Identities and frequencies of mutations of the otoferlin gene (<i>OTOF</i>) causing DFNB9 deafness in Pakistan

Choi, Hyung-Wook; Ahmed, Zaheer; Riazuddin, Saima; Bhinder, MA; Shahzad, Mohsin; Husnain, Tayyab; Griffith, AJ; Tb, Friedman

doi:10.1111/j.1399-0004.2008.01128.x

Cited by 92 publications

(92 citation statements)

References 23 publications

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“…Mutations in otoferlin that prevent neurotransmitter release from sensory hair cells result in a form of nonsyndromic hearing loss known as DFNB9 (21,22). One such pathogenic mutation in humans is L1011P in the C2D domain (L1010P in mouse), which has recently been shown to diminish binding to Loop1.3 (2).…”

Section: Synaptotagmin Does Not Interact With the Cytoplasmic Loop Ofmentioning

confidence: 99%

Otoferlin is a multivalent calcium-sensitive scaffold linking SNAREs and calcium channels

Hams

Padmanarayana

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Sensory hair cells rely on otoferlin as the calcium sensor for exocytosis and encoding of sound preferentially over the neuronal calcium sensor synaptotagmin. Although it is established that synaptotagmin cannot rescue the otoferlin KO phenotype, the large size and low solubility of otoferlin have prohibited direct biochemical comparisons that could establish functional differences between these two proteins. To address this challenge, we have developed a singlemolecule colocalization binding titration assay (smCoBRA) that can quantitatively characterize full-length otoferlin from mammalian cell lysate. Using smCoBRA, we found that, although both otoferlin and synaptotagmin bind membrane fusion SNARE proteins, only otoferlin interacts with the L-type calcium channel Cav1.3, showing a significant difference between the synaptic proteins. Furthermore, otoferlin was found capable of interacting with multiple SNARE and Cav1.3 proteins simultaneously, forming a heterooligomer complex. We also found that a deafness-causing missense mutation in otoferlin attenuates binding between otoferlin and Cav1.3, suggesting that deficiencies in this interaction may form the basis for otoferlin-related hearing loss. Based on our results, we propose a model in which otoferlin acts as a calcium-sensitive scaffolding protein, localizing SNARE proteins proximal to the calcium channel so as to synchronize calcium influx with membrane fusion. Our findings also provide a molecular-level explanation for the observation that synaptotagmin and otoferlin are not functionally redundant. This study also validates a generally applicable methodology for quantitatively characterizing large, multivalent membrane proteins.exocytosis | membrane fusion | calcium | otoferlin | calcium channel S ensory hair cells encode sound by converting mechanical motion into chemical signals. Hair cell synapses accommodate this unique functional demand via a set of adaptations that distinguish it from neuronal synapses, including reliance on the L-type calcium channel Cav1.3 in place of the P-and N-type calcium channels found at most neuronal synapses ( Fig. 1 A and B) (1-6). During maturation, hair cells also cease expression of the two C2 domain protein synaptotagmin I, which serves as the calcium sensor for neurotransmitter release at neuronal synapses (7). Although lacking synaptotagmin, mature hair cells express the six C2 domain protein otoferlin, which is proposed to function as the calcium sensor for exocytosis in mature sound-encoding synapses (8). In agreement with this belief, KO studies have linked otoferlin to sensory hair cell exocytosis, and in vitro studies on otoferlin have concluded that several C2 domains bind SNARE proteins and stimulate membrane fusion in a calcium-sensitive manner (2,(8)(9)(10). However, a recent cell-based study concluded that synaptotagmin cannot rescue the otoferlin KO phenotype, arguing against a simple functional redundancy between these C2 domain proteins (11). The functional differences between synaptotagmin and otofer...

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Section: Synaptotagmin Does Not Interact With the Cytoplasmic Loop Ofmentioning

confidence: 99%

Otoferlin is a multivalent calcium-sensitive scaffold linking SNAREs and calcium channels

Hams

Padmanarayana

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Most of the pathogenic alleles of OTOF are private, each one being reported in only one family. A total of 13 (2.3%) families linked to DFNB9 were identified in a screening of 557 large consanguineous Pakistani families (Choi et al, 2009). Probable pathogenic variants in the OTOF gene were found among all 13 families.…”

Section: Dfnb9/otofmentioning

confidence: 99%

The Genetic Basis of Nonsyndromic Hearing Loss in Indian and Pakistani Populations

Yan

Kannan-Sundhari

Vishwanath

et al. 2015

Genetic Testing and Molecular Biomarkers

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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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Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan

Cited by 92 publications

References 23 publications

Otoferlin is a multivalent calcium-sensitive scaffold linking SNAREs and calcium channels

Otoferlin is a multivalent calcium-sensitive scaffold linking SNAREs and calcium channels

The Genetic Basis of Nonsyndromic Hearing Loss in Indian and Pakistani Populations

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

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