Down-regulation of EVA1A by miR-103a-3p promotes hepatocellular carcinoma cells proliferation and migration.

BACKGROUND: EVA1A (Eva-1 homolog A), a novel protein involved in autophagy and apoptosis, functions as a tumor suppressor in some human primary cancers, including hepatocellular carcinoma (HCC). While it is consistently downregulated in several cancers, its involvement in hepatocarcinogenesis is still largely unknown. METHODS: We first detected the expression of EVA1A in HCC tissues and cell lines using RT‒qPCR, immunohistochemistry and western blotting and detected the expression of miR-103a-3p by RT‒qPCR. Then, bioinformatics prediction, dual-luciferase reporter gene assays and western blotting were used to screen and identify the upstream microRNA of EVA1A. After manipulating the expression of miR-103a-3p or EVA1A, wound healing, invasion, proliferation, colony formation, apoptosis, autophagy, mitosis and mitochondrial function assays, including mitochondrial membrane potential, ROS and ATP production assays, were performed to investigate the functions of miR-103a-3p targeting EVA1A in HCC cells. Apoptosis-related proteins were assessed by RT‒qPCR (TP53) or western blotting (TP53, BAX, Bcl-2 and caspase-3). Autophagy level was evaluated by observing LC3 puncta and examining the protein levels of p62, Beclin1 and LC3-II/I. RESULTS: We found that EVA1A expression was decreased while miR-103a-3p expression was increased in HCC tissues and cell lines and that their expression was inversely correlated in HCC patients. The expression of miR-103a-3p was associated with HCC tumor stage and poor prognosis. miR-103a-3p could target EVA1A through direct binding to its 3'-UTR and suppress its expression. Overexpression of miR-103a-3p significantly downregulated the expression of EVA1A, TP53 and BAX, upregulated the JAK2/STAT3 pathway and promoted HCC cell migration, invasion and proliferation, while repression of miR-103a-3p dramatically upregulated the expression of EVA1A, TP53, BAX and cleaved-caspase-3, inhibited HCC cell migration, invasion and proliferation, and caused mitochondrial dysfunction and apoptosis. Overexpression of EVA1A significantly attenuated the cancer-promoting effects of miR-103a-3p in HCC cells, while knockdown of EVA1A alleviated the mitochondrial dysfunction and apoptosis caused by miR-103a-3p inhibition. Overexpression of EVA1A did not induce significant changes in autophagy levels, nor did it affect G2/M transition or mitosis. CONCLUSION: These findings indicate that the downregulation of the tumor suppressor EVA1A by miR-103a-3p potentially acts as a key mediator in HCC progression, mainly by inhibiting apoptosis and promoting metastasis. The miR-103a/EVA1A/TP53 axis provides a new potential diagnostic and therapeutic target for HCC treatment.

Genetic basis of Y-linked hearing impairment.

A single Mendelian trait has been mapped to the human Y chromosome: Y-linked hearing impairment. The molecular basis of this disorder is unknown. Here, we report the detailed characterization of the DFNY1 Y chromosome and its comparison with a closely related Y chromosome from an unaffected branch of the family. The DFNY1 chromosome carries a complex rearrangement, including duplication of several noncontiguous segments of the Y chromosome and insertion of ∼160 kb of DNA from chromosome 1, in the pericentric region of Yp. This segment of chromosome 1 is derived entirely from within a known hearing impairment locus, DFNA49. We suggest that a third copy of one or more genes from the shared segment of chromosome 1 might be responsible for the hearing-loss phenotype.

Structure-activity relationship of polypyridyl ruthenium(II) complexes as DNA intercalators, DNA photocleavage reagents, and DNA topoisomerase and RNA polymerase inhibitors.

To investigate the relationship between the molecular structure and biological activity of polypyridyl Ru(II) complexes, such as DNA binding, photocleavage ability, and DNA topoisomerase and RNA polymerase inhibition, six new [Ru(bpy)(2)(dppz)](2+) (bpy=2,2'-bipyridine; dppz=dipyrido[3,2-a:2,',3'-c]phenazine) analogs have been synthesized and characterized by means of (1)H-NMR spectroscopy, mass spectrometry, and elemental analysis. Interestingly, the biological properties of these complexes have been identified to be quite different via a series of experimental methods, such as spectral titration, DNA thermal denaturation, viscosity, and gel electrophoresis. To explain the experimental regularity and reveal the underlying mechanism of biological activity, the properties of energy levels and population of frontier molecular orbitals and excited-state transitions of these complexes have been studied by density-functional theory (DFT) and time-depended DFT (TDDFT) calculations. The results suggest that DNA intercalative ligands with better planarity, greater hydrophobicity, and less steric hindrance are beneficial to the DNA intercalation and enzymatic inhibition of their complexes.

