迟发性非综合征型耳聋及老年性、药物性耳聋的分子机制研究
|
摘要
耳聋是导致言语交流障碍的常见疾病,由环境因素和遗传因素共同致病。由遗传因素引起的耳聋不仅包括单基因遗传性耳聋(如:非综合征型耳聋),多基因遗传性耳聋(如:老年性耳聋),还包括线粒体相关性耳聋(如:药物性耳聋)等。以上各方面耳聋遗传病学的研究为聋病的防治奠定了坚实的基础。
随着人类基因组计划(Human genome project,HGP)的深入和完成,国际人类基因组单体型图计划(简称HapMap计划)的实施和不断完善,在遗传学高速发展的后基因组时代,遗传性耳聋的研究面临着前所未有的机遇和挑战。现如今,在现代分子遗传学研究技术平台的发展中应运而生的第三代遗传学标记单核苷酸多态(Single nucleotide polymorphism,SNP)在众多领域中发挥着重要作用,将其应用于遗传性耳聋致病基因及易感基因的定位、克隆研究也将成为遗传性耳聋研究的流行趋势和关注热点。
在本研究中,我们应用单核苷酸多态作为遗传标记,在一个常染色体显性非综合征型耳聋家系中成功定位及筛查出一个全新的耳聋相关基因;探讨了常见耳聋基因GJB2、12S rRNA和GSTT1/GSTM1基因多态性与老年性耳聋遗传易感性的关系;以及追溯了线粒体12SrRNA C1494T突变的起源。
一、非综合征型遗传性听力损失家系致病基因的定位、筛查及鉴定研究
本研究选用单核苷酸多态(SNP)及微卫星标记(STR)作为遗传标记,利用连锁分析的方法,分步对一个常染色体显性遗传的非综合征型耳聋大家系(HN-W078)进行了耳聋致病基因的定位、筛查和鉴定工作。HN-W078家系为一个5代相传的耳聋大家系,耳聋患者的听力学表型为迟发性、渐进性、以高频听力下降为主的感音神经性耳聋。首先,选取SNP作为遗传标记,利用Affymetrix 5.0 SNP基因芯片进行全基因组扫描及连锁分析,将HN-W078家系的致病基因初步定位于12号染色体12q24.31-12q24.32区域(最大LOD值=5.656);之后,选取初步定位区域内及附近的16个微卫星标记进行精细定位及单倍体型分析,将该致病基因定位于微卫星标记D12S86和D12S1612之间的区域(最大LOD值=5.35)。通过定位区域候选基因直接测序筛查的方法,我们在DFNA60基因的EXON4外显子中发现了与此家系疾病表型共分离的突变位点c.377C＞T(p.S126L)。对整个家系和500个听力正常人进行该位点的酶切检测,均证明只有家系中的耳聋患者携带此突变。通过免疫组织化学方法显示,DFNA60基因编码的蛋白在耳蜗中多处表达,包括Corti's器,血管纹,螺旋韧带等。此结果为阐明DFNA60基因突变引起的迟发性非综合征型耳聋的致病机制奠定了基础。(注:此位点及致病基因为全新发现,尚未发表,均暂用DFNA60表示)。
二、老年性耳聋遗传易感基因的筛查
老年性耳聋,亦指年龄相关性耳聋,是指随着年龄的增加逐渐出现的听力下降。随着现代生活环境的影响,衰老的过程逐渐提前,听觉器官也不例外。本研究通过普查的方法共收集到662名不同听力水平的中老年人研究对象(40岁至90岁);根据听力下降水平共分为四组;首先选取GJB2基因、12s rRNA基因及GSTT1/GSTM1基因作为老年性耳聋的遗传易感候选基因,通过直接测序和多重PCR的方法,研究了GJB2、12S rRNA和GSTT1/GSTM1基因与老年性耳聋遗传易感性的关系,初步探讨了不同听力水平中老年人的老年性耳聋遗传易感性差异的遗传学基础。关联性分析结果显示,GJB2基因的109G＞A、608T＞C杂合突变和12S rRNA A827G同质性突变均可增加老年性耳聋的遗传易感性,但没有检测到GSTT1/GSTM1基因的多态与老年性耳聋遗传易感性的关联性。本研究不仅为大规模、多中心、多学科联合研究老年性耳聋遗传易感基因收集了宝贵的老年性耳聋研究对象资源,同时提供了常见耳聋基因与老年性耳聋遗传易感性关联性分析的基础。
三、线粒体12S rRNA C1494T突变的遗传学及起源性分析
线粒体12S rRNA基因是一个与耳聋相关的热点基因,其中位于高度保守区域的12S rRNAA1555G和C1494T突变与药物性耳聋和非综合征型耳聋密切相关。迄今为止,一共报道了8个12S rRNA C1494T突变的药物性耳聋和非综合征型耳聋中国家系,这些家系内及家系间母系亲属的发病年龄、外显率以及听力下降程度均存在一定的差异,这说明12S rRNA C1494T突变不是影响耳聋表型的唯一因素,药物、线粒体单体型、核修饰基因以及线粒体第二突变均可能影响耳聋的外显率。本研究对基于聋病分子流行病调查发现的13个12S rRNA C1494T突变家系进行了线粒体基因组全序列测定以及全面的遗传学特征和单体型分析。通过线粒体基因组全序列分析,排除了线粒体DNA第二突变位点以及mt DNA变异体对12S rRNA C1494T突变耳聋家系外显率的影响;通过13个家系先证者的线粒体单体型分析发现,来自中国7个不同省份的13个12S rRNA C1494T突变耳聋家系分别属于A,B,D,D4,D4b2,F1,M,M7c,N9a1,和H2b单体型,明确了12S rRNA C1494T突变在进化过程中具有多起源性。对以上结果的综合分析表明,氨基糖甙类药物是目前唯一明确的12S rRNA C1494T突变外显率的影响因素,12S rRNAC1494T突变携带者避免接触氨基糖甙类药物是预防药物性耳聋最有效的方法。此研究为在正常人群中大规模筛查12S rRNA C1494T突变提供了确实的遗传学理论基础。
Hearing impairment is the most common perception disorder in the world. It is caused by both environmental factors and genetic factors.The hearing loss attributable to genetic factors include not only single gene genetic deafness(such as non-syndromic hearing loss),but also multi-gene genetic deafness(such as age-related heating loss),as well as mitochondrion-related deafness(such as aminoglycoside-induced hearing loss).The research of over all aspects of genetic hearing loss has provided a solid foundation for prevention and treatment of hearing loss.
With the gradual completion of the Human Genome Project(Human genome project,HGP),implementation and constant improvement of the International Human Genome HapMap Project(HapMap Project),in the post-genomic era with the rapid development of the genetics,the research of the genetic hearing loss is faced with unprecedented opportunities and challenges.In recent years,the third generation of genetic markers,single nucleotide polymorphisms(SNPs),which came into being because of demand with the development of modern molecular genetics technology platform,were applied in many fields and played an important role in many aspects.It will be the new concerns and fashion trends to apply the SNP in the mapping and cloning pathogenic gene or susceptibility gene of genetic heating loss.
