A novel missense mutation in a C2 domain ofOTOF results in autosomal recessive auditory neuropathy

Division of Pediatric Molecular Genetics, Ankara University School of Medicine, Ankara, Turkey.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 09/2005; 138(1):6-10. DOI: 10.1002/ajmg.a.30907
Source: PubMed


Screening of 12 Turkish families with apparently autosomal recessive nonsyndromic sensorineural deafness without GJB2 and mtDNA m.1555A > G mutations for 11 previously mapped recessive deafness loci showed a family in which hearing loss cosegregated with the DFNB9 (OTOF) locus. Three affected children were later found to carry a novel homozygous c.3032T > C (p.Leu1011Pro) mutation in the OTOF gene. Both parents were heterozygous for the mutation. p.Leu1011Pro alters a conserved leucine residue in the C2D domain of otoferlin. Pure tone audiometry of the family showed severe to profound sensorineural hearing loss (with U-shape audiograms) in children, and normal hearing in the parents. Otoacoustic emissions and auditory brainstem response (ABR) suggested the presence of auditory neuropathy in affected individuals.

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    • "As evaluations for AN/ AD are not routinely performed on every individual with HL, audiogram shapes are sometimes helpful for identifying genetic causes. Patients with OTOF mutations may have better thresholds at high frequencies on puretone audiograms or fluctuation in hearing level between tests, as might be expected in AN/AD (Tekin et al., 2005). As spiral ganglion neurons are normal in these patients, cochlear implants have been successful (Rouillon et al., 2006). "
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    ABSTRACT: This article is a review of the genes and genetic disorders that affect hearing in humans and a few selected mouse models of deafness. Genetics is playing an increasingly critical role in the practice of medicine. This is not only in part to the importance that genetic knowledge has on traditional genetic diseases but also in part to the fact that genetic knowledge provides an understanding of the fundamental biological process of most diseases. The proteins coded by the genes related to hearing loss (HL) are involved in many functions in the ear, such as cochlear fluid homeostasis, ionic channels, stereocilia morphology and function, synaptic transmission, gene regulation, and others. Mouse models play a crucial role in understanding of the pathogenesis associated with these genes. Different types of familial HL have been recognized for years; however, in the last two decades, there has been tremendous progress in the discovery of gene mutations that cause deafness. Most of the cases of genetic deafness recognized today are monogenic disorders that can be broadly classified by the mode of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance) and by the presence of associated phenotypic features (i.e., syndromic; and nonsyndromic). In terms of nonsyndromic HL, the chromosomal locations are currently known for ∼ 125 loci (54 for dominant and 71 for recessive deafness), 64 genes have been identified (24 for dominant and 40 for recessive deafness), and there are many more loci for syndromic deafness and X-linked and mitochondrial DNA disorders ( Thus, today's clinician must understand the science of medical genetics as this knowledge can lead to more effective disease diagnosis, counseling, treatment, and prevention. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.
    Preview · Article · Nov 2012 · The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology
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    • "In the current study, we describe one of these antibodies, hair cell soma 1 (HCS-1), which specifically recognizes a protein found in the hair cell soma in a variety of species and has been used by numerous laboratories as a hair cell marker (Gale et al. 2000, 2002; Daudet and Lewis 2005; Forlano et al. 2005; Lopez-Schier and Hudspeth 2005, 2006; Taylor and Forge 2005; Blasiole et al. 2006; Bricaud and Collazo 2006; Hu and Corwin 2007; Warchol and Speck 2007; Ma et al. 2008; Bird et al. 2010). We have used the HCS-1 antibody to immunoprecipitate the antigen it recognizes and have identified this protein by mass spectrometry as otoferlin, a member of the ferlin protein family known to be important for proper auditory function (Yasunaga et al. 1999, 2000; Tekin et al. 2005; Roux et al. 2006; Longo-Guess et al. 2007). Using the HCS-1 antibody, we describe the distribution of otoferlin in chick, fish, guinea pig, and bullfrog inner ears and characterize its biochemical properties. "
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    ABSTRACT: Hair cells, the mechanosensitive receptor cells of the inner ear, are critical for our senses of hearing and balance. The small number of these receptor cells in the inner ear has impeded the identification and characterization of proteins important for hair cell function. The binding specificity of monoclonal antibodies provides a means for identifying hair cell-specific proteins and isolating them for further study. We have generated a monoclonal antibody, termed hair cell soma-1 (HCS-1), which specifically immunolabels hair cells in at least five vertebrate classes, including sharks and rays, bony fish, amphibians, birds, and mammals. We used HCS-1 to immunoprecipitate the cognate antigen and identified it as otoferlin, a member of the ferlin protein family. Mutations in otoferlin underlie DFNB9, a recessive, nonsyndromic form of prelingual deafness characterized as an auditory neuropathy. Using immunocytochemistry, we find that otoferlin is associated with the entire basolateral membrane of the hair cells and with vesicular structures distributed throughout most of the hair cell cytoplasm. Biochemical assays indicate that otoferlin is tightly associated with membranes, as it is not solubilized by alterations in calcium or salt concentrations. HCS-1 immunolabeling does not co-localize with ribeye, a constituent of synaptic ribbons, suggesting that otoferlin may, in addition to its proposed function in synaptic vesicle release, play additional roles in hair cells.
    Full-text · Article · Dec 2010 · Journal of the Association for Research in Otolaryngology
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    • "They found a consistent linkage with the OTOF locus and identified OTOF mutations in these families [9]. Further studies described biallelic OTOF mutations in patients affected by AN and confirmed that two mutated OTOF alleles can be responsible for AN in patients [10] [11] [12] [13] [14]. Besides, mutant mice defective for otoferlin show profound HI presenting the characteristics of AN [15]. "
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    ABSTRACT: Transient deafness associated with an increase in core body temperature is a rare and puzzling disorder. Temperature-dependent deafness has been previously observed in patients suffering from auditory neuropathy. Auditory neuropathy is a clinical entity of sensorineural deafness characterized by absent auditory brainstem response and normal otoacoustic emissions. Mutations in OTOF, which encodes otoferlin, have been previously reported to cause DFNB9, a non-syndromic form of deafness characterized by severe to profound prelingual hearing impairment and auditory neuropathy. Here we report a novel mutation in OTOF gene in a large family affected by temperature-dependent auditory neuropathy. Three siblings aged 10, 9 and 7 years from a consanguineous family were found to be affected by severe or profound hearing impairment that was only present when they were febrile. The non-febrile patients had only mild if any hearing impairment. Electrophysiological tests revealed auditory neuropathy. Mapping with microsatellite markers revealed a compatible linkage in the DFNB9/OTOF region in the family, prompting us to run a molecular analysis of the 48 exons and of the OTOF intron-exon boundaries. This study revealed a novel mutation p.Glu1804del in exon 44 of OTOF. The mutation was found to be homozygous in the three patients and segregated with the hearing impairment within the family. The deletion affects an amino acid that is conserved in mammalian otoferlin sequences and located in the calcium-binding domain C2F of the protein.
    Full-text · Article · Mar 2010 · Biochemical and Biophysical Research Communications
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