Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants

Morín, Matías; Booth, Kevin T.; Lachgar, María; Huygen, P.L.M.; Villamar, Manuela; Mayo, Fernando; Barrio, Luis C.; Castro, L. Sa ntos Serrão de; Morales, Cecilia M.; Castillo, Ignacio del; Arellano, B; Tellerı́a, Dolores; Smith, Richard J.H.; Azaiez, Héla; Moreno-Pelayo, Miguel A.

doi:10.1038/s41598-020-63256-5

Cited by 19 publications

(14 citation statements)

References 69 publications

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“…Yet, the detailed investigation of the cardiac phenotype was not performed for the patient. Two recent studies further weaken this view by reporting more patients with non‐syndromic HL and N‐terminal truncating mutations, such as c.160G>T (p.Glu54Ter), c.223_224del (p.Val75PhefsTer32, Figure 5), and c.517C>T (p.Gln173Ter) (Morin et al, 2020; Shinagawa et al, 2020). The novel mutation we reported here c.543C>G, in exon 8 of EYA4 , resulted in a shortened protein lacking part of the N‐terminal variable region in a Chinese family with no apparent cardiac phenotypes, and further complicated the relationship between EYA4 mutation and phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Early truncation of the N‐terminal variable region of EYA4 gene causes dominant hearing loss without cardiac phenotype

Liu

Zeng

et al. 2020

Molec Gen & Gen Med

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Section: Discussionmentioning

confidence: 99%

“…Until now, more than 50 pathogenic or likely pathogenic mutations in EYA4 have been reported (Morin et al, 2020); among these, ~40% of mutations have been found in the East Asia population. The EYA4 gene is not a common gene for ADNSHL, and thus far, only a limited number of mutations have been reported.…”

Section: Discussionmentioning

confidence: 99%

Early truncation of the N‐terminal variable region of EYA4 gene causes dominant hearing loss without cardiac phenotype

Liu

Zeng

et al. 2020

Molec Gen & Gen Med

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“…The index case of the family (II:2) was subjected for the genetic screening for causative hearing-loss mutations by using a custom gene panel, OTO-NGS-v2, designed in our laboratory [ 20 ]. As the causative mutation was identified following this approach, whole exome sequencing (WES) on the individual II:2 was not further performed.…”

Section: Methodsmentioning

confidence: 99%

“…The sequence data were mapped against the human genome sequence (build GRCh37/hg19), and data analysis was performed using the Sophia Genetics’ software that enables the single nucleotide variations (SNVs) and the copy number variation (CNV) analysis of the targeted exonic sequences. Variant prioritization was carried out using a custom filtering strategy [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family

Lachgar

Morín

Villamar

et al. 2021

Genes

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Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype–phenotype correlations of DFNA68 hearing loss.

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“…EYA3 is an orthologous gene previously shown to encode several proteins of transcriptional co‐activators, which are commonly co‐expressed along with Pax6, Six2, Six1 and Dach genes 7‐10 . It has actually been assumed that the Eya genes are involved in eye development by interacting with Pax6 as well as Dach genes 11 .…”

Section: Introductionmentioning

confidence: 99%

Up‐regulation of circRNA_0068481 promotes right ventricular hypertrophy in PAH patients via regulating miR‐646/miR‐570/miR‐885

Guo

Liu

2021

J Cellular Molecular Medi

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CircRNA‐0068481 and several miRNAs are important in the pathogenesis of right ventricular hypertrophy (VH), while the inhibition of eye absent transcriptional coactivator and phosphatase 3 (EYA3) was proved to reverse vascular remodelling in rats. In this study, we tried to study the diagnostic value and mechanistic role of circRNA_0068481 in the diagnosis of RVH in PAH patients. qPCR was done to measure circRNA‐0068481, miR‐646, miR‐750, miR‐885 and EYA3 mRNA expression. Luciferase assay was done to explore the regulatory relationship between circRNA‐0068481/EYA3 and the miRNAs. Western blot was done to measure EYA3 expression in AC16 cells. The expression of circRNA‐0068481, miR‐646 and miR‐570 showed a considerable capability to diagnose RVH in PAH patients. The luciferase activity of circRNA‐0068481 was remarkably suppressed by miR‐646, miR‐570 or miR‐885. The luciferase signal of EYA3 was also inhibited by miR‐646, miR‐570 and miR‐885. Up‐regulation of circRNA‐0068481 expression in AC16 significantly decreased miR‐646, miR‐570 and miR‐885 expression, and up‐regulated EYA3 expression, whereas circRNA‐0068481 down‐regulation significantly increased miR‐646, miR‐570 and miR‐885 expression, and repressed EYA3 expression. CircRNA_0068481 sponged several miRNAs including miR‐646, miR‐570 and miR‐885. These miRNAs were all found to target the expression of EYA3 mRNA, which is involved in the onset of right ventricular hypertrophy. Therefore, it can be concluded that the up‐regulation of circRNA_0068481 can predict the diagnosis of right ventricular hypertrophy in pulmonary arterial hypertension patients.

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Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants

Cited by 19 publications

References 69 publications

Early truncation of the N‐terminal variable region of EYA4 gene causes dominant hearing loss without cardiac phenotype

Early truncation of the N‐terminal variable region of EYA4 gene causes dominant hearing loss without cardiac phenotype

A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family

Up‐regulation of circRNA_0068481 promotes right ventricular hypertrophy in PAH patients via regulating miR‐646/miR‐570/miR‐885

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