In our research,by taking single nucleotide polymorphisms as the genetic marker,we successfully mapped and identified a novel heating loss locus and gene in an autosomal dominant non-syndromic deafness family,completed the screening of common deafness gene GJB2,12Sr RNA and GSTT1/GSTM1 for the susceptibility of presbyacusis,and traced the origin of mitochondrial 12SrRNA C 1494T mutation.
Part 1:Mapping,screening and identification of pathogenic gene in one autosomal-dominant nonsyndromic hearing loss family
In this study,by taking both SNP and STR as the genetic markers,and making use of the linkage analysis,we successfully mapped,screened and identified the pathogenic gene in one autosomal-dominant nonsyndromic hearing loss family step by step.Family HN-W078 was a large Chinese family with hearing loss transmitted through 5 generations.The clinical evaluation of audiology revealed that the hearing loss was late-onset and gradual sensorineural hearing loss which first developed in high frequencies.First of all,we mapped the locus on chromosome 12q24.31-q24.32 region(two-point lod-score of 5.656) with application of the Affymetrix 5.0 SNP Genechip,and then by refined mapping and analysis of haplotype,we mapped the same locus to the region between D12S86 and D 12S 1612(two-point lod-score of 5.35) with application of 16 microsatellite markers.By direct sequencing of candidate genes in mapping region,we found a missense mutation c.377C＞T(p.S126L) in EXON4 of DFNA60 gene,which was totally segregated with the disease phenotype.We confirmed that only the patients in HN-W078 carried this mutation by failing in detecting this mutation in 500 normal subjects.With the method of immunohistochemistry,we found out that the DFNA60 widely expressed in the cochlear,including the organ of Corti,stria vascularis,and spiral ligament,and so on.It had laid the foundation for pathogenic mechanism study of deafness caused by DFNA60 gene mutation.(The locus and gene is novel and has not been published anywhere,it is represented by DFNA60 temporarily).
Part 2:Genetic screening for susceptibility genes of presbyacusis
Presbyacusis,also refers to age-related hearing loss,is gradual hearing loss with age.With the environmental impact of modern life,the process of aging is being in advance,no exception of the hearing organ.In our study,662 elder people with different age(40-90years old) and different hearing threshold levels through census were collected.According to audiological data,all elder were divided into four groups.Through the direct sequencing and multi-polymerase chain reaction,we had investigated the relationship of GJB2,12S rRNA and GSTT1/GSTM1 genes and susceptibility of presbyacusis and initially explored the hereditary agent of susceptibility for presbyacusis.The findings indicated that 109G＞A and 608T＞C heterozygotic mutations of GJB2 gene,and homoplasmy A827G mutation of mitochondrial 12S rRNA may increase susceptibility of presbyacusis.No relationship was deteced between GSTT1/GSTM1 gene and presbyacusis.In summary,this study not only collected the large scale of subjects with presbyacusis for large-scale,multi-center,multi-disciplinary joint research of presbyacusis' genetic susceptibility,but also provided foundation of analysis for relationship of common deafness genes and genetic susceptibility of presbyacusis.
