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Yasunaga, S. et al. A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat. Genet. 21, 363-369

Unité de Génétique des Déficits Sensoriels, CNRS URA 1968, Institut Pasteur, Paris, France.
Nature Genetics (Impact Factor: 29.65). 05/1999; 21(4):363-9. DOI: 10.1038/7693
Source: PubMed

ABSTRACT Using a candidate gene approach, we identified a novel human gene, OTOF, underlying an autosomal recessive, nonsyndromic prelingual deafness, DFNB9. The same nonsense mutation was detected in four unrelated affected families of Lebanese origin. OTOF is the second member of a mammalian gene family related to Caenorhabditis elegans fer-1. It encodes a predicted cytosolic protein (of 1,230 aa) with three C2 domains and a single carboxy-terminal transmembrane domain. The sequence homologies and predicted structure of otoferlin, the protein encoded by OTOF, suggest its involvement in vesicle membrane fusion. In the inner ear, the expression of the orthologous mouse gene, mainly in the sensory hair cells, indicates that such a role could apply to synaptic vesicles.

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Available from: Aziz El-Amraoui, Sep 02, 2015
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    • "The currently-known spectrum of sequence variants of the OTOF gene includes more than 90 pathogenic mutations and over 50 neutral variants (Mahdieh et al., 2012; Rodríguez-Ballesteros et al., 2008). Pathogenic variants are responsible for the DFNB9 type of autosomal recessive non-syndromic hearing impairment (Yasunaga et al., 1999). "
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    ABSTRACT: 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. 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. 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. Copyright © 2015. Published by Elsevier B.V.
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    • "Second, analysis of bassoon knockout (KO) mice showed a larger quantal size, an increased P r (evidenced by faster and stronger depression) and a decreased RRP size at ANF-BC synapses (Mendoza Schulz et al. 2014). Third, another deaf mutant strain is provided by mice lacking otoferlin, a cytosolic protein that senses calcium, regulates vesicle membrane fusion and mediates efficient replenishment of synaptic vesicles in inner hair cells (Yasunaga et al. 1999; Roux et al. 2006; Beurg et al. 2010; Johnson and Chapman 2010; Pangrsic et al. 2010). Mice lacking functional otoferlin are deprived of most normal, patterned spontaneous activity that originates in the cochlea and is propagated throughout the auditory system before hearing onset (Roux et al. 2006). "
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    ABSTRACT: Synaptic transmission via chemical synapses is dynamic, i.e., the strength of postsynaptic responses may change considerably in response to repeated synaptic activation. Synaptic strength is increased during facilitation, augmentation and potentiation, whereas a decrease in synaptic strength is characteristic for depression and attenuation. This review attempts to discuss the literature on short-term and long-term synaptic plasticity in the auditory brainstem of mammals and birds. One hallmark of the auditory system, particularly the inner ear and lower brainstem stations, is information transfer through neurons that fire action potentials at very high frequency, thereby activating synapses >500 times per second. Some auditory synapses display morphological specializations of the presynaptic terminals, e.g., calyceal extensions, whereas other auditory synapses do not. The review focuses on short-term depression and short-term facilitation, i.e., plastic changes with durations in the millisecond range. Other types of short-term synaptic plasticity, e.g., posttetanic potentiation and depolarization-induced suppression of excitation, will be discussed much more briefly. The same holds true for subtypes of long-term plasticity, like prolonged depolarizations and spike-time-dependent plasticity. We also address forms of plasticity in the auditory brainstem that do not comprise synaptic plasticity in a strict sense, namely short-term suppression, paired tone facilitation, short-term adaptation, synaptic adaptation and neural adaptation. Finally, we perform a meta-analysis of 61 studies in which short-term depression (STD) in the auditory system is opposed to short-term depression at non-auditory synapses in order to compare high-frequency neurons with those that fire action potentials at a lower rate. This meta-analysis reveals considerably less STD in most auditory synapses than in non-auditory ones, enabling reliable, failure-free synaptic transmission even at frequencies >100 Hz. Surprisingly, the calyx of Held, arguably the best-investigated synapse in the central nervous system, depresses most robustly. It will be exciting to reveal the molecular mechanisms that set high-fidelity synapses apart from other synapses that function much less reliably.
    Cell and Tissue Research 04/2015; DOI:10.1007/s00441-015-2176-x · 3.33 Impact Factor
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    • "Globally, hearing loss is the most frequent sensory deficit [1] [2]. Each year, approximately one in 1000 children is born with prelingual deafness [3] [4] [5] [6]. In Ecuador, this rate increases to approximately 2.3 for every 1000 children [7]. "
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