Screening mutations of OTOFgene in Chinese patients with auditory neuropathy, including a familial case of temperature-sensitive auditory neuropathy

Abstract

BackgroundMutations in OTOF gene, encoding otoferlin, cause DFNB9 deafness and non-syndromic auditory neuropathy (AN). The aim of this study is to identify OTOF mutations in Chinese patients with non-syndromic auditory neuropathy.Methods73 unrelated Chinese Han patients with AN, including one case of temperature sensitive non-syndromic auditory neuropathy (TS-NSRAN) and 92 ethnicity-matched controls with normal hearing were screened. Forty-five pairs of PCR primers were designed to amplify all of the exons and their flanking regions of the OTOF gene. The PCR products were sequenced and analyzed for mutation identification.ResultsFive novel possibly pathogenic variants (c.1740delC, c.2975_2978delAG, c.1194T>A, c.1780G>A, c.4819C > T) were identified in the group of 73 AN patients, in which two novel mutant alleles (c.2975_2978delAG + c.4819C > T) were identified in one Chinese TS-NSRAN case. Besides, 10 non-pathogenic variants of the OTOF gene were found in AN patients and controls.ConclusionsScreening revealed that mutations in the OTOF gene account for AN in 4 of 73(5.5%) sporadic AN patients, which shows a lower genetic load of that gene in contrast to the previous studies based on other populations. Notably, we found two novel mutant alleles related to temperature sensitive non-syndromic auditory neuropathy. This mutation screening study further confirms that the OTOF gene contributes to ANs and to TS-NSRAN.

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

“…Some mutations of this group deviate from the usual phenotype, however, suggesting a conditional or residual function of the mutated proteins. Among them, six mutations (p.I515T, p.G541S, p.G614E, p.R1080P, p.R1607W, and p.E1804del) have been reported in patients with a temperaturesensitive phenotype (Marlin et al, 2010;Matsunaga et al, 2012;Romanos et al, 2009;Varga et al, 2006;Wang et al, 2010). In addition, mutation p.E1700Q (which affects a residue in the linker region between domains C2E and C2F) results in progressive hearing loss that may range in severity from mild to profound (Chiu et al, 2010).…”

“…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). This wide range of frequencies may reflect an actual diversity between populations, as exemplified by the very high frequency seen in the Spanish population, which is probably related to a genetic founder effect for a single, very frequent mutation.…”

Auditory neuropathy — neural and synaptic mechanisms

“…It has the audiological signature of auditory neuropathy, and was suspected to reflect a defect of pre synaptic function in inner hair cells 42 soon after its char acterization. During the past decade, rare cases of less severe otoferlinrelated auditory synapt opathies have been reported [43][44][45][46][47] . In some patients with these disorders, an elevation in body temperature (even by only 1 o C) as a result of exercise or fever [43][44][45][46][47] can exacerbate the condi tion into complete deafness accompanied by tinnitus.…”

“…To date, six OTOF mutations have been associated with temperature sensitive deafness [43][44][45][46][47] . The 'pachanga' missense otoferlin mouse mutant, generated in a forward genetic screen 61 , provided important additional insight into the function of otoferlin.…”

Research of genetic bases of hereditary non-syndromic hearing loss

“…It was determined that mutations in this gene led to non-syndromic recessive auditory neuropathy, which is a special type of hearing loss. Up to this point, more than 40 pathologic allelic variants have been reported (39).…”