Part 3:Genetics and origin analysis of mitochondrial 12S rRNA C1494T mutation
Mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and nonsyndromic hearing loss.The 12S rRNA A1555G and C1494T mutations in the highly conserved A-site of the 12SrRNA have been associated with both aminoglycoside-induced and nonsyndromic hearing loss in many families worldwid.Previous investigations revealed the highly variable penetrance and expressivity of hearing loss in 8 Han Chinese families carrying the C1494T mutation.Matrilineal relatives within and among families carrying the C1494T mutation exhibited a wide range of penetrance,severity,and age-of-onset in hearing loss.These results indicated that the mtDNA mutation 12S rRNA C1494T itself is insufficient to produce the clinical phenotype.Therefore,other modifiers including aminoglycosides,nuclear modifier genes,second mutation,and mitochondrial haplotypes may modulate the phenotypic manifestations of the C1494T mutation.In this study,we reported the clinical,genetic,and molecular characteristics of 13 Han Chinese families with aminoglycoside-induced and nonsyndromic bilateral hearing loss collected by screening of nationwide molecular epidemic.Through the whole mitochondrial genome DNA sequence analysis,we precluded the possibility that the second mutations might significantly modify the manifestation of the C1494T mutation. Through analysis of haplotypes of the probands,13 families come from 7 different provience were classified into 10 haplogroups by the distinct sets of mtDNA polymorphisms belonged to different haplogroups,including haplogroups A,B,D, D4,D4b2,F1,M,M7c,N9al,and H2b.This result suggested that the C1494T mutation occurred sporadically and might be multi-origin mutation through evolution of the mtDNA in China,and these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in these Chinese families with different penetrance of hearing loss. Therefore,aminoglycoside-antibiotics is solo well-established factor to contribute to the deafness expression of the C 1494T mutation.So prevention by avoiding the administration of aminoglycoside in individuals carrying C1494T mutation is the most effective way to protect their vulnerable hearing,and a systematic and extended mutational screening of the 12S rRNA C1494T mutation not only for hearing loss patients but also for normal Chinese subjects is necessary before the use of aminoglycosides.
随着人类基因组计划(Human genome project,HGP)的深入和完成,国际人类基因组单体型图计划(简称HapMap计划)的实施和不断完善,在遗传学高速发展的后基因组时代,遗传性耳聋的研究面临着前所未有的机遇和挑战。现如今,在现代分子遗传学研究技术平台的发展中应运而生的第三代遗传学标记单核苷酸多态(Single nucleotide polymorphism,SNP)在众多领域中发挥着重要作用,将其应用于遗传性耳聋致病基因及易感基因的定位、克隆研究也将成为遗传性耳聋研究的流行趋势和关注热点。
在本研究中,我们应用单核苷酸多态作为遗传标记,在一个常染色体显性非综合征型耳聋家系中成功定位及筛查出一个全新的耳聋相关基因;探讨了常见耳聋基因GJB2、12S rRNA和GSTT1/GSTM1基因多态性与老年性耳聋遗传易感性的关系;以及追溯了线粒体12SrRNA C1494T突变的起源。
一、非综合征型遗传性听力损失家系致病基因的定位、筛查及鉴定研究
本研究选用单核苷酸多态(SNP)及微卫星标记(STR)作为遗传标记,利用连锁分析的方法,分步对一个常染色体显性遗传的非综合征型耳聋大家系(HN-W078)进行了耳聋致病基因的定位、筛查和鉴定工作。HN-W078家系为一个5代相传的耳聋大家系,耳聋患者的听力学表型为迟发性、渐进性、以高频听力下降为主的感音神经性耳聋。首先,选取SNP作为遗传标记,利用Affymetrix 5.0 SNP基因芯片进行全基因组扫描及连锁分析,将HN-W078家系的致病基因初步定位于12号染色体12q24.31-12q24.32区域(最大LOD值=5.656);之后,选取初步定位区域内及附近的16个微卫星标记进行精细定位及单倍体型分析,将该致病基因定位于微卫星标记D12S86和D12S1612之间的区域(最大LOD值=5.35)。通过定位区域候选基因直接测序筛查的方法,我们在DFNA60基因的EXON4外显子中发现了与此家系疾病表型共分离的突变位点c.377C＞T(p.S126L)。对整个家系和500个听力正常人进行该位点的酶切检测,均证明只有家系中的耳聋患者携带此突变。通过免疫组织化学方法显示,DFNA60基因编码的蛋白在耳蜗中多处表达,包括Corti's器,血管纹,螺旋韧带等。此结果为阐明DFNA60基因突变引起的迟发性非综合征型耳聋的致病机制奠定了基础。(注:此位点及致病基因为全新发现,尚未发表,均暂用DFNA60表示)。
二、老年性耳聋遗传易感基因的筛查
老年性耳聋,亦指年龄相关性耳聋,是指随着年龄的增加逐渐出现的听力下降。随着现代生活环境的影响,衰老的过程逐渐提前,听觉器官也不例外。本研究通过普查的方法共收集到662名不同听力水平的中老年人研究对象(40岁至90岁);根据听力下降水平共分为四组;首先选取GJB2基因、12s rRNA基因及GSTT1/GSTM1基因作为老年性耳聋的遗传易感候选基因,通过直接测序和多重PCR的方法,研究了GJB2、12S rRNA和GSTT1/GSTM1基因与老年性耳聋遗传易感性的关系,初步探讨了不同听力水平中老年人的老年性耳聋遗传易感性差异的遗传学基础。关联性分析结果显示,GJB2基因的109G＞A、608T＞C杂合突变和12S rRNA A827G同质性突变均可增加老年性耳聋的遗传易感性,但没有检测到GSTT1/GSTM1基因的多态与老年性耳聋遗传易感性的关联性。本研究不仅为大规模、多中心、多学科联合研究老年性耳聋遗传易感基因收集了宝贵的老年性耳聋研究对象资源,同时提供了常见耳聋基因与老年性耳聋遗传易感性关联性分析的基础。
三、线粒体12S rRNA C1494T突变的遗传学及起源性分析
