Disruption of the autism-related gene Pak1 causes stereocilia disorganization, hair cell loss, and deafness in mice

Optic atrophy1 (OPA1) is crucial for inner mitochondrial membrane (IMM) fusion and essential for maintaining crista structure and mitochondrial morphology. Optic atrophy and hearing impairment are the most prevalent clinical features associated with mutations in the OPA1 gene, but the function of OPA1 in hearing is still unknown. In this study, we examined the ability of Opa1 to protect against cisplatin-induced cochlear cell death in vitro and in vivo. Our results revealed that knockdown of Opa1 affects mitochondrial function in HEI-OC1 and Neuro 2a cells, as evidenced by an elevated reactive oxygen species (ROS) level and reduced mitochondrial membrane potential. The dysfunctional mitochondria release cytochrome c, which triggers apoptosis. Opa1 expression was found to be significantly reduced after cell exposed to cisplatin in HEI-OC1 and Neuro 2a cells. Loss of Opa1 aggravated the apoptosis and mitochondrial dysfunction induced by cisplatin treatment, whereas overexpression of Opa1 alleviated cisplatin-induced cochlear cell death in vitro and in explant. Our results demonstrate that overexpression of Opa1 prevented cisplatin-induced ototoxicity, suggesting that Opa1 may play a vital role in ototoxicity and/or mitochondria-associated cochlear damage.

Section: Discussionsupporting

confidence: 60%

Opa1 Prevents Apoptosis and Cisplatin-Induced Ototoxicity in Murine Cochleae

Dong

Zhang

Liu

et al. 2021

“…While supporting cells function as potential resources to regenerate HCs after damage (Lu et al, 2017;Zhang et al, 2017;Tan et al, 2019;Zhang S. et al, 2019Chen et al, 2021). Sensorineural hearing loss has many etiologies, varying from genetic defects (Zhu et al, 2018;Fang et al, 2019;Yang et al, 2019;Qian et al, 2020;Cheng et al, 2021;Fu et al, 2021a;Lv et al, 2021;Zhang et al, 2021) to environmental factors, including aging (Zhang et al, 2017;Fu et al, 2018;Li H. et al, 2018;He et al, 2020He et al, , 2021, noise and ototoxic drugs (Liu et al, 2016;He et al, 2017;Gao et al, 2020;Zhong et al, 2020;Fu et al, 2021b). TSAN is a rare phenotype with high clinical heterogeneity, manifesting as transient bilateral HL due to an increase in the core body temperature.…”

Section: Discussionmentioning

confidence: 99%

Familial Temperature-Sensitive Auditory Neuropathy: Distinctive Clinical Courses Caused by Variants of the OTOF Gene

Zhu

Gao³

et al. 2021

Objective: To investigate the clinical course and genetic etiology of familial temperature-sensitive auditory neuropathy (TSAN), which is a very rare subtype of auditory neuropathy (AN) that involves an elevation of hearing thresholds due to an increase in the core body temperature, and to evaluate the genotype–phenotype correlations in a family with TSAN.Methods: Six members of a non-consanguineous Chinese family, including four siblings complaining of communication difficulties when febrile, were enrolled in this study. The clinical and audiological profiles of the four siblings were fully evaluated during both febrile and afebrile episodes, and the genetic etiology of hearing loss (HL) was explored using next-generation sequencing (NGS) technology. Their parents, who had no complaints of fluctuating HL due to body temperature variation, were enrolled for the genetics portion only.Results: Audiological tests during the patients’ febrile episodes met the classical diagnostic criteria for AN, including mild HL, poor speech discrimination, preserved cochlear microphonics (CMs), and absent auditory brainstem responses (ABRs). Importantly, unlike the pattern observed in previously reported cases of TSAN, the ABRs and electrocochleography (ECochG) signals of our patients improved to normal during afebrile periods. Genetic analysis identified a compound heterozygous variant of the OTOF gene (which encodes the otoferlin protein), including one previously reported pathogenic variant, c.5098G > C (p.Glu1700Gln), and one novel variant, c.4882C > A (p.Pro1628Thr). Neither of the identified variants affected the C2 domains related to the main function of otoferlin. Both variants faithfully cosegregated with TSAN within the pedigree, suggesting that OTOF is the causative gene of the autosomal recessive trait segregation in this family.Conclusion: The presence of CMs with absent (or markedly abnormal) ABRs is a reliable criterion for diagnosing AN. The severity of the phenotype caused by dysfunctional neurotransmitter release in TSAN may reflect variants that alter the C2 domains of otoferlin. The observations from this study enrich the current understanding of the phenotype and genotype of TSAN and may lay a foundation for further research on its pathogenesis.

“…It is estimated that more than half of hearing loss cases are attributable to genetic factors Wang et al, 2017;Zhu et al, 2018;Fang et al, 2019;He Z. et al, 2019;Fu et al, 2021), while the other half of hearing loss could be caused by aging, chronic infections, infectious diseases, ototoxic drugs, and noise exposure (Liu L. et al, 2016;He Z. et al, 2017;Cheng et al, 2019;Gao et al, 2019;Tan et al, 2019;Zhang et al, 2019;Zhong et al, 2020). The functions of these hearing loss genes play an essential role in the development and function of hair cells and synaptic transmission of spiral ganglion neurons (Qi et al, 2020;Qian et al, 2020;Zhang et al, 2020Zhang et al, , 2021Cheng et al, 2021;Lv et al, 2021). Thus, hearing loss is often induced by loss of sensory hair cells Qi et al, 2019;Han et al, 2020;He et al, 2020He et al, , 2021Chen et al, 2021) and spiral ganglion neurons (Guo et al, 2016(Guo et al, , 2019(Guo et al, , 2020(Guo et al, , 2021Hu et al, 2021;Liu W. et al, 2021) in the inner ear cochlea.…”

Section: Discussionmentioning

confidence: 99%

Auditory Neuropathy as the Initial Phenotype for Patients With ATP1A3 c.2452 G > A: Genotype–Phenotype Study and CI Management

Wang

Jin

Lan

et al. 2021

Objective: The objective of this study is to analyze the genotype–phenotype correlation of patients with auditory neuropathy (AN), which is a clinical condition featuring normal cochlear responses and abnormal neural responses, and ATP1A3 c.2452 G > A (p.E818K), which has been generally recognized as a genetic cause of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome.Methods: Four patients diagnosed as AN by clinical evaluation and otoacoustic emission and auditory brainstem responses were recruited and analyzed by next-generation sequencing to identify candidate disease-causing variants. Sanger sequencing was performed on the patients and their parents to verify the results, and short tandem repeat-based testing was conducted to confirm the biological relationship between the parents and the patients. Furthermore, cochlear implantation (CI) was performed in one AN patient to reconstruct hearing.Results: Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene. Except for the AN phenotype, patients 1 and 2 exhibited varying degrees of neurological symptoms, implying that they can be diagnosed as CAPOS syndrome. During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA). Patient 2 underwent CI on his left ear, and the result was poor. The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms.Conclusion:ATP1A3 p.E818K has rarely been documented in the Chinese AN population. Our study confirms that p.E818K in the ATP1A3 gene is a multiethnic cause of AN in Chinese individuals. Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome and offers a more accurate genetic counseling about the specific de novo mutation.