The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells

Zou, Juan; Chen, Qian; Almishaal, Ali A.; Mathur, Pranav Dinesh; Zheng, Tianyu; Tian, Cong; Zheng, Qing Yin; Yang, Jun

doi:10.1093/hmg/ddw421

Cited by 34 publications

(33 citation statements)

References 58 publications

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“…The profound deafness observed in CIB2 −/− mice, lacking a functional CIB2 protein for all four Cib2 splice isoforms (Fig A, see also Giese et al , ; Zou et al , ), is reminiscent of the prelingual severe‐to‐profound hearing loss observed in DFNB48‐affected patients (Riazuddin et al , ; Patel et al , ; Seco et al , ; and this study). However, none of the cochlear phenotypes associated with the lack of CIB2 described above were observed in CIB2‐defective vestibular organs.…”

Section: Discussionsupporting

confidence: 67%

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

et al. 2017

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Defects of CIB2, calcium‐ and integrin‐binding protein 2, have been reported to cause isolated deafness, DFNB48 and Usher syndrome type‐IJ, characterized by congenital profound deafness, balance defects and blindness. We report here two new nonsense mutations (pGln12* and pTyr110*) in CIB2 patients displaying nonsyndromic profound hearing loss, with no evidence of vestibular or retinal dysfunction. Also, the generated CIB2 −/− mice display an early onset profound deafness and have normal balance and retinal functions. In these mice, the mechanoelectrical transduction currents are totally abolished in the auditory hair cells, whilst they remain unchanged in the vestibular hair cells. The hair bundle morphological abnormalities of CIB2 −/− mice, unlike those of mice defective for the other five known USH1 proteins, begin only after birth and lead to regression of the stereocilia and rapid hair‐cell death. This essential role of CIB2 in mechanotransduction and cell survival that, we show, is restricted to the cochlea, probably accounts for the presence in CIB2 −/− mice and CIB2 patients, unlike in Usher syndrome, of isolated hearing loss without balance and vision deficits.

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Section: Discussionsupporting

confidence: 67%

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

et al. 2017

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“…7b). These results are consistent with previous studies showing that Ush2a KO/KO mice have severe hearing loss at high frequencies 10,48,49 . In contrast, in the Ush2a ∆Ex12/KO mice, hearing recovered to a level that is indistinguishable from wild type and Ush2a ∆Ex12/∆Ex12 mice by ABR and DPOAE ( Fig.…”

Section: Figure 6 Characterization Of Ush2a-δex12 Cochlear Hair Cellsupporting

confidence: 93%

Exon 13-skipped USH2A protein retains functional integrity in mice, suggesting an exo-skipping therapeutic approach to treat USH2A-associated disease

Pendse

Lamas

Maeder

et al. 2020

Preprint

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Mutations in the USH2A gene are the most common cause of non-syndromic inherited retinal degeneration and Usher syndrome, which is characterized by congenital deafness and progressive vision loss. Development of a vector mediated therapy for USH2A-associated disease has been challenging due to its large size of coding sequence (~15.6kb). Therefore, there is an unmet need to develop alternative therapeutic strategies. The USH2A protein (Usherin) contains many repetitive domains, and it has been hypothesized that some domains may be dispensable with regard to protein function. Here, we show that skipping of exon 13 of the human USH2A gene or the equivalent exon 12 of the mouse Ush2a gene results in an in-frame transcript that produces functional Usherin protein. This nearly full length Usherin rescues the ciliogenesis in Ush2a null cells as well as the cochlear and retinal phenotypes in Ush2a null mice. Together, our results support the development of exon-skipping strategies to treat both visual and hearing loss in patients with USH2A-associated disease due to mutations in exon 13.

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“…Myosin 7A (MYO7A) is an actin-based motor protein required for the localization of many proteins of the hair bundle, including PCDH15 and USH1C/Harmonin, along with several proteins of the Usher type 2 complex (Boëda et al, 2002;Senften et al, 2006;Lefevre et al, 2008;Morgan et al, 2016;Maeda et al, 2017;Zou et al, 2017). Results in both mice and zebrafish suggest that MYO7A is not required for CDH23 bundle localization (Senften et al, 2006;Blanco-Sanchez et al, 2014).…”

Section: Gfp-lhfpl5a Localization In Stereocilia Requires Pcdh15a CDmentioning

confidence: 99%

The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish

Erickson

Pacentine

Venuto

et al. 2020

Front. Mol. Neurosci.

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Hair cells sense and transmit auditory, vestibular, and hydrodynamic information by converting mechanical stimuli into electrical signals. This process of mechano-electrical transduction (MET) requires a mechanically gated channel localized in the apical stereocilia of hair cells. In mice, lipoma HMGIC fusion partner-like 5 (LHFPL5) acts as an auxiliary subunit of the MET channel whose primary role is to correctly localize PCDH15 and TMC1 to the mechanotransduction complex. Zebrafish have two lhfpl5 genes (lhfpl5a and lhfpl5b), but their individual contributions to MET channel assembly and function have not been analyzed. Here we show that the zebrafish lhfpl5 genes are expressed in discrete populations of hair cells: lhfpl5a expression is restricted to auditory and vestibular hair cells in the inner ear, while lhfpl5b expression is specific to hair cells of the lateral line organ. Consequently, lhfpl5a mutants exhibit defects in auditory and vestibular function, while disruption of lhfpl5b affects hair cells only in the lateral line neuromasts. In contrast to previous reports in mice, localization of Tmc1 does not depend upon Lhfpl5 function in either the inner ear or lateral line organ. In both lhfpl5a and lhfpl5b mutants, GFP-tagged Tmc1 and Tmc2b proteins still localize to the stereocilia of hair cells. Using a stably integrated GFP-Lhfpl5a transgene, we show that the tip link cadherins Pcdh15a and Cdh23, along with the Myo7aa motor protein, are required for correct Lhfpl5a localization at the tips of stereocilia. Our work corroborates the evolutionarily conserved co-dependence between Lhfpl5 and Pcdh15, but also reveals novel requirements for Cdh23 and Myo7aa to correctly localize Lhfpl5a. In addition, our data suggest that targeting of Tmc1 and Tmc2b proteins to stereocilia in zebrafish hair cells occurs independently of Lhfpl5 proteins.

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The roles of USH1 proteins and PDZ domain-containing USH proteins in USH2 complex integrity in cochlear hair cells

Cited by 34 publications

References 58 publications

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival

Exon 13-skipped USH2A protein retains functional integrity in mice, suggesting an exo-skipping therapeutic approach to treat USH2A-associated disease

The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish

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