线粒体12S rRNA基因是一个与耳聋相关的热点基因,其中位于高度保守区域的12S rRNAA1555G和C1494T突变与药物性耳聋和非综合征型耳聋密切相关。迄今为止,一共报道了8个12S rRNA C1494T突变的药物性耳聋和非综合征型耳聋中国家系,这些家系内及家系间母系亲属的发病年龄、外显率以及听力下降程度均存在一定的差异,这说明12S rRNA C1494T突变不是影响耳聋表型的唯一因素,药物、线粒体单体型、核修饰基因以及线粒体第二突变均可能影响耳聋的外显率。本研究对基于聋病分子流行病调查发现的13个12S rRNA C1494T突变家系进行了线粒体基因组全序列测定以及全面的遗传学特征和单体型分析。通过线粒体基因组全序列分析,排除了线粒体DNA第二突变位点以及mt DNA变异体对12S rRNA C1494T突变耳聋家系外显率的影响;通过13个家系先证者的线粒体单体型分析发现,来自中国7个不同省份的13个12S rRNA C1494T突变耳聋家系分别属于A,B,D,D4,D4b2,F1,M,M7c,N9a1,和H2b单体型,明确了12S rRNA C1494T突变在进化过程中具有多起源性。对以上结果的综合分析表明,氨基糖甙类药物是目前唯一明确的12S rRNA C1494T突变外显率的影响因素,12S rRNAC1494T突变携带者避免接触氨基糖甙类药物是预防药物性耳聋最有效的方法。此研究为在正常人群中大规模筛查12S rRNA C1494T突变提供了确实的遗传学理论基础。
Hearing impairment is the most common perception disorder in the world. It is caused by both environmental factors and genetic factors.The hearing loss attributable to genetic factors include not only single gene genetic deafness(such as non-syndromic hearing loss),but also multi-gene genetic deafness(such as age-related heating loss),as well as mitochondrion-related deafness(such as aminoglycoside-induced hearing loss).The research of over all aspects of genetic hearing loss has provided a solid foundation for prevention and treatment of hearing loss.
With the gradual completion of the Human Genome Project(Human genome project,HGP),implementation and constant improvement of the International Human Genome HapMap Project(HapMap Project),in the post-genomic era with the rapid development of the genetics,the research of the genetic hearing loss is faced with unprecedented opportunities and challenges.In recent years,the third generation of genetic markers,single nucleotide polymorphisms(SNPs),which came into being because of demand with the development of modern molecular genetics technology platform,were applied in many fields and played an important role in many aspects.It will be the new concerns and fashion trends to apply the SNP in the mapping and cloning pathogenic gene or susceptibility gene of genetic heating loss.
In our research,by taking single nucleotide polymorphisms as the genetic marker,we successfully mapped and identified a novel heating loss locus and gene in an autosomal dominant non-syndromic deafness family,completed the screening of common deafness gene GJB2,12Sr RNA and GSTT1/GSTM1 for the susceptibility of presbyacusis,and traced the origin of mitochondrial 12SrRNA C 1494T mutation.
Part 1:Mapping,screening and identification of pathogenic gene in one autosomal-dominant nonsyndromic hearing loss family
In this study,by taking both SNP and STR as the genetic markers,and making use of the linkage analysis,we successfully mapped,screened and identified the pathogenic gene in one autosomal-dominant nonsyndromic hearing loss family step by step.Family HN-W078 was a large Chinese family with hearing loss transmitted through 5 generations.The clinical evaluation of audiology revealed that the hearing loss was late-onset and gradual sensorineural hearing loss which first developed in high frequencies.First of all,we mapped the locus on chromosome 12q24.31-q24.32 region(two-point lod-score of 5.656) with application of the Affymetrix 5.0 SNP Genechip,and then by refined mapping and analysis of haplotype,we mapped the same locus to the region between D12S86 and D 12S 1612(two-point lod-score of 5.35) with application of 16 microsatellite markers.By direct sequencing of candidate genes in mapping region,we found a missense mutation c.377C＞T(p.S126L) in EXON4 of DFNA60 gene,which was totally segregated with the disease phenotype.We confirmed that only the patients in HN-W078 carried this mutation by failing in detecting this mutation in 500 normal subjects.With the method of immunohistochemistry,we found out that the DFNA60 widely expressed in the cochlear,including the organ of Corti,stria vascularis,and spiral ligament,and so on.It had laid the foundation for pathogenic mechanism study of deafness caused by DFNA60 gene mutation.(The locus and gene is novel and has not been published anywhere,it is represented by DFNA60 temporarily).
