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Alternative splicing of inner-ear-expressed genes

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Frontiers of Medicine 2016年第3期10卷 250-257页

作者： Yanfei Wang Yueyue Liu Hongyun Nie Xin Ma Zhigang Xu Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology School of Life Sciences Shandong University Jinan 250100 China School of Control Science and Engineering Shandong University Jinan 250061 China

Alternative splicing plays a fundamental role in the development and physiological function of the inner ear. Inner-ear-specific gene splicing is necessary to establish the identity and maintain the function of the inner ear. For example, exon 68 of Cadherin 23 （Cdh23） gene is subject to inner-ear-specific alternative splicing, and as a result, Cdh23（＋ 68） is only expressed in inner ear hair cells. Alternative splicing along the tonotopic axis of the cochlea contributes to frequency tuning, particularly in lower vertebrates, such as chickens and turtles. Differential splicing of Kcnmal, which encodes for the a subunit of the Ca2＋-activated K~ channel （BK channel）, has been suggested to affect the channel gating properties and is important for frequency tuning. Consequently, deficits in alternative splicing have been shown to cause hearing loss, as we can observe in Bronx Waltzer Cov） mice and Sfswap mutant mice. Despite the advances in this field, the regulation of alternative splicing in the inner ear remains elusive. Further investigation is also needed to clarify the mechanism of hearing loss caused by alternative splicing deficits.

关键词： alternative splicing inner ear hearing loss hair cells

Disruption of the autism-related gene Pak1 causes stereocilia disorganization,hair cell loss,and deafness in mice

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Journal of Genetics and Genomics 2021年第4期48卷 324-332页

作者： Cheng Cheng Yilin Hou Zhonghong Zhang Yanfei Wang Ling Lu Liyan Zhang Pei Jiang Song Gao Qiaojun Fang Chengwen Zhu Junyan Gao Xufeng Liu Wei Xie Zhengping Jia Zhigang Xu Xia Gao Renjie Chai Department of Otolaryngology Head and Neck Surgery Affiliated Drum Tower Hospital of Nanjing University Medical SchoolJiangsu Provincial Key Medical Discipline(Laboratory)NanjingJiangsu 210008China Research Institute of Otolaryngology NanjingJiangsu 210008China State Key Laboratory of Bioelectronics School of Life Sciences and TechnologyJiangsu Province High-Tech Key Laboratory for Bio-Medical ResearchSoutheast UniversityNanjingJiangsu 210096China Department of Military Psychology Fourth Military Medical UniversityXi'anShanxi 710032China Department of Ophthalmology Zhongda Hospital Southeast UniversityNanjingJiangsu 210009China Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology Shandong University School of Life SciencesQingdaoShandong 266237China Jiangsu Rehabilitation Research Center for hearing and Speech Impairment NanjingJiangsu 210004China Neurosciences&Mental Health The Hospital for Sick ChildrenTorontoOntario M5G 1X8Canada Department of Physiology Faculty of MedicineUniversity of TorontoTorontoOntario M5S 2E8Canada Co-Innovation Center of Neuroregeneration Nantong UniversityNantongJiangsu 226019China Institute for Stem Cell and Regeneration Chinese Academy of ScienceBeijing 100864China Beijing Key Laboratory of Neural Regeneration and Repair Capital Medical UniversityBeijing 100069China

Several clinical studies have reported that hearing loss is correlated with autism in children.However,little is known about the underlying mechanism between hearing loss and autism.p21-activated kinases(PAKs)are a family of serine/threonine kinases that can be activated by multiple signaling molecules,particularly the Rho family of small GTPases.Previous studies have shown that Pak1 mutations are associated with autism.In the present study,we take advantage of Pak1 knockout(Pak1a/a)mice to investigate the role of PAK1 in hearing function.We find that PAK1 is highly expressed in the postnatal mouse cochlea and that PAK1 deficiency leads to hair cell(HC)apoptosis and severe hearing loss.Further investigation indicates that PAK1 deficiency downregulates the phosphorylation of cofilin and ezrin-radixin-moesin and the expression of b II-spectrin,which further decreases the HC synapse density in the basal turn of cochlea and disorganized the HC stereocilia in all three turns of cochlea in Pak1à/àmice.Overall,our work demonstrates that the autism-related gene Pak1 plays a crucial role in hearing function.As the first candidate gene linking autism and hearing loss,Pak1 may serve as a potential target for the clinical diagnosis of autism-related hearing loss.