Spatial and temporal change of tetrabromobisphenol A and hexabromocyclododecane in mangrove sediments from the Pearl River Estuary, South China.

Spatial and temporal trends of tetrabromobisphenol (TBBPA) and hexabromocyclododecane (HBCD) in mangrove sediments from the Pearl River Estuary (PRE) in South China were evaluated. Concentrations of TBBPA and HBCD in mangrove sediments ranged from 0.23 to 13.3 and 0.36 to 54.7 ng g-1 dry weight. The highest TBBPA concentration was seen in Guangzhou mangrove wetland near a dockyard and a ferry terminal where TBBPA is utilized in the coatings for the shipbuilding industry. The rapid development of building might elucidate the higher concentrations of HBCD in Shenzhen mangrove sediments. γ-HBCD and α-HBCD was the two main diastereoisomer of HBCD in mangrove sediments with contributions of 56.1 % and 34.0 %. Sediments from the three PRE mangrove ecosystems were selectively enriched for (-)-γ-HBCD. TBBPA concentrations in mangrove sediments from Guangzhou rose during 2012-2015 and declined from 2015 to 2021. HBCD concentrations in the PRE mangrove sediments exhibited an increasing trend from 2012 to 2021.

Bioaccumulation and Biomagnification of Polychlorinated Biphenyls and Dichlorodiphenyltrichloroethane in Biota from Qilianyu Island, South China Sea.

Six biota species were collected from Qilianyu Island, South China Sea to determine the bioaccumulation and biomagnification of polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane and its metabolites (DDTs). Concentrations of ΣPCBs and ΣDDTs in biota from Qilianyu Island ranged from 6.88 to 519.1 ng/g lipid weight (lw) and 7.0 to 19,413 ng/g lw, respectively. Significant differences for PCBs and DDTs concentrations were found among the six biota species from Qilianyu Island. The levels of PCBs and DDTs in intermediate egret were significantly higher than the other five biota species, which can be attributed to their different feeding and living habits. Significantly negative relationships between concentrations of PCBs and DDTs and δ13C values in the six biota species confirmed that dietary source is an important factor to determine the levels of PCBs and DDTs in biota species. ΣPCBs, ΣDDTs, PCB 28/31, PCB 52, and p,p'-DDE were biomagnified in the biota species from Qilianyu Island, and native species are suitable for studying the biomagnification of the contaminants. The toxic equivalent concentrations in birds from Qilianyu Island were significantly and positively correlated with PCBs concentrations, indicating that high concentrations of non- and mono-ortho-PCB congeners may induce adverse effects on bird species.

The Degradation of TMEM166 by Autophagy Promotes AMPK Activation to Protect SH-SY5Y Cells Exposed to MPP.

Neuronal oxidative stress caused by mitochondrial dysfunction plays a crucial role in the development of Parkinson's disease (PD). Growing evidence shows that autophagy confers neuroprotection in oxidative-stress-associated PD. This work aims to investigate the involvement of TMEM166, an endoplasmic-reticulum-localized autophagy-regulating protein, in the process of PD-associated oxidative stress through the classic cellular PD model of neuroblastoma SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+). Reactive oxygen species (ROS) production and mitochondrial membrane potential were checked to assess the oxidative stress induced by MPP+ and the cellular ATP generated was determined to evaluate mitochondrial function. The effect on autophagy induction was evaluated by analyzing p62 and LC3-II/I expression and by observing the LC3 puncta and the colocalization of LC3 with LAMP1/ LAMP2. The colocalization of mitochondria with LC3, the colocalization of Tom20 with LAMP1 and Tom20 expression were analyzed to evaluate mitophagy. We found that TMEM166 is up-regulated in transcript levels, but up-regulated first and then down-regulated by autophagic degradation in protein levels upon MPP+-treatment. Overexpression of TMEM166 induces mitochondria fragmentation and dysfunction and exacerbates MPP+-induced oxidative stress and cell viability reduction. Overexpression of TMEM166 is sufficient to induce autophagy and mitophagy and promotes autophagy and mitophagy under MPP+ treatment, while knockdown of TMEM166 inhibits basal autophagic degradation. In addition, overexpressed TMEM166 suppresses AMPK activation, while TMEM166 knockdown enhances AMPK activation. Pharmacological activation of AMPK alleviates the exacerbation of oxidative stress induced by TMEM166 overexpression and increases cell viability, while pharmacological inhibition mitophagy aggravates the oxidative stress induced by MPP+ treatment combined with TMEM166 overexpression. Finally, we find that overexpressed TMEM166 partially localizes to mitochondria and, simultaneously, the active AMPK in mitochondria is decreased. Collectively, these findings suggest that TMEM166 can translocate from ER to mitochondria and inhibit AMPK activation and, in response to mitochondrial oxidative stress, neuronal cells choose to up-regulate TMEM166 to promote autophagy/mitophagy; then, the enhancing autophagy/mitophagy degrades the TMEM166 to activate AMPK, by the two means to maintain cell survival. The continuous synthesis and degradation of TMEM166 in autophagy/mitochondria flux suggest that TMEM166 may act as an autophagy/mitochondria adaptor.

Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China.

The myosin VIIA (MYO7A) gene encodes a protein classified as an unconventional myosin. Mutations within MYO7A can lead to both syndromic and non-syndromic hearing impairment in humans. Among different mutations reported in MYO7A, only five led to non-syndromic sensorineural deafness autosomal dominant type 11 (DFNA11). Here, we present the clinical, genetic and molecular characteristics of two large Chinese DFNA11 families with either high- or low-frequency hearing loss. Affected individuals of family DX-J033 have a sloping audiogram at young ages with high frequency are most affected. With increasing age, all test frequencies are affected. Affected members of family HB-S037 present with an ascending audiogram affecting low frequencies at young ages, and then all frequencies are involved with increasing age. Genome-wide linkage analysis mapped the disease loci within the DFNA11 interval in both families. DNA sequencing of MYO7A revealed two novel nucleotide variations, c.652G > A (p.D218N) and c.2011G > A (p.G671S), in the two families. It is for the first time that the mutations identified in MYO7A in the present study are being implicated in DFNA11 in a Chinese population. For the first time, we tested electrocochleography (ECochG) in a DFNA11 family with low-frequency hearing loss. We speculate that the low-frequency sensorineural hearing loss in this DFNA11 family was not associated with endolymphatic hydrops.

Effects of Atmospheric Fine Particulate Matter and Its Carrier Microbes on Pulmonary Microecology in Patients with COPD.

Objective: The aim of this paper was to analyse the influence of atmospheric fine particulate matter (AFPM) and atmospheric microorganisms on the pulmonary microecology of chronic obstructive pulmonary disease (COPD) patients in northeast China. Methods: Collected bronchoalveolar lavage fluid (BALF) of COPD patients in the high-risk period (group A) and low-risk period (group B) of AFPM inhalation and samples of AFPM in the same time range (group C) were collected. DNA sample sequencing, the bacterial abundance, and diversity bioinformatics of BALFs were performed by methods of Illumina MiSeq™ platform and Mothur and Uclust. Results: A total of 58 samples were sequenced, including 22 samples from group A, 26 samples from group B and 10 samples from group C. A total of 2,005,790 bacterial sequences and 34,256 bacterial numbers were detected. Group B had the highest bacterial diversity of the three groups. Group B also had the highest bacterial abundance index value. There were differences in the classification of bacterial colonies for the three groups at the genus level. The types of bacteria in group C were more numerous than other groups, and group B was higher than group A, which indicates that there were more bacteria in BALF during the high-risk period of AFPM inhalation. The detection rates of Streptococcus, Mycoplasma, Roche, Pushia, Chlamydia trachomatis and Brucella for group C were significantly higher than group A. The COG and KEGG databases' difference analysis results for the bacterial gene function abundance of group A and group B were 40.7% in group A and 38.9% in group B (R=0.098, P=0.006). The human disease abundance in group A and group B was 1.16% and 1.12%, respectively (P>0.05). Conclusion: The increase in the concentration of AFPM can increase the diversity and abundance of bacteria in the BALF of stable COPD patients. Clinical Trial Registration Number: 2020XS04-02.