Part 2:Genetic screening for susceptibility genes of presbyacusis
Presbyacusis,also refers to age-related hearing loss,is gradual hearing loss with age.With the environmental impact of modern life,the process of aging is being in advance,no exception of the hearing organ.In our study,662 elder people with different age(40-90years old) and different hearing threshold levels through census were collected.According to audiological data,all elder were divided into four groups.Through the direct sequencing and multi-polymerase chain reaction,we had investigated the relationship of GJB2,12S rRNA and GSTT1/GSTM1 genes and susceptibility of presbyacusis and initially explored the hereditary agent of susceptibility for presbyacusis.The findings indicated that 109G＞A and 608T＞C heterozygotic mutations of GJB2 gene,and homoplasmy A827G mutation of mitochondrial 12S rRNA may increase susceptibility of presbyacusis.No relationship was deteced between GSTT1/GSTM1 gene and presbyacusis.In summary,this study not only collected the large scale of subjects with presbyacusis for large-scale,multi-center,multi-disciplinary joint research of presbyacusis' genetic susceptibility,but also provided foundation of analysis for relationship of common deafness genes and genetic susceptibility of presbyacusis.
Part 3:Genetics and origin analysis of mitochondrial 12S rRNA C1494T mutation
Mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and nonsyndromic hearing loss.The 12S rRNA A1555G and C1494T mutations in the highly conserved A-site of the 12SrRNA have been associated with both aminoglycoside-induced and nonsyndromic hearing loss in many families worldwid.Previous investigations revealed the highly variable penetrance and expressivity of hearing loss in 8 Han Chinese families carrying the C1494T mutation.Matrilineal relatives within and among families carrying the C1494T mutation exhibited a wide range of penetrance,severity,and age-of-onset in hearing loss.These results indicated that the mtDNA mutation 12S rRNA C1494T itself is insufficient to produce the clinical phenotype.Therefore,other modifiers including aminoglycosides,nuclear modifier genes,second mutation,and mitochondrial haplotypes may modulate the phenotypic manifestations of the C1494T mutation.In this study,we reported the clinical,genetic,and molecular characteristics of 13 Han Chinese families with aminoglycoside-induced and nonsyndromic bilateral hearing loss collected by screening of nationwide molecular epidemic.Through the whole mitochondrial genome DNA sequence analysis,we precluded the possibility that the second mutations might significantly modify the manifestation of the C1494T mutation. Through analysis of haplotypes of the probands,13 families come from 7 different provience were classified into 10 haplogroups by the distinct sets of mtDNA polymorphisms belonged to different haplogroups,including haplogroups A,B,D, D4,D4b2,F1,M,M7c,N9al,and H2b.This result suggested that the C1494T mutation occurred sporadically and might be multi-origin mutation through evolution of the mtDNA in China,and these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in these Chinese families with different penetrance of hearing loss. Therefore,aminoglycoside-antibiotics is solo well-established factor to contribute to the deafness expression of the C 1494T mutation.So prevention by avoiding the administration of aminoglycoside in individuals carrying C1494T mutation is the most effective way to protect their vulnerable hearing,and a systematic and extended mutational screening of the 12S rRNA C1494T mutation not only for hearing loss patients but also for normal Chinese subjects is necessary before the use of aminoglycosides.
引文
1.Gefel D,Maslovsky I,Hillel J.Application of single nucleotide polymorphisms(SNPs) for the detection of genes involved in the control of complex diseases.Harefuah,2008.147(5):449-476.
2.Hughes AL,Welch R,Puff V,et al.Genome-wide SNP typing reveals signatures of population history.Genomics,2008.92(1):1-8.
3.Cann R.Mitochondrial DNA and human evolution.Nature,1987.325:31-36.
4.Maciejewski JP,Mufti GJ.Whole genome scanning as a cytogenetic tool in hematologic malignancies.Blood,2008.112(4):965-974.
1.Beckstead WA,Bjork BC,Stottmann RW,et al.SNP2RFLP:a computational tool to facilitate genetic mapping using benchtop analysis of SNPs.Mamm Genome,2008.19(10-12):687-690.
2.Van Laer L,Cryns K,Smith RJ,et al.Nonsyndromic Heating Loss.Ear Hear,2003.24:275-288.
