POU3F4, POU4F3, LMX1A, and EYA4), which is indicative of a narrow molecular etiologic spectrum of TF genes, and the functional redundancy of many other TF genes, in the context of non-syndromic deafness. The audiological and radiological characteristics associated with the four TF genes differed significantly, with a wide phenotypic spectrum. The results of this study reveal the genetic load of TF gene alterations among a cohort with non-syndromic hearing loss. Additionally, we have further refined the clinical profiles associated with TF gene variants as a basis for a personalized, genetically tailored approach to audiological rehabilitation.

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Section: Discussionmentioning

confidence: 99%

Genetic Load of Alternations of Transcription Factor Genes in Non-Syndromic Deafness and the Associated Clinical Phenotypes: Experience from Two Tertiary Referral Centers

Han

Lee

et al. 2022

Biomedicines

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“…BioMed Research International resulting in an incomplete protein with restricted transcriptional control [7,16]. Thus far, 32 variations of the POU4F3 gene have been associated with ADNSHL, which presents with a vast range in age of onset and disease severity among different ethnic populations [7,12,[17][18][19][20][21][22][23][24]. In a clinical audiological analysis of 15 ADNSHL families associated with POU4F3 pathogenic variants, it was shown that 20% of the patients had early MFNSHL, which progressed to high-frequency hearing loss and further led to complete hearing loss.…”

Section: Discussionmentioning

confidence: 99%

A Missense POU4F3 Variant Associated with Autosomal Dominant Midfrequency Hearing Loss Alters Subnuclear Localization and Transcriptional Capabilities

Bai

Zhang

et al. 2021

BioMed Research International

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Background. The pathogenic variant, POU class 4 transcription factor 3 (POU4F3), is reported to cause autosomal dominant nonsyndromic hearing loss (ADNSHL). Previously, we have examined a four-generation midfrequency sensorineural hearing loss (MFSNHL) family (no. 6126) and established POU4F3 c.602T>C (p.Leu201Pro) as a potential disease-causing variant. Objectives. We explored the structural and functional alterations that the c.602T>C (p.Leu201Pro) variant enforces on the POU4F3 protein. Methods. We utilized wild-type (WT) and mutant (MUT) POU4F3 c.602T>C plasmid incorporation into HeLa cells to assess functional changes, by immunofluorescence and luciferase assays. To predict protein structural alterations in the MUT versus WT POU4F3, we also generated 3D structures to compare both types of POU4F3 proteins. Results. The WT POU4F3 is ubiquitously present in the nucleus, whereas the MUT form of POU4F3 exhibits a more restricted nuclear presence. This finding is different from other publications, which report a cytoplasmic localization of the MUT POU4F3. We also demonstrated that, as opposed to WT POU4F3, the MUT POU4F3 had 40% reduced luciferase activity. Conclusions. The reduced nuclear presence, combined with reduced transcriptional activity, suggests that the POU4F3 c.602T>C variant alters cellular activity and may contribute to the pathogenicity of POU4F3-related hearing loss. It, also, provides more evidence of the pathophysiological characteristics of MFSNHL.

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“…Targeted deafness gene capture and NGS were performed as previously reported [ 16 ]. DNA samples of 64 cases from 58 families were subjected to targeted NGS, 35 cases of them conducted trio (proband and parents) targeted NGS and 29 cases conducted quarto (proband, parents and sibling) targeted NGS.…”

Section: Methodsmentioning

confidence: 99%

Analysis of the genotype–phenotype correlation of MYO15A variants in Chinese non-syndromic hearing loss patients

Huang

Gao³

et al. 2022

BMC Med Genomics

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Background Mutations in the MYO15A gene are a widely recognized cause of autosomal recessive non-syndromic sensorineural hearing loss (NSHL) globally. Here, we examined the role and the genotype–phenotype correlation of MYO15A variants in a cohort of Chinese NSHL cases. Methods Eighty-one cases with evidenced MYO15A variants from the 2263 Chinese NSHL cases, who underwent next-generation sequencing (NGS), were enrolled in the study. We investigated the association of MYO15A variants with the severity, progression and age of onset of hearing loss, as well as compared it to the previous reports in different nationalities. The cases were divided into groups according to the number of truncating variants: 2 truncating, 1 truncating and 1 non-truncating, 2 non-truncating variants, and compared the severity of HL among the groups. Results MYO15A accounted for 3.58% (81/2263) of all NSHL cases. We analyzed 81 MYO15A-related NSHL cases, 73 of whom were with congenital bilateral, symmetric or severe-to-profound hearing loss (HL), however, 2 of them had a postlingual, asymmetric, mild or moderate HL. There were 102 variants identified in all MYO15A structural domains, 76.47% (78/102) of whom were novel. The most common types of detected variants were missense (44/102, 43.14%), followed by frameshift (27/102, 26.47%), nonsense (14/102, 13.72%), splice site (10/102, 9.80%), in frame (4/102, 3.92%), non-coding (2/102, 1.96%) and synonymous (1/102, 0.98%). The most recurrent variant c.10245_10247delCTC was detected in 12 cases. We observed that the MYO15A variants, located in its N-terminal, motor and FERM domains, led to partial deafness with better residual hearing at low frequencies. There were 34 cases with biallelic truncating variants, 37 cases with monoallelic truncating variants, and 13 cases with biallelic non-truncating variants. The biallelic non-truncating variants group had the least number of cases (12/81), and most of them (10/12) were with profound NSHL. Conclusions MYO15A is a major gene responsible for NSHL in China. Cases with MYO15A variants mostly showed early-onset, symmetric, severe-to-profound hearing loss. This study is by far the largest focused on the evaluation of the genotype–phenotype correlations among the variants in the MYO15A gene and its implication in the outcome of NSHL. The biallelic non-truncating MYO15A variants commonly caused profound HL, and the cases with one or two truncating MYO15A variants tended to increase the risk of HL. Nevertheless, further investigations are needed to clarify the causes for the variable severities and progression rates of hearing loss and the detected MYO15A variants in these cases.

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Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Cited by 6 publications

References 52 publications

Genetic Load of Alternations of Transcription Factor Genes in Non-Syndromic Deafness and the Associated Clinical Phenotypes: Experience from Two Tertiary Referral Centers

Genetic Load of Alternations of Transcription Factor Genes in Non-Syndromic Deafness and the Associated Clinical Phenotypes: Experience from Two Tertiary Referral Centers

A Missense POU4F3 Variant Associated with Autosomal Dominant Midfrequency Hearing Loss Alters Subnuclear Localization and Transcriptional Capabilities

Analysis of the genotype–phenotype correlation of MYO15A variants in Chinese non-syndromic hearing loss patients

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