Environmental and Genetic Factors in the Pathogenesis of COPD in the Road-Working Population.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a typical heterogeneous condition caused by environmental and genetic risk factors. OBJECTIVES: We investigated extrinsic (environmental) and intrinsic (genetic) factors contributing to the development of COPD in a nonsmoker road-working population in Northeast China. METHOD: The target population was divided into a COPD group and an exposed control group. Another healthy nonroad working nonsmoker control group was also included for environmental factor comparison. Peripheral blood was collected and analyzed using inductively coupled plasma mass spectrometry for inorganic elements of PM2.5, and microarray, rt-PCR, and Multiplex ELISA for genetic factors. RESULTS: Forty-three COPD road workers, thirty-nine non-COPD road workers, and 52 age and gender-matched healthy nonroad workers were enrolled. There were significantly higher levels in all 24 inorganic elements in the COPD group compared with the healthy control group except potassium and manganese, while the majority of inorganic elements were similar between the COPD group and the exposed control group except in aluminum and cobalt. There were 39 genes showing significant differences between the COPD group and the exposed control group. Collagen, type XV, alpha 1 (COL15A1), Meis homeobox 1 (MEIS1), carbonyl reductase 3 (CBR3), and amine oxidase, copper containing 3 (AOC3) were confirmed by rt-PCR to be differentially expressed. Their correlations with blood cytokines were also evaluated. CONCLUSIONS: Aluminum might contribute to the development of COPD in the road-working population. CBR3 and AOC3 seem expressed in different patterns than previously reported, evidenced by their correlation with proinflammatory and anti-inflammatory cytokines.

Distinct and novel SLC26A4/Pendrin mutations in Chinese and U.S. patients with nonsyndromic hearing loss.

Mutations of the human SLC26A4/PDS gene constitute the most common cause of syndromic and nonsyndromic hearing loss. Definition of the SLC26A4 mutation spectrum among different populations with sensorineural hearing loss is important for development of optimal genetic screening services for congenital hearing impairment. We screened for SLC26A4 mutations among Chinese and U.S. subjects with hearing loss, using denaturing HPLC (DHPLC) and direct DNA sequencing. Fifty-two of 55 Chinese subjects with deafness accompanied by enlargement of the vestibular aqueduct (EVA) exhibited at least one mutant SLC26A4 allele, whereas SLC26A4 mutations were found in only 2 of 116 deaf Chinese patients without EVA. The spectrum of SLC26A4 mutations differed among Chinese and U.S. subjects and included 10 previously unreported SLC26A4 variants: 4 in the Chinese population (p.E303Q, p.X329, p.X467, p.X573) and 6 in the U.S. population (p.V250A, p.D266N, p.F354S, p.D697A, p.K715N, p.E737D). Among the seven novel in-frame missense mutations, five encoded SLC26A4 proteins with substantially reduced Cl(-)/anion exchange activity as expressed and measured in Xenopus oocytes, but four of these were sufficiently active to allow study of anion selectivity. The only mutant polypeptide exhibiting complete loss of anion exchange function, p.E303Q, was expressed at or near the oocyte surface at near-wild-type levels. Two variants, p.F354S and p.E737D, displayed selective reduction in relative rate of Cl(-)/HCO(3)(-) exchange compared with similarly measured rates of Cl(-)/Cl(-) and Cl(-)/I(-) exchange. Our data show that mutation analysis of the SLC26A4 gene is of high diagnostic yield among subjects with deafness and bilateral EVA in both China and the U.S. However, the pathogenicity of monoallelic SLC26A4 gene variants in patients with hearing loss remains unclear in many instances.

Long-term white noise exposure-induced mtDNA deletion in the auditory system.

CONCLUSION: Long-term exposure to broadband noise can lead to increased levels of mtDNA4834 deletion in the auditory system in rats. OBJECTIVE: This study aimed to determine if long-term noise exposure induces mtDNA deletion in the auditory system. MATERIALS AND METHODS: Wistar rats aged 3 months (n =20) were exposed to 110 dB SPL white noise, 4 h per day, for 20 consecutive days. The control group included Wistar rats of the same age (n=20) with no noise exposure. Auditory brainstem responses (ABRs) were tested as an indicator of hearing function. The cochlea, cochlear nucleus, temporal lobe brain tissue, and blood specimens were collected for DNA extraction. The mtDNA was amplified to identify the highly conserved ND1 segment, as well as mtDNA4834 deletion. RESULTS: Animals in the noise-exposed group demonstrated permanent loss of auditory sensitivity following noise exposure compared with the control animals (p<0.01). The majority of animals in the noise-exposed group demonstrated mtDNA4834 deletion in cochlea, cochlear nucleus and temporal lobe brain tissues, while only a few in the control group showed such deletion (p<0.01). In contrast, mtDNA4834 deletion in blood specimens was identified at an extremely low rate in both the noise-exposed and the control groups.