3.Su MC,Yang JJ,Su CC,Hsin CH,Li SY.Identification of novel variants in the Myosin ⅦA gene of patients with nonsyndromic heating loss from Taiwan.Int J Pediatr Otorhinolaryngol,2009.17.
4.Weil D,Blanchard S,Kaplan J,Guilford P,Gibson F,Walsh J,Mburu P,Varela A,Levilliers J,Weston MD,et al.Defective myosin ⅦA gene responsible for Usher syndrome type 1B.Nature,1995.374(6517):60-61.
5.International Organization for Standardization Acoustics:reference zero for the calibration of audiometric equipment - part 1:reference equivalent threshold sound pressure levels for pure tones and supra - aural earphones,BS EN ISO 389 - 1.International Organization for Standardization,Geneva,Switzerland,2000.
6.International Organization for Standardization Acoustics:audiometric test methods,Ⅰ:basic pure tone air and bone conduction threshold audiometry,ISO 8253-1.International Organization for Standardization,Geneva,Switzerland,1998.
7.孙开来,熊第志,译。医学遗传学原理[M]．北京：科学出版社,2001：190-197．
8.Abecasis GR,Cherny SS,Cookson WO,et al.Merlin-rapid analysis of dense genetic maps using sparse gene flow trees.Nat Genet,2002.30:97-101.
9.Du C,Fang M,Li Y,et al.DFNA60,a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.Cell,2000.102(1):33-42.
10.Verhagen AM,Ekert PG,Pakusch M,et al.Identification of DFNA60,a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.Cell,2000.102(1):43-53.
11.Lalwani AK,Castelein CM.Cracking the auditory genetic code:nonsyndromic hereditary hearing impairment.Am J Otol,1999.20:115-132.
12.Greene CC,McMillan PM,Barker SE,Kurnool P,Lomax MI,Burmeister M,Lesperance MM.DFNA25,a novel locus for dominant nonsyndromic hereditary hearing impairment,maps to 12q21-24.Am J Hum Genet,2001.68(1):254-260.
13.Ruel J,Emery S,Nouvian R,et al.Impairment of SLC17A8 encoding vesicular glutamate transporter-3,VGLUT3,underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice.Am J Hum Genet,2008.83(2):278-292.
14.Blanton SH,Liang CY,Cai MW,Pandya A,Du L,Landa B,Mummalanni S,Li KS,Chen ZY,Qin XN,Liu YF,Balkany T,Nance WE,Liu XZ.A novel locus for autosomal dominant non-syndromic deafness(DFNA41) maps to chromosome 12q24-qter.J Med Genet,2002.39:567-570.
15.D'Adamo P,Pinna M,Capobianco S,Cesarini A,D'Eustacchio A,Fogu P,Carella M,Seri M,Gasparini P.A novel autosomal dominant non-syndromic deafness locus(DFNA48) maps to 12q13-q14 in a large Italian family.Hum Genet,2003.112:319-320.
16.Donaudy F,Ferrara A,Esposito L,Hertzano R,Ben-David O,Bell RE,Melchionda S,Zelante L,Avraham KB,Gasparini P.Multiple mutations of MYO1A,a cochlear-expressed gene,in sensorineural hearing loss.Am J Hum Genet,2003.72:1571-1577.
17.Smith RJ,Steel KP,Barkway C,Soucek S,Michaels L.A histologic study of nonmorphogenetic forms of hereditary hearing impairment.Arch Otolaryngol Head Neck Surg,1992.118(10):1085-1094.
18.Chai J,Du C,Wu JW,et al.Structural and biochemical basis of apoptotic activation by DFNA60.Nature,2000.406(6798):855-862.
19.Wu G,Chai J,Suber TL,Wu JW,Du C,Wang X,Shi Y.Structural basis of IAP recognition by DFNA60.Nature,2000.408:1008-1012.
20.Takasawa R,Tanuma S.Sustained release of DFNA60 from mitochondria commits to undergo UVB induced apoptosis.Apoptosis,2003.8(3):291-299.
21.Orrenius S,Gogvadze V,Zhivotovsky B.Mitochondrial oxidative stress:implications for cell death.Annu Rev Pharmacol Toxicol,2007.47:143-183.
22.Roberts DL,Merrion W,MacFarlane M,et al.The inhibitor of apoptosis protein-binding domain of DFNA60 is not essential for its proapoptotic activity.J Cell Biol,2001.153(1):221-228.
23.Adrain C,Creagh EM,Martin SJ.Apoptosis-associated release of DFNA60 from mitochondria requires active caspases and is blocked by Bcl-2.Embo J,2001.20(23):6627-6636.
24.Yoo NJ,Kim HS,Kim SY,et al.Immunohistochemical analysis of DFNA60 expression in human carcinomas and sarcomas.APMIS,2003.111(3):382-388.
25.郑丽瑞,陶凯雄,等。DFNA60基因过表达对胃癌细胞株MKN245化疗敏感性的影响。癌症,2004,23(4)：361。
26.Li R,Ruttinger D,Urba W,Fox BA,Hu HM.Targeting and amplificatim of immune killing of tumor cells by pro-DFNA60.Int J Cancer,2004.109(1):85-94.
