Han Chinese population takes about 20% of the entire global population, and distributes mainly in China. This population has its unique genetic background, and that is why Han Chinese in Beijing (CHB) was chosen by the international HapMap project as one of the four populations for DNA analysis, the result of which http://www.hapmap.org/
also showed the great variation between CHB and the other three populations. So far, the screen of OTOF
gene has been preformed on Spanish, Caucasians, Pakistani and Brazilian populations[10
], however, it is not well studied on Han Chinese population.
In the present study, we performed a mutation screening of the OTOF
gene within 73 unrelated AN patients and 92 controls in Chinese population. Of those, 5 novel possibly pathogenic variants were identified in four AN patients with the mutation frequency of 5.5% (4 of 73) and revealed a quiet different mutation spectrum and a comparatively lower genetic load of that gene in Chinese AN patients. Surprisingly, none of the pathologic allelic variants reported previously were found in the collected Chinese Han sample, including the most frequently reported one, Q829X, which was shown to be responsible for at least 3% of NSHL cases in some populations[11
]. Close scrutiny of the previous reports revealed that most of the studies were based on Spanish, Caucasian and Pakistani populations with the mutation frequencies varying from 5.1% to 3.1% to 2.3% respectively[11
], which proportion was even higher in NSRAN cases[10
]. According to haplotype data of the international HapMap project, the CHB displayed a notable difference from the other three groups at the 2p22-p23 loci where the OTOF
gene is located. These data suggested that great discrepancies in the mutation spectra of the OTOF
gene could be observed in different ethnic populations. Our perception is supported by two recent study that reported in Pakistani[16
] and Brazilian[10
] populations, in which was found a quite different mutation spectrum from those previously reported as well.
Another striking finding in our study was the occurrence of two novel mutant alleles in the TS-NSRAN patient, thus being the second reported case of the temperature-sensitive phenotype related to OTOF
gene mutations in the literature. Temperature-sensitive auditory neuropathy (TS-AN) was first reported in 1998[27
], and the responsible heterozygous mutation of the OTOF
gene, p.I515T, was first found in two affected children and their father[23
], but no available information on their maternal mutation was in the study. However, in our study, the patient's two mutant alleles were clearly identified from both parents. The mutation of c.2975_2978delAG led to a premature stop codon that was transmitted from the maternally inherited mutation, and which could trigger the nonsense-mediated decay (NMD) response. Even if the truncated protein could be produced, it could not function well, because the c.2975_2978delAG occurred at the beginning of the C2D domain and the last four C2 domains are predicted to be critical for protein function[8
]. The paternally inherited mutation p.R1607W is a missense mutation, and p.R1607W was the consequence of replacement of an alkaline arginine to a neutral tryptophan. The manifestation of TS-AN described here may be caused by a cumulative effect of the frameshift combined with the missense mutations. The combined effect of the two mutations could interfere with normal production of otoferlin protein.
Excepting NSRAN patient, each of the other three patients with pathogenic variants (Table ) carries only one copy of an OTOF
variants, which we assume are causative factor for their disease. In previous study, there is familial case linked to OTOF gene but with single heterozygous variant[9
]. Moreover, among the recessive hereditary hearing loss genes, the high prevalence genes of GJB2 or SLC26A4 also can be found only one mutant allele in the congenital hearing loss or enlarged vestibular aqueduct syndrome patients. Multi-gene related disease and epigenetic imprinting could be two possible explanations. Further studies to elucidate the compound heterozygous mutation interactions and the role of those possibly pathogenic variants to OTOF
gene and AN are worth conducting. Additionally, considering the comparative lower genetic load of the OTOF
gene, other genetic or environmental etiology of AN should be searched in Chinese population.