The Many Faces of DFNB9: Relating OTOF Variants to Hearing Impairment

Vona, Barbara; Rad, Abolfazl; Reisinger, Ellen

doi:10.3390/genes11121411

Cited by 35 publications

(56 citation statements)

References 73 publications

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“…Mutations in the gene OTOF encoding for the protein otoferlin cause hearing impairment with autosomal recessive inheritance, DFNB9 ( Yasunaga et al, 1999 ). To date, more than 200 pathogenic mutations have been identified in the OTOF gene ( Vona et al, 2020 ). While most mutations lead to profound deafness, a few non-truncating mutations result in mild to moderate progressive or temperature sensitive forms of hearing loss (reviewed in Vona et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9

Stalmann

Franke

Al-Moyed

et al. 2021

Front. Cell. Neurosci.

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Deficiency of otoferlin causes profound prelingual deafness in humans and animal models. Here, we closely analyzed developmental deficits and degenerative mechanisms in Otof knock-out (Otof–/–) mice over the course of 48 weeks. We found otoferlin to be required for proper synapse development in the immature rodent cochlea: In absence of otoferlin, synaptic pruning was delayed, and postsynaptic boutons appeared enlarged at 2 weeks of age. At postnatal day 14 (P14), we found on average ∼15 synapses per inner hair cell (IHC) in Otof–/– cochleae as well as in wild-type controls. Further on, the number of synapses in Otof–/– IHCs was reduced to ∼7 at 8 weeks of age and to ∼6 at 48 weeks of age. In the same period, the number of spiral ganglion neurons (SGNs) declined in Otof–/– animals. Importantly, we found an age-progressive loss of IHCs to an overall number of 75% of wildtype IHCs. The IHC loss more prominently but not exclusively affected the basal aspects of the cochlea. For outer hair cells (OHCs), we observed slightly accelerated age-dependent degeneration from base to apex. This was associated with a progressive decay in DPOAE amplitudes for high frequency stimuli, which could first be observed at the age of 24 weeks in Otof–/– mice. Our data will help to plan and predict the outcome of a gene therapy applied at various ages of DFNB9 patients.

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Section: Introductionmentioning

confidence: 99%

“…To date, more than 200 pathogenic mutations have been identified in the OTOF gene ( Vona et al, 2020 ). While most mutations lead to profound deafness, a few non-truncating mutations result in mild to moderate progressive or temperature sensitive forms of hearing loss (reviewed in Vona et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9

Stalmann

Franke

Al-Moyed

et al. 2021

Front. Cell. Neurosci.

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“…Given no patients showed a positive OAE passed 5 years of age, we presume that the OAE response in OTOF-related ANSD disappears by 4-5 years of age at most, a little longer than previously thought. Related to the disappearance of OAE, some reports suggest that the disappearance of OAE could occur due to OHC damage originating from hearing aid use (Rouillon et al 2006;Vona et al 2020). On the other hand, it is also suggested that the use of hearing aids is not a de nitive factor for deterioration of OAE (Kitao et al 2019).…”

Section: Discussionmentioning

confidence: 99%

“…AAV-based gene therapy is considered to be a promising tool for actual human gene therapy due to its low immunogenicity, long-lasting transgene expression and ability to infect both dividing and non-dividing cells (Chandran et al 2017). At present, a few companies around the world are preparing for clinical trials using AAV (Akouos, Boston, MA, USA; Decibel Therapeutics, Boston, MA, USA; Sensorion, Montpellier, France) (Vona et al 2020). A new era of next-generation treatments for hereditary hearing loss, such as gene therapy, is certainly approaching; however, we should not forget that accurate treatment is based on accurate diagnosis and understanding of the clinical course.…”

Section: Discussionmentioning

confidence: 99%

“…The prevalence of OTOF mutations has been reported to be 1.4-8.3% of nonsyndromic hearing loss cases and 1.72% in Japan (Iwasa et al 2019). To date, more than 220 mutations in OTOF have been reported (Vona et al 2020). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, such as mild-to-moderate progressive cases (Chiu et al 2010).…”

Section: Introductionmentioning

confidence: 99%

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Detailed Clinical Features and Genotype-Phenotype Correlation in an OTOF-Related Hearing Loss Cohort in Japan

Iwasa¹,

Nishio²,

Yoishimura³

et al. 2021

Preprint

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OTOF is one of the most frequent causes of hereditary hearing loss and a main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in the patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 65 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.8%) showed a “typical” phenotype, prelingual and severe-to-profound hearing loss. Forty-seven patients (72.3%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39dB with cochlear implant and a CAP scale (Categories of Auditory Performance) level 6 or better. Although truncating mutations and p.R1939Q were clearly related to severe phenotype, almost half of patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.H513R, p.I1573T and p.E1910K showed “true” auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

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Preclinical Efficacy And Safety Evaluation of AAV‐OTOF in DFNB9 Mouse Model And Nonhuman Primate

Qi,

Zhang,

Tan

et al. 2023

Advanced Science

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OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof‐related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell‐specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual‐AAV‐OTOF‐hybrid strategy to transfer full‐length OTOF is generated, which can stably restore hearing in adult OTOFp.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild‐type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application.

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The Many Faces of DFNB9: Relating OTOF Variants to Hearing Impairment

Cited by 35 publications

References 73 publications

Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9

Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9

Detailed Clinical Features and Genotype-Phenotype Correlation in an OTOF-Related Hearing Loss Cohort in Japan

Preclinical Efficacy And Safety Evaluation of AAV‐OTOF in DFNB9 Mouse Model And Nonhuman Primate

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