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: 6.34). 08/2006; 43(7):576-81. DOI: 10.1136/jmg.2005.038612
Source: PubMed


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.

Full-text preview

Available from:
    • "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.
    No preview · Article · Oct 2015 · The EMBO Journal
    • "In afebrile conditions, speech perception is normal or only slightly impaired in quiet environments, but it is abnormally reduced in the presence of background noise (Starr et al., 1998; Varga et al., 2006). Speech perception deteriorates when the core temperature rises, invariably becoming impaired even in quiet environments regardless of the extent of the individual's hearing threshold elevation (Starr et al., 1998; Marlin et al., 2010; Matsunaga et al., 2012; Varga et al., 2006). Wynne et al. (2013) recently studied adaptation in patients with temperature-sensitive AN by measuring the perceived loudness changes during the presentation of a continuous tone with a fixed intensity for 3 min. "
    [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.
    No preview · Article · Jul 2015 · Hearing research
  • 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.
    Full-text · Article · Jan 2014 · International journal of pediatric otorhinolaryngology
Show more