27.Jia L,Patwari Y,Kelsey SM,et al.Role of DFNA60 in human leukaemic cell apoptosis and proliferation.Oncogene,2003.22(11):1589-1599.
28.Arnt CR,Chiorean MV,Heldebrant MP,Gores GJ,Kaufmann SH.Synthetic DFNA60 peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ.Biol Chem,2002.277(46):44236-44243.
1.Gates GA,Couropmitree NN,Myers RH.Genetic associations in age-related hearing thresholds.Arch Otolaryngol Head Neck Surg,1999.125:654-659.
2.Viljanen A,Era P,Kaprio J,et al.Genetic and environmental influences on hearing in older women.J Gerontol A Biol Sci Med Sci,2007.62:447-452.
3.Christensen K,Frederiksen H,Hoffman HJ.Genetic and environmental influences on self-reported reduced hearing in the old and oldest old.J Am Geriatr Soc,2001.49(11):1512-1517.
4.Dalton DS,Cruickshanks KJ,Klein BE,et al.The impact of hearing loss on quality of life in older adults.Gerontologist,2003.43(5):661-668.
5.Dobie RA.The relative contributions of occupational noise and aging in individual cases of hearing loss.Ear Hear,1992.13(1):19-27.
6.Mills JH,Matthews LJ,Lee FS,et al.Gender-specific effects of drugs on hearing levels of older persons.Ann NY Acad Sci,1999.884:381-388.
7.Kurien M,Thomas K,Bhanu TS.Hearing threshold in patients with diabetes mellitus.J Laryngol Otol,1989.103(2):164-168.
8.Gates GA,Cobb JL,D'Agostino RB,Wolf PA.The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors.Arch Otolaryngol Head Neck Surg,1993.119(2):156-161.
9.Risch N,Merikangas K.The future of genetic studies of complex human diseases.Science,1996.273(5281):1516-1517.
10.John H,Mills PRL.Otorhinolaryngology Head and Neck Surgery-Sixteenth Edition.Presbyacusis.2003.443.
11.赫尔辛基宣言,第52届世界医学大会,2000,10,苏格兰,爱丁堡。
12.世界人类基因组与人权宣言,联合国教科文组织第29届大会,1997,11,11,巴黎。
13.HUGO Ethics Committee:Statement on DNA Sampling:Control and Access,GD,1999,6(1):8-9.
14.Van Camp G.Hereditary Hearing Loss Homepage.
15.Kelsell DP,Dunlop J,Stevens HP,et al.Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.Nature,1997.387(6628):80-83.
16.肖自安,冯永,等:非综合征性耳聋患者连接蛋白26基因突变的研究。中华耳鼻咽喉科杂志,2000,35(3):188-191.
17.Murgia A,Orzan E,Polli R,et al.Cx26 deafness:mutation analysis and clinical variability.J Med Genet,1999.36:829-832.
18.Petersen MB,Willems PJ.Non-syndromic,autosomal-recessive deafness.Clin Genet,2006.69(5):371-92.
19.Engel-Yeger B,Zaaroura S,Zlotogora J,et al.The effects of a connexin 26mutation--35delG--on oto-acoustic emissions and brainstem evoked potentials:homozygotes and carriers.Hear Res,2002.163(1-2):93-100.
20.Wilcox SA,Saunders K,Osborn AH,et al.High frequency heating loss correlated with mutations in the GJB2 gene.Hum Genet,2000.106:399-405.
21.Franz(?) A,et al.Audiometric evaluation of carriers of the connexin 26mutation 35delG.Eur Arch Otorhinolaryngol,2005.262:921-924.
22.Lefebvre PP,Van De Water TR.Connexins,hearing and deafness:clinical aspects of mutations in the connexin 26 gene.Brain Res Brain Res Rev,2000.32(1):159-162.
23.Kikuchi T,Kimura RS,Paul DL,et al.Gap junction systems in the mammalian cochlea.Brain Res Brain Res Rev,2000.32:163-166.
24.Gasparini P,Rabionet R,Barbujani G,et al.High carrier frequency of the 35delG deafness mutation in European populations.European Journal of Human Genetics,2000.8(1):19-23.
25.Liu XZ,Xia X J,Ke XM,et al.The prevalence of connexin 26(GJB2)mutations in the Chinese population.Hum Genet,2002.111(4-5):394-397.
26.Kelley PM,Harris DJ,Comer BC,et al.Novel mutations in the connexin 26gene(GJB2) that cause autosomal recessive(DFNB1) hearing loss.Am J Hum Genet,1998.62(4):792-799.
27.Wilcox SA,Saunders K,Oshorn AH,et al.High-frequency hearing Loss correlated with mutations in the GJB2 gene.Hum Genet,2000.106:399-405.
28.Troen BR.The biology of aging.Mt Sinai J Med,2003.70(1):3-22.
29.Seidman MD,Ahmad N,Bai U.Molecular mechanisms of age-related hearing loss.Ageing Res Rev,2002.1(3):331-343.