关键词： PAK1 hearing loss Synapse Hair bundle ERM

Phosphatidylinositol 4-kinase β is required for the ciliogenesis of zebrafish otic vesicle

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Journal of Genetics and Genomics 2020年第10期47卷 627-636页

作者： Yufei Feng Ping Yu Jingyu Li Ying Cao Jingjing Zhang Affiliated Hospital of Guangdong Medical University&Key Laboratory of Zebrafish Model for Development and Disease of Guangdong Medical University Zhanjiang 524001China Clinical and Translational Research Center Shanghai First Maternity and Infant HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200092China

The primary cilium,an important microtubule-based organelle,protrudes from nearly all the vertebrate cells.The motility of cilia is necessary for various developmental and physiological processes.Phosphoinositides(PIs)and its metabolite,Ptd Ins(4,5)P2,have been revealed to contribute to cilia assembly and disassembly.As an important kinase of the PI pathway and signaling,phosphatidylinositol 4-kinaseβ(PI4 KB)is the one of the most extensively studied phosphatidylinositol 4-kinase isoform.However,its potential roles in organ development remain to be characterized.To investigate the developmental role of Pi4 kb,especially its function on zebrafish ciliogenesis,we generated pi4 kb deletion mutants using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9 technique.The homozygous pi4 kb mutants exhibit an absence of primary cilia in the inner ear,neuromasts,and pronephric ducts accompanied by severe edema in the eyes and other organs.Moreover,smaller otic vesicle,malformed semicircular canals,and the insensitivity on sound stimulation were characteristics of pi4 kb mutants.At the protein level,both in vivo and in vitro analyses revealed that synthesis of Pi4 p was greatly reduced owing to the loss of Pi4 kb.In addition,the expression of the Pi4 kb-binding partner of neuronal calcium sensor-1,as well as the phosphorylation of phosphatidylinositol-4-phosphate downstream effecter of Akt,was significantly inhibited in pi4 kb mutants.Taken together,our work uncovers a novel role of Pi4 kb in zebrafish inner ear development and the functional formation of hearing ability by determining hair cell ciliogenesis.

关键词： Ciliogenesis Pi4kb Hair cell hearing loss Zebrafish

Mitochondrial rRNA and tRNA and hearing function

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Cell Research 2007年第3期17卷 227-239页

作者： Guangqian Xing~1 Zhibin Chen~1 Xin Cao~2 ~1Department of Otolaryngology,the First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China ~2Department of Biotechnology,Nanjing Medical University,Nanjing 210029,China Department of Otolaryngology the First Affiliated Hospital of Nanjing Medical University Nanjing China Department of Biotechnology Nanjing Medical University Nanjing China

The human ear is a delicate sensory apparatus of hearing for normal communication,and its proper functioning is highlydependent on mitochondrial oxidative phosphorylation.The first mitochondrial point mutation for nonsyndromic andaminoglycoside-induced hearing loss was identified in 1993.Since then a number of inherited mitochondrial mutationshave been implicated in hearing loss.Most of the molecular defects responsible for mitochondrial disorder-associatedhearing loss are mutations in the 12S rRNA gene and tRNA genes.In this review,after a short description of normal hear-ing mechanisms and mitochondrial genetics,we outline the recent advances that have been made in the identification ofdeafness-associated mitochondrial mutations,and discuss how mitochondrial dysfunction contributes to hearing loss.

