Variants of OTOF and PJVK Genes in Chinese Patients with Auditory Neuropathy Spectrum Disorder

BACKGROUND: Mutations in OTOF and PJVK genes cause DFNB9 and DFNB59 types of hearing loss, respectively. The patients carrying pathogenic mutations in either of these genes may show the typical phenotype of auditory neuropathy spectrum disorder (ANSD). The aim of the present study was to identify OTOF and PJVK mutations in sporadic ANSD patients. METHODS AND FINDINGS: A total of 76 unrelated Chinese non-syndromic ANSD patients were sequenced on the gene OTOF and PJVK exon by exon. Variants were valued in 105 controls with normal hearing to verify the carrying rate. We identified one pathogenic mutation (c.1194T>A) and three novel, possibly pathogenic, variants (c.3570+2T>C, c.4023+1 G>A, and c.1102G>A) in the OTOF gene, and one novel, possibly pathogenic, variant (c.548G>A) in PJVK. Moreover, we found three novel missense mutations within the exons of OTOF. CONCLUSIONS: As we identified 4 and 1 possible pathogenic variants of the OTOF gene and the PJVK gene, respectively, we believe that screening in these genes are important in sporadic ANSD patients. The pathogenicity of these novel mutations needs further study because of their single heterozygous nature. Knowledge on the mutation spectra of these genes in Chinese would be beneficial in understanding the genetic character of this worldwide disease

Evolutionary patterns of two major reproduction candidate genes (Zp2 and Zp3) reveal no contribution to reproductive isolation between bovine species

<p>Abstract</p> <p>Background</p> <p>It has been established that mammalian egg zona pellucida (ZP) glycoproteins are responsible for species-restricted binding of sperm to unfertilized eggs, inducing the sperm acrosome reaction, and preventing polyspermy. In mammals, ZP apparently represents a barrier to heterospecific fertilization and thus probably contributes to reproductive isolation between species. The evolutionary relationships between some members of the tribe Bovini are complex and highly debatable, particularly, those involving <it>Bos </it>and <it>Bison </it>species for which interspecific hybridization is extensively documented. Because reproductive isolation is known to be a major precursor of species divergence, testing evolutionary patterns of ZP glycoproteins may shed some light into the speciation process of these species. To this end, we have examined intraspecific and interspecific genetic variation of two ZP genes (<it>Zp2 </it>and <it>Zp3</it>) for seven representative species (111 individuals) from the Bovini tribe, including five species from <it>Bos </it>and <it>Bison</it>, and two species each from genera <it>Bubalus </it>and <it>Syncerus</it>.</p> <p>Results</p> <p>A pattern of low levels of intraspecific polymorphism and interspecific divergence was detected for the two sequenced fragments each for <it>Zp2 </it>and <it>Zp3</it>. At intraspecific level, none of neutrality tests detected deviations from neutral equilibrium expectations for the two genes. Several haplotypes in both genes were shared by multiple species from <it>Bos </it>and <it>Bison</it>.</p> <p>Conclusions</p> <p>Here we argue that neither ancestral polymorphism nor introgressive hybridization alone can fully account for haplotype sharing among species from <it>Bos </it>and <it>Bison</it>, and that both scenarios have contributed to such a pattern of haplotype sharing observed here. Additionally, codon-based tests revealed strong evidence for purifying selection in the <it>Zp3 </it>coding haplotype sequences and weak evidence for purifying selection in the <it>Zp2 </it>coding haplotype sequences. Contrary to a general genetic pattern that genes or genomic regions contributing to reproductive isolation between species often evolve rapidly and show little or no gene flow between species, these results demonstrate that, particularly, those sequenced exons of the <it>Zp2 </it>and the <it>Zp3 </it>did not show any contribution to reproductive isolation between the bovine species studied here.</p

Auditory neuropathy.

Ten patients presented as children or young adults with hearing impairments that, by behavioural and physiological testing, were compatible with a disorder of the auditory portion of the VIII cranial nerve. Evidence of normal cochlear outer hair cell function was provided by preservation of otoacoustic emissions and cochlear microphonics in all of the patients. Auditory brainstem potentials showed evidence of abnormal auditory pathway function beginning with the VIII nerve: the potentials were absent in nine patients and severely distorted in one patient. Auditory brainstem reflexes (middle ear muscles; crossed suppression of otoacoustic emissions) were absent in all of the tested patients. Behavioural audiometric testing showed a mild to moderate elevation of pure tone threshold in nine patients. The extent of the hearing loss, if due to cochlear receptor damage, should not have resulted in the loss of auditory brainstem potentials. The shape of the pure tone loss varied, being predominantly low frequency in five patients, flat across all frequencies in three patients and predominantly high frequency in two patients. Speech intelligibility was tested in eight patients, and in six was affected out of proportion to what would have been expected if the pure tone loss were of cochlear origin. The patients were otherwise neurologically normal when the hearing impairment was first manifest. Subsequently, eight of these patients developed evidence for a peripheral neuropathy. The neuropathy was hereditary in three and sporadic in five. We suggest that this type of hearing impairment is due to a disorder of auditory nerve function and may have, as one of its causes, a neuropathy of the auditory nerve, occurring either in isolation or as part of a generalized neuropathic process

Auditory neuropathy.

Ten patients presented as children or young adults with hearing impairments that, by behavioural and physiological testing, were compatible with a disorder of the auditory portion of the VIII cranial nerve. Evidence of normal cochlear outer hair cell function was provided by preservation of otoacoustic emissions and cochlear microphonics in all of the patients. Auditory brainstem potentials showed evidence of abnormal auditory pathway function beginning with the VIII nerve: the potentials were absent in nine patients and severely distorted in one patient. Auditory brainstem reflexes (middle ear muscles; crossed suppression of otoacoustic emissions) were absent in all of the tested patients. Behavioural audiometric testing showed a mild to moderate elevation of pure tone threshold in nine patients. The extent of the hearing loss, if due to cochlear receptor damage, should not have resulted in the loss of auditory brainstem potentials. The shape of the pure tone loss varied, being predominantly low frequency in five patients, flat across all frequencies in three patients and predominantly high frequency in two patients. Speech intelligibility was tested in eight patients, and in six was affected out of proportion to what would have been expected if the pure tone loss were of cochlear origin. The patients were otherwise neurologically normal when the hearing impairment was first manifest. Subsequently, eight of these patients developed evidence for a peripheral neuropathy. The neuropathy was hereditary in three and sporadic in five. We suggest that this type of hearing impairment is due to a disorder of auditory nerve function and may have, as one of its causes, a neuropathy of the auditory nerve, occurring either in isolation or as part of a generalized neuropathic process