A mutation in OTOF, encoding OTOFerlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness

Unité de Génétique des Déficits Sensoriels, CNRS URA 1968, Institut Pasteur, Paris, France.
Nature Genetics (Impact Factor: 29.35). 05/1999; 21(4):363-9. DOI: 10.1038/7693
Source: PubMed


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.

Download full-text


Available from: Aziz El-Amraoui,
    • "Rapid vesicle turnover requires sufficient amounts of the hair cell C 2 -domain protein otoferlin (Roux et al, 2006; Pangr si c et al, 2010) that when defective causes human hearing impairment (Yasunaga et al, 1999; Varga et al, 2006). However, a role of otoferlin in prefusion priming could so far not be distinguished from a post-fusion function in clearing previously exocytosed membrane from release sites (Pangr si c et al, 2010; Pangr si c et al, 2012; Duncker et al, 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2μ (AP-2μ) is required for release site replenishment and hearing. We show that hair cell-specific disruption of AP-2μ slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval. Sound-driven postsynaptic spiking was reduced in a use-dependent manner, and the altered interspike interval statistics suggested a slowed reloading of release sites. Sustained strong stimulation led to accumulation of endosome-like vacuoles, fewer clathrin-coated endocytic intermediates, and vesicle depletion of the membrane-distal synaptic ribbon in AP-2μ-deficient IHCs, indicating a further role of AP-2μ in clathrin-dependent vesicle reformation on a timescale of many seconds. Finally, we show that AP-2 sorts its IHC-cargo otoferlin. We propose that binding of AP-2 to otoferlin facilitates replenishment of release sites, for example, via speeding AZ clearance of exocytosed material, in addition to a role of AP-2 in synaptic vesicle reformation.
    The EMBO Journal 10/2015; 34(21). DOI:10.15252/embj.201591885 · 10.43 Impact Factor
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the OTOF gene encoding otoferlin result in a disrupted function of the ribbon synapses with impairment of the 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.
    Hearing research 07/2015; DOI:10.1016/j.heares.2015.07.007 · 2.97 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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; 361(1). DOI:10.1007/s00441-015-2176-x · 3.57 Impact Factor
Show more