Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Dulon, Didier; Papal, Samantha; Patni, Pranav; Cortese, Matteo; Vincent, Philippe; Tertrais, Margot; Emptoz, Alice; Tlili, Abdelaziz; Bouleau, Yohan; Michel, Vincent; Delmaghani, Sedigheh; Aghaie, Asadollah; Pepermans, Elise; Alegria-Prévot, Olinda; Akil, Omar; Lustig, Lawrence R.; Avan, Paul; Safieddine, Saaïd; Petit, Christine; El-Amraoui, Aziz

doi:10.1172/jci94351

Cited by 110 publications

(91 citation statements)

References 48 publications

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“…Moreover, throughout Clrn2 clarinet / clarinet cochleae, stereocilin localizes as expected at the tips of the tallest stereocilia (Fig C and E, n = 3), indicating normal coupling between OHC stereocilia and the overlying tectorial membrane (Verpy et al , ). These data contrast with the grossly misshapen auditory OHC hair bundles exhibited by Clrn1 mutant mice (Geller et al , ; Geng et al , ; Dulon et al , ) (see also Fig D). By P8, scanning electron microscopy shows Clrn2 clarinet / clarinet mutants do not exhibit any gross patterning defects, or differences in the overall number of OHC and IHC bundles compared to controls (Fig F and G).…”

Section: Resultsmentioning

confidence: 55%

“…Interestingly, almost all USH3A patients develop normal speech, and a number display only mild‐to‐moderate hearing threshold elevation at the time of hearing loss diagnosis, at an age of 30–40 years (Ness et al , ). This contrasts with the phenotype of Clrn1 knockout mice, where lack of clarin‐1 has been shown to cause an early profound hearing loss (Geller et al , ; Geng et al , , ; Dulon et al , ). Additionally, Clrn1 N48K mouse mutants exhibit profound hearing loss by P25, even though USH3A patients with the CLRN1 N48K mutation display post‐lingual progressive hearing loss (Ness et al , ; Geng et al , ).…”

Section: Discussionmentioning

confidence: 93%

“…To investigate the cause of hearing loss in Clrn2 clarinet / clarinet mice, and considering the previously reported disrupted organization of auditory hair bundles in neonatal Clrn1 mutant mice (Geller et al , ; Geng et al , , ; Dulon et al , ), we used confocal and scanning electron microscopy to monitor the progression of hair cell stereocilia bundle development and maturation from birth (Figs and ).…”

Section: Resultsmentioning

confidence: 99%

“…During phase 1, growth of the stereocilia rows is uniform, whereas in phase 2 differential elongation leads to the staircase pattern, with concomitant regression of supernumerary stereocilia in the mature hair bundle (Kaltenbach et al , ). Previous work has shown that clarin‐1 is critically involved in formation of properly shaped IHC and OHC hair bundles (Geller et al , ; Geng et al , , ; Dulon et al , ). Importantly, no such disorganization occurs in the absence of clarin‐2.…”

Section: Discussionmentioning

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: Resultsmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

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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“…Mice lacking any one of the components of this complex, such as clarin-1 or CDHR15, suffer defective synaptic maturation, thus reinforcing the role of Usher proteins at IHC synapses. Finally, the role of clarin-1 in auditory hair cells was recently clarified through the characterization of two knockout mouse models for the protein, one with a total deletion of the gene coding for clarin-1, and another with a conditional deletion of this gene occurring during postnatal stages (Dulon et al 2018). Comparative morphofunctional analyses of these mice, combined with protein-protein interaction studies showed that clarin-1 is essential for normal auditory hair bundle structure and function, as well as for the function of the presynaptic Ca v 1.3 Ca 2+ channels at IHC ribbon synapses and, subsequently, for the normal distribution of postsynaptic AMPA receptors.…”

Section: Synaptic Physiology and Pathophysiology Of Usher Proteinsmentioning

confidence: 99%

Hair Cell Afferent Synapses: Function and Dysfunction

Johnson

Safieddine

Mustapha

et al. 2019

Cold Spring Harb Perspect Med

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To provide a meaningful representation of the auditory landscape, mammalian cochlear hair cells are optimized to detect sounds over an incredibly broad range of frequencies and intensities with unparalleled accuracy. This ability is largely conferred by specialized ribbon synapses that continuously transmit acoustic information with high fidelity and sub-millisecond precision to the afferent dendrites of the spiral ganglion neurons. To achieve this extraordinary task, ribbon synapses employ a unique combination of molecules and mechanisms that are tailored to sounds of different frequencies.Here we review the current understanding of how the hair cell's presynaptic machinery and its postsynaptic afferent connections are formed, how they mature, and how their function is adapted for an accurate perception of sound.

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AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness

Qi,

Tan,

Zhang

et al. 2024

Advanced Science

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Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno‐associated virus (AAV)‐mediated OTOF gene replacement therapy is extensively validated in Otof‐deficient mice. However, the clinical safety and efficacy of AAV‐OTOF is not reported. Here, AAV‐OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non‐human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV‐OTOF is delivered into one cochlea of a 5‐year‐old deaf patient and into the bilateral cochleae of an 8‐year‐old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure‐tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5‐year‐old patient can be restored to the normal range at 1 month after AAV‐OTOF injection, while the 8‐year‐old patient can hear the conversational sounds. Most importantly, the 5‐year‐old patient can hear and recognize speech only through the AAV‐OTOF‐injected ear. This study is the first to demonstrate the safety and efficacy of AAV‐OTOF in patients, expands and optimizes current OTOF‐related gene therapy and provides valuable information for further application of gene therapies for deafness.

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Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

Cited by 110 publications

References 48 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

Hair Cell Afferent Synapses: Function and Dysfunction

AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness

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