Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF)

Abstract

Inherited hearing impairment affects one in 2,000 newborns. Nonsyndromic prelingual forms are inherited mainly as autosomal recessive traits, for which 16 genes are currently known. Mutations in the genes encoding connexins 26 and 30 account for up to 50% of these cases. However, the individual contribution of the remaining genes to the whole remains undetermined. In addition, for most of the genes there is a need for studies on genotype-phenotype correlations, to identify distinctive clinical features which may direct the molecular diagnosis to specific genes. Here we present a mutation analysis and a genotype-phenotype correlation study on the gene encoding otoferlin (OTOF), responsible for the DFNB9 subtype of prelingual hearing impairment. Four novel mutations were identified: c.2122C>T (p.Arg708Ter), c.4275G>A (p.Trp1425Ter), c.4362+2T>G, and c.5860_5862delATC (p.Ile1954del). A total of 37 subjects with mutations in OTOF were studied clinically. They were phenotypically homogeneous, having profound hearing impairment with very early onset, as shown by pure-tone audiometry and auditory brainstem responses. Magnetic resonance imaging and computed tomography did not reveal any inner ear malformation. Unexpectedly, transient evoked otoacoustic emissions (TEOAEs) were present, either bilaterally or unilaterally in 11 subjects. Altogether, clinical data of these subjects met the diagnostic criteria of auditory neuropathy. A total of 10 subjects had been successfully provided with cochlear implants. The results of our study indicate that genetic diagnosis of subjects with auditory neuropathy and profound hearing impairment should be directed to the otoferlin gene. Our data are of concern to universal screening programs which use TEOAEs as the first detection test for hearing impairment in newborns, since this technique may overlook a nonnegligible proportion of cases.

A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9

“…Phenotypes caused by mutations of otoferlin have been classified as auditory neuropathies because patients lack auditory brainstem responses but exhibit normal otoacoustic emissions (Rodriguez-Ballesteros et al, 2003;Varga et al, 2003). This phenotype also has been demonstrated in genetically engineered Otof-deficient mice (Roux et al, 2006) and in mice with an ENU-induced D1772G missense mutation in the C2F domain of otoferlin (Schwander et al, 2007).…”

Neural and receptor cochlear potentials obtained by transtympanic electrocochleography in auditory neuropathy

“…The involvement of optic nerves as well as the post-lingual onset is inconsistent with mutations of both otoferlin (Rodriguez-Ballesteros et al, 2003) and pejvakin genes (Delmaghani et al, 2006). Mutations affecting mitochondrial functions of both optic and auditory nerves are candidate etiologies in these patients (Ceranić and Luxon, 2004;Amati-Bonneau et al, 2005).…”

“…However, it is known that AN accompanies disorders of the auditory nerve (post-synaptic or Type I AN; Starr et al, 2003), and disorders of inner hair cells and their synapses with auditory nerve terminals (pre-synaptic or Type II AN; Starr et al, 2004;Rodriguez-Ballesteros et al, 2003). Temporal bone analyses from patients with Type I AN (Spoendlin, 1974;Hallpike et al, 1980;Starr et al, 2003) reveal loss of auditory ganglion cells and their processes with remaining axons and dendrites showing myelin and axonal abnormalities.…”

“…Temporal bone analyses from patients with AN due to disordered IHC functions (Type II AN) as might accompany mutations of otoferlin gene (Varga et al, 2003;Rodriguez-Ballesteros et al, 2003) have not yet been reported. The gene mutation is thought to adversely affect neurotransmitter release and absence of ABRs in this disorder is consistent with a functional loss of auditory nerve input.…”

The otoferlin interactome in neurosensory hair cells: Significance for synaptic vesicle release and trans-Golgi network (Review)

“…Such studies should show whether a different, yet uncharacterized protein replaces otoferlin's function or whether the otoferlin interactome may only be required for a defined time span during cochlear maturation. Despite such open questions it is clear that otoferlin plays a crucial role in the inner ear's function with mutations resulting in auditory neuropathy (44). …”