OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele

Department of Hearing and Speech Sciences, Vanderbilt University, Нашвилл, Michigan, United States
Journal of Medical Genetics (Impact Factor: 5.64). 08/2006; 43(7):576-81. DOI: 10.1136/jmg.2005.038612
Source: PubMed

ABSTRACT The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene.
In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin.
Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype.
Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

  • Source
    • "on mice lacking VGLUT3 support that hypothesis. This neurotransmitter hypothesis was clinically supported by the genetic research that showed that ANSD in some children is due to mutation in the otoferlin gene (OTOF) [37]. Otoferlin is expressed in the IHCs and it is essential for the process of neurotransmitter release; therefore otoferlin deficiency leaves the IHC/synapse not functioning and leads to the clinical manifestations of ANSD [38]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This work was designed to study electroencephalogram findings in children with congenital sensorineural hearing loss and correlate these findings with the SNHL parameters as duration, etiology, severity, and type. Ninety children with bilateral congenital sensorineural hearing loss served as the study group. They were free from any neurological disorders or symptoms that are commonly associated with abnormal electroencephalogram as convulsions or loss of consciousness. Twenty children having normal hearing with no history of otological or neurological disorders served as the control group. All children participating in the study were subjected to full medical and audiological history, otological examination, neurological examination, audiological evaluation and electroencephalogram recording. Mean age of the children in the control group was 3.56±2.1 years and mean age of the children in the study group was 3.8±2.2 years. While none of the control children had abnormal electroencephalogram, 38 (42.2%) of children with congenital SNHL had epileptiform electroencephalogram abnormality. The epileptiform abnormality was generalized in 14 children (36.8%), focal temporal in 17 children (44.7%) and focal other than temporal in 7 children (18.4%). According to the hemispheric side affected, the abnormality was right in 14 children (36.8%), left in 10 children (26.3%) and bilateral in 14 children (36.8%). No statistically significant predominance of specific site or side of the epileptiform abnormality was found. Similarly, no statistical significant prevalent of the epileptiform abnormality was found in relation to the age or sex of children, duration of hearing loss or etiology of hearing loss (i.e., genetic vs. neonatal insults). On the other hand, the epileptiform abnormality was statistically prevalent in children with moderate degree of hearing loss, and in children with auditory neuropathy spectrum disorder. The epileptiform electroencephalogram abnormality is a common finding in children with congenital sensorineural hearing loss especially those with auditory neuropathy spectrum disorder, suggesting the affection of the central nervous system despite the absence of neurological symptoms or signs. These findings raise the question of the requirement of medical treatment for those children and the effect of such treatment in their rehabilitation.
    International journal of pediatric otorhinolaryngology 01/2014; 78(4). DOI:10.1016/j.ijporl.2014.01.018 · 1.32 Impact Factor
  • Source
    • "Two of these subjects have mutations, FRDA (in Subject AN34) and MPZ (in Subject AN2), that have been shown to be associated with marked loss of auditory ganglion cells in temporal bones (Spoendlin, 1974; Starr et al., 2003). Dys-synchronous activation of auditory nerve fibres may be likely in subjects with temperature-sensitive ribbon synapse disorder due to mutation of OTOF (Varga et al., 2006; Marlin et al., 2010). ABRs were abnormal (delayed latency, reduced amplitude ) to the first click in the stimulus train and then were further delayed or absent to subsequent clicks. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormal auditory adaptation is a standard clinical tool for diagnosing auditory nerve disorders due to acoustic neuromas. In the present study we investigated auditory adaptation in auditory neuropathy owing to disordered function of inner hair cell ribbon synapses (temperature-sensitive auditory neuropathy) or auditory nerve fibres. Subjects were tested when afebrile for (i) psychophysical loudness adaptation to comfortably-loud sustained tones; and (ii) physiological adaptation of auditory brainstem responses to clicks as a function of their position in brief 20-click stimulus trains (#1, 2, 3 … 20). Results were compared with normal hearing listeners and other forms of hearing impairment. Subjects with ribbon synapse disorder had abnormally increased magnitude of loudness adaptation to both low (250 Hz) and high (8000 Hz) frequency tones. Subjects with auditory nerve disorders had normal loudness adaptation to low frequency tones; all but one had abnormal adaptation to high frequency tones. Adaptation was both more rapid and of greater magnitude in ribbon synapse than in auditory nerve disorders. Auditory brainstem response measures of adaptation in ribbon synapse disorder showed Wave V to the first click in the train to be abnormal both in latency and amplitude, and these abnormalities increased in magnitude or Wave V was absent to subsequent clicks. In contrast, auditory brainstem responses in four of the five subjects with neural disorders were absent to every click in the train. The fifth subject had normal latency and abnormally reduced amplitude of Wave V to the first click and abnormal or absent responses to subsequent clicks. Thus, dysfunction of both synaptic transmission and auditory neural function can be associated with abnormal loudness adaptation and the magnitude of the adaptation is significantly greater with ribbon synapse than neural disorders.
    Brain 03/2013; DOI:10.1093/brain/awt056 · 10.23 Impact Factor
  • Source
    • "In contrast to individuals with non-AN/AD HL, hearing aids may provide little help in speech understanding in most individuals with AN/AD. Cochlear implantation has been shown to help the speech understanding in some cases of AN/AD; however, other cases have not had favorable results (Varga et al., 2006). The HL can be congenital or late onset, and the hearing level in patients with AN can vary from mild to profound. "
    [Show abstract] [Hide abstract]
    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.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 11/2012; 295(11):1812-29. DOI:10.1002/ar.22579 · 1.53 Impact Factor
Show more


Available from