OTOF mutation screening in Japanese severe to profound recessive hearing loss patients

Iwasa, Yoh-ichiro; Nishio, Shin‐ya; Yoshimura, Hidekane; Kanda, Yukihiko; Kumakawa, Kozo; Abe, Satoko; Naito, Yasushi; Nagai, Kyoko; Usami, Shin‐ichi

doi:10.1186/1471-2350-14-95

Cited by 34 publications

(37 citation statements)

References 36 publications

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“…Various hypotheses of the pathophysiology of AN are proposed: presynaptic or postsynaptic disorders of synapses between inner hair cells and the cochlear nerve, desynchronization within the cochlear nerve, demyelination or axonal atrophy of the cochlear nerve. Genetic mutations in AN involving OTOF, OPA1 and other genes have been reported [27,28]. However, there is the possibility of unknown mutations because the reported gene mutations are not commonly detected.…”

Section: Conclusion Of Adult An and Ansd In Newbornsmentioning

confidence: 94%

Auditory nerve disease and auditory neuropathy spectrum disorders

Kaga

2016

Auris Nasus Larynx

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Section: Conclusion Of Adult An and Ansd In Newbornsmentioning

confidence: 94%

Auditory nerve disease and auditory neuropathy spectrum disorders

Kaga

2016

Auris Nasus Larynx

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“…Mutations in OTOF account for 1.4e5% of cases of autosomal recessive non-syndromic hearing impairment in the populations that have been studied to date (Choi et al, 2009;Duman et al, 2011;Hutchin et al, 2005;Iwasa et al, 2013;Jin et al, 2014;Mahdieh et al, 2012;Rodríguez-Ballesteros et al, 2003;Romanos et al, 2009;Varga et al, 2006). These mutations have been found in very different proportions in cohorts of subjects from several countries, ranging from about 5% in some Chinese and Korean studies, through 50e60% in studies from the USA, Brazil and Japan, to 86% in Spanish cohorts (Bae et al, 2013;Chiu et al, 2010;Jin et al, 2014;Matsunaga et al, 2012;Rodríguez-Ballesteros et al, 2008;Romanos et al, 2009;Varga et al, 2006;Wang et al, 2010).…”

Section: Spectrum Of Otof Mutationsmentioning

confidence: 99%

Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations

et al. 2015

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Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with an impaired multivesicular glutamate release. Most affected subjects present with congenital hearing loss and abnormal auditory brainstem potentials associated with preserved cochlear hair cell activities (otoacoustic emissions, cochlear microphonics [CMs]). Transtympanic electrocochleography (ECochG) has recently been proposed for defining the details of potentials arising in both the cochlea and auditory nerve in this disorder, and with a view to shedding light on the pathophysiological mechanisms underlying auditory dysfunction.\ud We review the audiological and electrophysiological findings in children with congenital profound deafness carrying two mutant alleles of the OTOF gene. We show that cochlear microphonic (CM) amplitude, summating potential (SP) amplitude and latency are normal, consistently with a preserved outer and inner hair cell function. In the majority of OTOF children, the SP component is followed by a markedly prolonged low-amplitude negative potential by comparison with the compound action potential (CAP) recorded in normally-hearing children. This potential is identified at intensities as low as 90 dB below the behavioral threshold. In some ears, a synchronized CAP is superimposed on the prolonged responses at high intensity. Stimulation at high rates reduces the amplitude and duration of the prolonged potentials, consistently with their neural generation. In some children, however, the ECochG response only consists of the SP, with no prolonged potential. Cochlear implants restore hearing sensitivity, speech perception and neural CAP by electrically stimulating the auditory nerve fibers.\ud These findings indicate that an impaired multivesicular glutamate release in OTOF-related disorders leads to abnormal auditory nerve fiber activation and a consequent impairment of spike generation. The magnitude of these effects seems to vary, ranging from no auditory nerve fiber activation to an abnormal generation of EPSPs that occasionally trigger a synchronized electrical activity, resulting in high-threshold CAPs

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“…; Iwasa et al . ). Therefore, OTOF mutations (causative for non‐syndromic autosomal recessive hearing loss DFNB9; Yasunaga et al .…”

Section: Introductionmentioning

confidence: 97%

Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity

Müller

Sonntag

Maraslioglu

et al. 2019

The Journal of Physiology

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Key points Loss of the calcium sensor otoferlin disrupts neurotransmission from inner hair cells. Central auditory nuclei are functionally denervated in otoferlin knockout mice (Otof KOs) via gene ablation confined to the periphery. We employed juvenile and young adult Otof KO mice (postnatal days (P)10–12 and P27–49) as a model for lacking spontaneous activity and deafness, respectively. We studied the impact of peripheral activity on synaptic refinement in the sound localization circuit from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO). MNTB in vivo recordings demonstrated drastically reduced spontaneous spiking and deafness in Otof KOs. Juvenile KOs showed impaired synapse elimination and strengthening, manifested by broader MNTB–LSO inputs, imprecise MNTB–LSO topography and weaker MNTB–LSO fibres. The impairments persisted into young adulthood. Further functional refinement after hearing onset was undetected in young adult wild‐types. Collectively, activity deprivation confined to peripheral protein loss impairs functional MNTB–LSO refinement during a critical prehearing period. Abstract Circuit refinement is critical for the developing sound localization pathways in the auditory brainstem. In prehearing mice (hearing onset around postnatal day (P)12), spontaneous activity propagates from the periphery to central auditory nuclei. At the glycinergic projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) of neonatal mice, super‐numerous MNTB fibres innervate a given LSO neuron. Between P4 and P9, MNTB fibres are functionally eliminated, whereas the remaining fibres are strengthened. Little is known about MNTB–LSO circuit refinement after P20. Moreover, MNTB–LSO refinement upon activity deprivation confined to the periphery is largely unexplored. This leaves a considerable knowledge gap, as deprivation often occurs in patients with congenital deafness, e.g. upon mutations in the otoferlin gene (OTOF). Here, we analysed juvenile (P10–12) and young adult (P27–49) otoferlin knockout (Otof KO) mice with respect to MNTB–LSO refinement. MNTB in vivo recordings revealed drastically reduced spontaneous activity and deafness in knockouts (KOs), confirming deprivation. As RNA sequencing revealed Otof absence in the MNTB and LSO of wild‐types, Otof loss in KOs is specific to the periphery. Functional denervation impaired MNTB–LSO synapse elimination and strengthening, which was assessed by glutamate uncaging and electrical stimulation. Impaired elimination led to imprecise MNTB–LSO topography. Impaired strengthening was associated with lower quantal content per MNTB fibre. In young adult KOs, the MNTB–LSO circuit remained unrefined. Further functional refinement after P12 appeared absent in wild‐types. Collectively, we provide novel insights into functional MNTB–LSO circuit maturation governed by a cochlea‐specific protein. The central malfunctions in Otof KOs may have implications for patients with sensorineuronal hearing loss.

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OTOF mutation screening in Japanese severe to profound recessive hearing loss patients

Cited by 34 publications

References 36 publications

Auditory nerve disease and auditory neuropathy spectrum disorders

Auditory nerve disease and auditory neuropathy spectrum disorders

Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations

Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity

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