关键词： mitochondrial DNA rRNA tRNA gene mutation aminoglycosides hearing loss

Characteristics of the Cochlear Symptoms and Functions in Meniere＇s Disease

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Chinese Medical Journal 2016年第20期129卷 2445-2450页

作者： Yi Zhang Bo Liu Rui Wang Ruo Jia Xin Gu Department of Otolaryngology Head and Neck Surgery Beijing Tongren Hospital Capital Medical University Beijing 100730 China Beijing Institute of Otolaryngology Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University) Ministry of Education Beijing 100730 China

Background：Meniere＇s disease is a unique,progressive disease of the inner ear.The complex manifestation presents diagnostic challenges.The cochlear symptoms often present before vertigo and tend to be ignored.This study aimed to analyze the characteristics of cochlear symptoms and functions associated with Meniere＇s disease to investigate the regularity of the development of this disorder.Methods：One-hundred fifteen patients who were diagnosed with definite unilateral Meniere＇s disease at the hearing and Vestibular Clinic of the Department of Otorhinolaryngology of Beijing Tongren Hospital from August 2013 to November 2015 were recruited in this retrospective study.Initial symptoms,duration from initial symptoms to the diagnosis,hearing thresholds,audiogram patterns,and caloric test results were collected and analyzed for each patient.Data were analyzed using SPSS 13.0 statistical software by Spearman＇s correlation,Kruskal-Wallis H test,Chi-square test,and Fisher＇s exact test.Results：The average hearing threshold of these patients was 45.24 ± 18.40 dB HL.A majority of the patients （55.65%） were in Stage 3.The initial presentation of the disorder in 58 cases （50.43%） comprised only cochlear symptoms without vertigo.A weak,positive correlation was found between the degree of hearing loss and duration of the disease from initial symptoms to the diagnosis （rs =0.288,P =0.002）.Upward-sloping,inverted ＂V,＂ downward-sloping,and flat pattern were the main audiometric patterns observed with a distinctive distribution between stages （P 〈 0.001）.Based on the configurations of audiograms,the audiometric patterns had a weak correlation to the duration （rs =0.269,P =0.004）,and there was a tendency of duration to rising from upward-sloping,inverted ＂V＂,downward-sloping to flat pattern.（H =10.024,P =0.018）.Frequencies of tinnitus in 56 patients （64.4%） were at the lowest points of the audiograms,i.e.,the frequencies of the poorest hearing threshold.The patients at an advanced stage （Stage 3 [56] and Stage 4 [73]） exhibited a sig

关键词： Caloric Test hearing loss Meniere＇s disease Tinnitus Vertigo

Mitochondrial tRNA^(Glu) A14693G variant may modulate the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in a Han Chinese family

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Journal of Genetics and Genomics 2009年第4期36卷 241-250页

作者： Yu Ding Yongyan Li Junyan You Li Yang Bobei Chen Jianxin Lu Min-Xin Guan Zhejiang Provincial Key Laboratory of Medical Genetics School of Life Sciences Wenzhou Medical College Wenzhou 325025 China Division of Human Genetics and Center for hearing and Deafness Research Cincinnati Children's Hospital Medical Center Cincinnati Ohio 45229 USA Department of Otolaryngology the SecondAffiliated Hospital Wenzhou Medical College Wenzhou 325000 China Deparment of Pediatrics University of Cincinnati College of Medicine Cincinnati Ohio 45229 USA