[Visual evoked potentials in adults with migrainous vertigo].

OBJECTIVE: To investigate the visual evoked potentials in adults with migrainous vertigo (MV). METHODS: Totally 113 patients with MV were enrolled from vertigo clinic. Patients received necessary laboratory examinations as well as pattern visual evoked potential (PVEP) testing. RESULTS: Definite MV accounted for 46.9% (53/113) and probable MV accounted for 53.1% (60/113). Among 74 patients who received PVEP, the results were normal in 35 patients (47.3%) and abnormal in 39 patients (52.7%). The abnormal manifestations included lowered N75-P100 amplitude, elongated latency of P100, and lowered N75-P100 amplitude combined with delayed latency of P100. Seven patients with MV had unilateral lowered N75-P100 amplitude and 4 had bilateral abnormal amplitude. Nine patients had unilateral delayed latency of P100 and 11 had bilateral abnormal latency. Four patients had unilateral and 4 had bilateral abnormal N75-P100 amplitude and latency of P100. CONCLUSIONS: MV patients usually have abnormal PVEP. PVEP may become a useful electrophysiological test in the diagnosis of MV.

Primary tumours of the facial nerve: diagnostic and surgical treatment experience in Chinese PLA General Hospital.

CONCLUSIONS: The commonest manifestation of facial nerve tumours was facial paralysis, followed by hearing loss. During tumour resection facial nerve continuity should be maintained and reconstructed in one stage wherever possible. If this is not a viable option, second-stage surgery should be performed as soon as possible after surgery. OBJECTIVE: To summarize the clinical characteristics of tumours of the facial nerve and discuss their diagnosis and treatment. PATIENTS AND METHODS: Twenty-two cases of primary facial nerve tumours were reviewed. These cases were confirmed pathologically and treated in the Chinese PLA General Hospital during the period 1986-2003, where the clinical manifestations, diagnosis and treatment of this series were analysed. RESULTS: Among the 22 cases, 14 were facial neurilemmomas, 6 were facial neurofibromas and 2 were facial nerve haemangiomas. The commonest presenting symptom in all cases was facial paralysis (14/22) followed by hearing loss (10/22). Facial paralysis was also the commonest sign of a facial nerve tumour (18/22), followed by a swollen mass in the tympanic cavity (8/22) and a swollen mass in the external auditory canal (5/22). The 22 tumours were totally resected surgically. The function of the facial nerve was normal (grade I) in two cases where the integrity of the nerve was preserved during the operation, grade II in one case and grade III in another case where it was possible to maintain partial continuity of the facial nerve. The facial nerve was reconstructed in one stage when the tumours were resected, with facial-great auricular-facial nerve cable grafting (10 cases) and facial-lateral femoral cutaneous-facial nerve cable grafting (1 case). The facial nerve function consequently recovered to grade II-IV. The second stage facial-hypoglossal nerve anastomosis was carried out in two cases, and facial function consequently recovered to grade II in one case at 3 years and grade III in another with 2 years follow-up. In five cases, the facial nerve remained discontinuous and the facial nerve function showed no recovery (grade VI).

Nonsense mutations in the PAX3 gene cause Waardenburg syndrome type I in two Chinese patients.

BACKGROUND: Waardenburg syndrome type I (WS1) is an autosomal dominant disorder characterized by sensorineural hearing loss, pigmental abnormalities of the eye, hair and skin, and dystopia canthorum. The gene mainly responsible for WS1 is PAX3 which is involved in melanocytic development and survival. Mutations of PAX3 have been reported in familiar or sporadic patients with WS1 in several populations of the world except Chinese. In order to explore the genetic background of Chinese WS1 patients, a mutation screening of PAX3 gene was carried out in four WS1 pedigrees. METHODS: A questionnaire survey and comprehensive clinical examination were conducted in four Chinese pedigrees of WS1. Genomic DNA from each patient and their family members was extracted and exons of PAX3 were amplified by PCR. PCR fragments were ethanol-purified and sequenced in both directions on an ABI_Prism 3100 DNA sequencer with the BigDye Terminator Cycle Sequencing Ready Reaction Kit. The sequences were obtained and aligned to the wild type sequence of PAX3 with the GeneTool program. RESULTS: Two nonsense PAX3 mutations have been found in the study population. One is heterozygous for a novel nonsense mutation S209X. The other is heterozygous for a previously reported mutation in European population R223X. Both mutations create stop codons leading to truncation of the PAX3 protein. CONCLUSIONS: This is the first demonstration of PAX3 mutations in Chinese WS1 patients and one of the few examples of an identical mutation of PAX3 occurred in different populations.

