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

Michel, Vincent; Booth, Kevin T.; Patni, Pranav; Cortese, Matteo; Azaiez, Héla; Bahloul, Amel; Kahrizi, Kimia; Labbé, Ménélik; Emptoz, Alice; Lelli, Andrea; Dégardin, Julie; Dupont, Typhaine; Aghaie, Asadollah; Oficjalska‐Pham, Danuta; Picaud, Serge; Najmabadi, Hossein; Smith, Richard J.H.; Bowl, Michael R.; Brown, Steven Dm; Avan, Paul; Petit, Christine; El-Amraoui, Aziz

doi:10.15252/emmm.201708087

Cited by 70 publications

(86 citation statements)

References 95 publications

(162 reference statements)

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“…To measure electroretinograms (ERGs), animals were kept in the dark to adapt to darkness overnight as previously described (Michel et al , ). Each mouse was anesthetized with a mixture of ketamine (80 mg/kg, Axience, France) and xylazine (8 mg/kg, Axience, France), and placed over a warming pad to maintain body temperature at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…For all other immunofluorescence experiments, samples were processed as previously described (Michel et al , ). Briefly, for cochlear whole‐mount preparations, micro‐dissected, fixed mouse organs of Corti (4% PFA in PBS, pH 7.4 for 1 h at RT) were rinsed, then blocked by incubation in PBS supplemented with 20% normal goat serum and 0.3% Triton X‐100 for 1 h at RT.…”

Section: Methodsmentioning

confidence: 99%

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Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

et al. 2019

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Hearing relies on mechanically gated ion channels present in the actin‐rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound‐receptive structure is limited. Utilizing a large‐scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early‐onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non‐syndromic progressive hearing loss. Our in‐depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin‐2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin‐2 leads to loss of mechano‐electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin‐2 in mammalian hearing, providing insights into the interplay between mechano‐electrical transduction and stereocilia maintenance.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

et al. 2019

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“…Ion channels, such as the cystic fibrosis transmembrane conductance regulator, are multifunctional and perform functions other than ion conduction. Moreover, a previous study suggested that PCDH15-CD1 in adult IHCs was distributed similarly as TMC1 (27); it is unknown whether other MT-complex proteins such as the other 2 isoforms of PCDH15 (28,29), transmembrane inner ear expressed protein (30), and calcium and integrin-binding protein 2 (31,32) are distributed similarly as TMC1 and LHFPL5 in adult hair cells. All these key questions warrant further investigation.…”

Section: Uniform Distribution Of Tmc1 and Lhfpl5 In The Hair Bundle Omentioning

confidence: 99%

Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice

Chen

et al. 2019

FASEB j.

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The channel that governs mechanotransduction (MT) by hair cells in the inner ear has been investigated intensively for 4 decades, but its precise molecular composition remains enigmatic. Transmembrane channel‐like protein 1 (TMC1) was recently identified as a component of the MT channel, and lipoma HMGIC fusion partner‐like 5 (LHFPL5) is considered to be part of the MT complex and may functionally couple the tip link to the MT channel. As components of the MT complex, TMC1 and LHFPL5 are expected to localize at the lower end of the tip link in hair cells, a notion generally supported by previous studies on neonatal mice. However, the localization of these 2 proteins, particularly in the hair cells of adult mice, remains incompletely elucidated. Because determination of TMC1 and LHFPL5 localization at distinct developmental stages is essential for understanding their function and regulation, we used several approaches to examine the localization of these proteins in neonatal and adult hair cells in the mouse. We report several notable findings: 1) TMC1 and LHFPL5 predominantly localize at the tip of the shorter rows of stereocilia in neonatal hair cells, which largely verifies the previously published findings in neonatal hair cells; 2) LHFPL5 persists in the hair bundle of hair cells after postnatal day (P)7, which clarifies the previously reported unexpected absence of LHFPL5 after P7 and supports the view that LHFPL5 is a permanent component in the MT complex; and 3) TMC1 and LHFPL5 remain at the tip of the shorter rows of stereocilia in adult outer hair cells, but in adult inner hair cells, TMC1 is uniformly distributed in both the tallest row and the shorter rows of stereocilia, whereas LHFPL5 is uniformly distributed in the shorter rows of stereocilia. These findings raise intriguing questions regarding the turnover rate, regulation, additional functions, and functional interaction of TMC1 and LHFPL5. Our study confirms the previous findings in neonatal hair cells and reveals several previously unidentified aspects of TMC1 and LHFPL5 localization in more mature hair cells.—Li, X., Yu, X., Chen, X., Liu, Z., Wang, G., Li, C., Wong, E. Y. M., Sham, M. H., Tang, J., He, J., Xiong, W., Liu, Z., Huang, P. Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice. FASEB J. 33,6838–6851 (2019). http://www.fasebj.org

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“…Thus, absence of CIB2 in the mouse inner ear does not compare phenotypically to absence of known USH1 proteins. 15,16 In summary, we implicate CIB2 as the cause of congenital profound ARNSHL in 6 families representing 3 ethnicities. In so doing, we expand the genetic spectrum of CIB2 variants to include CNVs, splice-site variants and frameshift variants, and show that the phenotype associated with null alleles of CIB2 is ARNSHL and not USH.…”

Section: Discussionmentioning

confidence: 79%

“…[35][36][37][38][39][40] Notably, mice homozygous for the targeted deletion of CIB2 or targeted knock-in animals have profound deafness but no obvious severe vestibular phenotype. 15,16 Ultrastructurally, while all USH1 mouse mutants exhibit hair cell disorganization and stereocilia defects, the CIB2 mutant does not share similar gross hair cell abnormalities. Thus, absence of CIB2 in the mouse inner ear does not compare phenotypically to absence of known USH1 proteins.…”

Section: Discussionmentioning

confidence: 99%

Variants in CIB2 cause DFNB48 and not USH1J

et al. 2018

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The genetic, mutational and phenotypic spectrum of deafness-causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non-syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf-blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non-syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss-of-function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH-causing gene.

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

Cited by 70 publications

References 95 publications

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

Clarin‐2 is essential for hearing by maintaining stereocilia integrity and function

Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice

Variants in CIB2 cause DFNB48 and not USH1J

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