Mutations in mitochondrial 12S rRNA gene are one of the most important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here we report the characterization of one Han Chinese pedigree with aminoglycoside-induced and nonsyndromic hearing loss. This Chinese family carrying the 12S rRNA A1555G mutation exhibited high penetrance and expressivity of heating impairment. In particular, penetrances of hearing loss in this family pedigree were 43.8% and 25%, respectively, when aminoglycoside-induced heating loss was included or excluded. Mutational analysis of entire mitochondrial genomes in this family showed the homoplasmic A1555G mutation and a set of variants belonging to haplogroup Y2. Of these, the A14693G variant occurred at the extremely conserved nucleotide （conventional position 54） of the TψC-loop of tRNA^Clu and was absent in 156 Chinese controls. Nucleotides at position 54 of tRNAs are often modified, thereby contributing to the structural formation and stabilization of functional tRNAs. Thus, the structural alteration of tRNA by the A14693G variant may lead to a failure in tRNA metabolism and impair mitochondrial protein synthesis, thereby worsening mitochondrial dysfunctions altered by the A1555G mutation. Therefore, the tRNA^Glu A14693G variant may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated A1555G mutation in this Chinese pedigree.

关键词： hearing loss mitochondrial DNA mutation modifier 12S rRNA tRNA Chinese family

Aminoglycoside ototoxicity in three murine strains and effects on NKCC1 of stria vascularis

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Chinese Medical Journal 2006年第12期119卷 980-985页

作者： CHU Han-qi XIONG Hao Zhou Xiao-qin HAN Fang WU Zhen-gong ZHANG Ping HUANG Xiao-wen CUl Yong-hua Department of Otolaryngology Tongji Hospital Tongji MedicalCollege Huazhong University of Science and Technology Wuhan430030 China Union Hospital Tongji Medical College Huazhong University ofScience and Technology Wuhan 430022 China

Background After establishing a murine model of aminoglycoside antibiotic （AmAn） induced ototoxicity, the sensitivity of AmAn induced ototoxicity in three murine strains and the effect of kanamycin on the expression of Na-K-2Cl cotransporter-1 （NKCC1） in stria vascularis were investigated. Methods C57BL/6J, CBA/CaJ, NKCC1^＋/- mice （24 of each strain） were randomly divided into four experimental groups： A： kanamycin alone; B： kanamycin plus 2,3-dihydroxybenzoate; C： 2,3-dihydroxybenzoate alone; and D： control group. Mice were injected with kanamycin or/and 2,3-dihydroxybenzoate twice daily for 14 days. Auditory brainstem response （ABR） was measured and morphology of cochlea delineated with succinate dehydrogenase staining. Expression of NKCC1 in stria vascularis was detected immunohistochemically. Results All three strains in groups A and B developed significant ABR threshold shifts （P〈0.01）, which were accompanied by outer hair cell loss. NKCC 1 expression in stria vascularis was the weakest in group A （A cf D, P〈0.01） and the strongest in groups C and D （P〈0.05）. CBA/CaJ mice had the highest sensitivity to AmAn.Conclusions Administration of kanamycin established AmAn induced ototoxicity. Kanamycin inhibited the expression of NKCC1 in stria vascularis. 2, 3-dihydroxybenzoate attenuated AmAn induced ototoxicity-possibly by enhancing the expression of NKCC 1. Age related hearing loss did not show additional sensitivity to AmAn induced ototoxicity in murine model.

关键词： kanamycin 2,3-dihydroxybenzoate ototoxicity reactive oxygen species hearing loss

GJB2 (Cx26) gene mutations in Chinese patients with congenital sensorineural deafness and a report of one novel mutation

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Chinese Medical Journal 2004年第12期17卷 1797-1801页

作者：肖自安谢鼎华 Department of Otolaryngology & hearing Research Laboratory Second Xiangya Hospital Xiangya School of Medicine Central South University Changsha 410011 China