[Mutation of GJB2 gene in nonsyndromic hearing impairment patients: analysis of 1190 cases].

OBJECTIVE: To analyze the sequence of GJB2 gene in nonsyndromic hearing impairment (NSHI) patients in China. METHODS: Peripheral blood samples were obtained from 1190 NSHI patients randomly selected from the Deaf and Mute Schools of Beijing, Hebei, Heilongjiang, Jilin, Inner Mongolia, Shanxi, Henan, Hubei, Shaanxi, Gansu, Ningxia, Qinghai, Anhui, Jiangsu, Shanghai, Fujian, Guangdong, and Guangxi, and 301 children with normal hearing level used as controls. Genomic DNA was extracted by extraction kits to undergo polymerase chain reaction and sequencing so as to detect the mutations of GJB2 gene. RESULTS: Sixteen pathogenic mutations of GJB2 gene were found, the most common of which included 235delC, 299-300delAT, and 176del16bp. 250 patients (21.05%) carried definite GJB2 mutations, 245 of which (98%) carried at least one of these 3 common mutations. 222 of the 250 patients (88.80%) carried the mutation 235delC with a detection rate of 18.66%. 62 of the 250 patients (24.80%) carried the mutation 299-300delAT with a detection rate of 5.21%. 19 of the 250 patients (7.60%) carried the mutation 176del16bp with a detection rate of 1.60%. The detection rates of these 3 mutations in the NSHI patients were all significantly higher than those among the controls (all P<0.01). CONCLUSION: The hot spot of GJB2 gene mutations in Chinese NSHI patients is 235delC, followed by 299-300delAT and 176del16bp. These results establish a fundamental basis for drawing a spectrum of GJB2 gene mutation among Chinese population.

A novel mutation of POU3F4 causes congenital profound sensorineural hearing loss in a large Chinese family.

OBJECTIVES/HYPOTHESIS: It is known that approximately 5% of congenital profound hearing impaired cases are inherited in X-linked inheritance. This study aimed at identifying its underlying molecular determinant(s) using a large, five-generation Chinese family with multiple familial cases. STUDY DESIGN: Model-based linkage analysis and positional cloning. METHODS: Model-based genetic linkage analyses were performed with the use of microsatellite polymorphisms to determine disease locus. Mutation screening was performed within the family and unrelated population-based controls to establish molecular evidence as to what caused the specific X-linked inheritance pattern in the family. RESULTS: Clinical investigations of the pedigree demonstrated the extremely high penetrance in the male members but no penetrance in the female members. Linkage analyses mapped the disease to the chromosomal region Xq13.I-Xq23 (maximum X-linkage logarithm of odds score = 3.27). Mutation screening of the candidate genes in the linkage region by direct sequencing revealed a de novo missense substitution (925T>C) in the well-known deaf gene. POU3F4. Direct sequencing on 240 unrelated controls did not detect any mutation. CONCLUSIONS: Multiple analysis approaches demonstrated that these disorders in the family were caused by a founder mutation in the POU3F4 gene. Our findings provided confirmatory molecular evidence to support that development of congenital profound sensorineural hearing loss in the Chinese population results from a novel mutation in the same gene.

Relationship between the external aperture and hearing loss in large vestibular aqueduct syndrome.