Background Mutations in GJB2 gene are a major cause of autosomal recessive congenital hearing loss and the cause in some rare cases of the autosomal dominant form The purpose of this study was to investigate the frequency and the features of GJB2 mutations in the Chinese patients with congenital sensorineural deafness Methods Using PCR amplifying the entire coding region of GJB2 gene and direct DNA sequencing to analyze mutations in this gene among unrelated 69 cases with autosomal recessive congenital nonsyndromic deafness and 27 cases of dominant congenital deafness and 35 sporadic cases We also detected mutations in GJB2 in 100 control subjects with normal hearing Results 17 4% (12/69) of the probands in the autosomal recessive, 7 4% (2/27) of dominant families and 5 7% (2/35) of the sporadic congenital deafness patients had deafness causing mutations in GJB2, respectively Nine types of the mutations in GJB2 were detected in the recessive and sporadic group They consisted of five types of polymorphism, and four types of deafness causing mutation with homozygous 35delG in 1 sporadic (1/35), and 235delC frameshift mutation in 1 sporadic (homozygotes) and 10 recessive patients (2 heterozygotes and 8 homozygotes), and homozygous 442G→A missense mutation and homozygous 465T→A nonsense mutation in 1 different recessive proband, respectively The 465T→A that related to recessive deafness was a novel mutation found by this study The homozygous (10/69, 14 5%) and the heterozygous (2/69, 2 9%) GJB2 mutation in the recessive patients (12/69, 17 4%) and the homozygotes in the sporadic patient (2/35, 5 7%) all had congenital severe to profound sensorineural hearing loss 511G→A missense mutation and 299-300delAT frameshift mutation were found in two autosomal dominant congenital deafness families (2/27, 7 4%) The total mutation frequency of GJB2 was 12 2% (16/131) in the Chinese patients with congenital sensorineural deafness and 235delC was the most common deafness causing mutation Six types of mutation—5 types of polymorph

关键词： hereditary hearing loss sensorieural genes GJB2 mutation

Associations of blood pressure and arterial compliance with occupational noise exposure in female workers of textile mill

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Chinese Medical Journal 2007年第15期120卷 1309-1313页

作者： NI Chun-hui CHEN Zhi-yong ZHOU Yin ZHOU Jian-wei Pan Jing-jing LIU Nian WANG Jun LIANG Chen-ke ZHANG Zhi-zhong ZHANG Yu-jun Department of Occupational Medicine and Environmental Health School of Public Health Nanjing Medical University Nanjing 210029 China Centres for Disease Prevention and Control Baoying County 225800 Jiangsu Province China

Background There are few studies on the arterial compliance of noise exposure. The purpose of this study was to understand the relationship between hearing loss, blood pressure and arterial compliance of female workers who exposed to occupational noise in a textile mill. Methods The noise levels in the workplace were measured with a HS6288 sound level meter. Cumulated noise exposure （CNE） was calculated according to the noise intensity and the exposure period. hearing ability and arterial compliance were measured in 618 noise exposed workers. The database was set up with EpiData and the statistical analysis was performed with SAS software 9.1.3. Results The noise levels were 80.1dB（A） to 113.5dB（A）, of which the levels at 92.5% of the noise monitoring sites were over the national standard. The incidence of high frequency hearing loss （HFHL） was 24.43% and language frequency hearing impairment （LFHI） was 0.81%. The incidence of hypertension was 7.93%. Both systolic blood pressure （SBP） and diastolic blood pressure （DBP） in the high frequency hearing loss group were significantly higher than those in the normal hearing group （P〈0.05）, while C1 （large artery compliance） and C2 （small artery compliance） were significantly lower （P〈0.05）. The high frequency hearing threshold （HFHT） of the hypertension group was significantly higher than in the normal blood pressure group （P〈0.05）, while C1 and C2 were significantly lower （P〈0.05）.C1 and C2 had a negative correlation with HFHT, SBP, DBP, mean of arterial pressure （MAP）, pulse pressure （PP） and pulse rate （PR）（P〈0.05）. The multiple regression analyses showed that blood pressure and PR were the main influencing factors on C1 and C2. LFHT was an influence on C2 and HFHT on C1. Conclusions Textile mill noise pollution is very serious and has an obvious influence on worker＇s auditory function. The female workers with low artery compliance or with high blood pressure might be suffering from hearing loss; those with noise induced hearing loss might be suffering from hy

关键词： hearing loss arterial compliance noise exposure female textiles