BACKGROUND: Large vestibular aqueduct syndrome (LVAS) is a major cause of hearing loss in childhood. This study aimed at measuring external aperture of enlargement of the vestibular aqueduct (EVA) and analyzing relationship between the size of external aperture and hearing loss. METHODS: Diagnostic criteria of LVAS were based on hearing loss and CT images. CT images of temporal bone of 100 LVAS patients were collected and 60 control subjects were reviewed retrospectively in the past 10 years. A battery of audiometric and vestibular function tests were performed. The width of the vestibular aqueduct (VA) was measured on axial CT images of the temporal bone. RESULTS: One hundred patients (65 men, 35 women) were diagnosed as having the isolated EVA. Hearing loss mostly occurred in early childhood. The diagnosis age of LVAS was 7.7 years on average. The causes of hearing loss could not be confirmed by initial consult. Typically, audiometric curve is the high-frequency down-sloping configuration. 92% of the cases had severe or profound sonsorineural hearing loss (SNHL). The mean size of the external aperture was (7.5 +/- 1.2) mm in present LVAS. Statistical analysis showed that the degree of hearing loss is unrelated to the width of VA. CONCLUSIONS: LVAS is a distinct clinical entity characterized by fluctuating, progressive SNHL. The degree of hearing loss is unrelated to the size of external aperture of VA. The protective management and hearing aid have become the main therapies. The cochlear implantation might be performed if the hearing loss affected learning at school.

SMAD4 Defect Causes Auditory Neuropathy Via Specialized Disruption of Cochlear Ribbon Synapses in Mice.

More than 100 genes have been associated with deafness. However, SMAD4 is rarely considered a contributor to deafness in humans, except for its well-defined role in cell differentiation and regeneration. Here, we report that a SMAD4 defect in mice can cause auditory neuropathy, which was defined as a mysterious hearing and speech perception disorder in human for which the genetic background remains unclear. Our study showed that a SMAD4 defect induces failed formation of cochlear ribbon synapse during the earlier stage of auditory development in mice. Further investigation found that there are nearly normal morphology of outer hair cells (OHCs) and post-synapse spiral ganglion nerves (SGNs) in SMAD4 conditional knockout mice (cKO); however, a preserved distortion product of otoacoustic emission (DPOAE) and cochlear microphonic (CM) still can be evoked in cKO mice. Moreover, a partial restoration of hearing detected by electric auditory brainstem response (eABR) has been obtained in the cKO mice using electrode stimuli toward auditory nerves. Additionally, the ribbon synapses in retina are not affected by this SMAD4 defect. Thus, our findings suggest that this SMAD4 defect causes auditory neuropathy via specialized disruption of cochlear ribbon synapses.

[Clinical features of a Chinese pedigree with Waardenburg syndrome type 2].

OBJECTIVE: To investigate detailed clinical features of a Chinese pedigree with Waardenburg syndrome type 2. METHODS: Members of this pedigree were interviewed to identify personal or family medical histories of hearing loss, the use of aminoglycosides, and other clinical abnormalities by filling questionnaire. The audiological and other clinical evaluations of the proband and other members of this family were conducted, including pure-tone audiometry, immittance and auditory brain-stem response and ophthalmological, dermatologic, hair, temporal bone CT examinations. RESULTS: This family is categorized as Waardenburg syndrome type 2 according to its clinical features. It's an autosomal dominant disorder with incomplete penetrance. The clinical features varied greatly among family members and characterized by sensorineural hearing loss, heterochromia irides, freckle on the face and premature gray hair. Hearing loss can be unilateral or bilateral, congenital or late onset in this family. CONCLUSION: This Chinese family has some unique clinical features comparing with the international diagnostic criteria for Waardenburg syndrome. This study may provide some evidences to amend the diagnostic criteria for Waardenburg syndrome in Chinese population.

Spontaneous and Partial Repair of Ribbon Synapse in Cochlear Inner Hair Cells After Ototoxic Withdrawal.

Ototoxicity is one of the major causes of sensorineural deafness. However, it remains unclear whether sensorineural deafness is reversible after ototoxic withdrawal. Here, we report that the ribbon synapses between the inner hair cells (IHCs) and spiral ganglion nerve (SGN) fibers can be restored after ototoxic trauma. This corresponds with hearing restoration after ototoxic withdrawal. In this study, adult mice were injected daily with a low dose of gentamicin for 14 consecutive days. Immunostaining for RIBEYE/CtBP2 was used to estimate the number and size of synaptic ribbons in the cochlea. Hearing thresholds were assessed using auditory brainstem responses. Auditory temporal processing between IHCs and SGNs was evaluated by compound action potentials. We found automatic hearing restoration after ototoxicity withdrawal, which corresponded to the number and size recovery of synaptic ribbons, although both hearing and synaptic recovery were not complete. Thus, our study indicates that sensorineural deafness in mice can be reversible after ototoxic withdrawal due to an intrinsic repair of ribbon synapse in the cochlea.