30.韩维举,韩东一,等:人听觉器官线粒体DNA4977缺失与老年聋的关系.中华耳鼻咽喉科杂志,2000.35:416.
31.Dai P,Yang W,Jiang S,et al.Correlation of cochlear blood supply with mitochondrial DNA common deletion in presbyacusis.Acta Otolaryngol,2004.124(2):130-136.
32.Staecker H,Zheng QY,Van De Water TR.Oxidative stress in aging in the C57B 16/J mouse cochlea.Acta Otolaryngol,2001.121(6):666-672.
33.Goto Y,Nonaka I,Horai S.A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.Nature,1990.348(6302):651-653.
34.Bacino C,Prezant TR,Bu X,Fournier P,Fischel-Ghodsian N.Susceptibility mutations in the mitochondrial small ribosomal RNA gene in aminoglycoside induced deafness.Pharmacogenetics,1995.5(3):165-172.
35.Zhao H,Li R,Wang Q,et al.Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.Am J Hum Genet,2004.74(1):139-152.
36.Reid FM,Vernham GA,Jacobs HT.A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness.Hum Mutat,1994.3:243-247.
37.Tiranti V,Chariot P,Carella F,et al.Maternally inherited hearing loss,ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNA~(Ser(UCN))gene.Hum Mol Genet,1995.4(8):1421-1427.
38.Verhoeven K,Ensink RJ,Tiranti V,et al.Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNA~(Ser(UCN)) gene.Eur J Hum Genet,1999.7(1):45-51.
39.Hutchin TP,Parker MJ,Young ID,et al.A novel mutation in the mitochondrial tRNA(Ser(UCN))gene in a family with non-syndromic sensorineural hearing impairment.J Med Genet,2000.37(9):692-694.
40.Castillo FJ,Moreno-Pelayo MA,et al.Maternally inherited non-syndromal hearing impariment in a Spanish family with the 7510T＞C mutation in the mitochondrial tRNA(Ser(UCN))gene.J Med Genet,2002.39:82.
41.Sue CM,Tanji K,Hadjigeorgiou G,et al.Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser(UCN))gene.Neurol,1999.52(9):1905-1908.
42.Chapiro E,Feldmann D,Denoyelle F,et al.Two large French pedigrees with nonsyndromic sensorineural deafness and the mitochondrial DNA T7511C mutation:evidence for a modulatory factor.Eur J Hum Genet,2002.10(12):851-856.
43.Jaksch M,Klopstock T,Kurlemann G,et al.Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA(Ser(UCN)gene.Ann Neurol,1998.44(4):635-640.
44.Majamaa K,Moilanen JS,Uimonen S,et al.Epidemiology of A3243G,the mutation for mitochondrial encephalomyopathy,lactic acidosis,and stroke-like episodes:prevalence of the mutation in an adult population.Am J Hum Genet,1998.63(2):447-454.
45.Li R,Ishikawa K,Deng JH,et al.Maternally inherited nonsyndromic hearing loss is associated with the mitochondrial tRNA~(ser(UCN)) T7511C mutation in a Japanese family.Biochem Biophys Res Commun,2005.328(1):32-37.
46.Tessa A,Giannotti A,Tieri L,et al.Maternally inherited deafness associated with a T1095C mutation in the mDNA.Eur J Hum Genet,2001.9:147-149.
47.HARMAN D.Aging:a theory based on free radical and radiation chemistry.J Gerontol,1956.11(3):298-300.
48.Richter C,Park JW,Ames BN.Normal oxidative damage to mitochondrial and nuclear DNA is extensive.Proc Natl Acad Sci U S A,1988.85(17):6465-6467.
49.Hayakawa M,Torii K,Sugiyama S,et al.Age-associated accumulation of 8-hydroxydeoxyguanosine in mitochondrial DNA of human diaphragm.Biochem Biophys Res Commum,1991.179(2):1023-1029.
50.Hayakawa M,Hattori K,Sugiyama S,Ozawa T.Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts.Biochem Biophys Res Comm,1992.189(2):979-985.
51.Mecocci P,MacGarvey U,Kaufman AE,et al.Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain.Ann Neurol,1993.34(4):609-616.
52.Zhao L,Young WY,Li R,Wang Q,Qian Y,Guan MX.Clinical evaluation and sequence analysis of the complete mitochondrial genome of three Chinese patients with hearing impairment associated with the 12S rRNA T1095C mutation.Biochem Biophys Res Commun,2004.325(4):1503-1538.
53.Reid FM,Vernham GA,Jacobs HT.A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness.Hum Mutat,1994.3:243-247.
54.del Castillo FJ,Rodriguez-Ballesteros M,Martin Y,et al.Heteroplasmy for the 1555A＞G mutation in the mitochondrial 12S rRNA gene in six Spanish families with non-syndromic hearing loss.J Med Genet,2003.40:632-636.
55.el-Schahawi M,Lopez de Munain A,Sarrazin AM,et al.Two large Spanish pedigrees with nonsyndromic sensorineural deafness and the mtDNA mutation at nt1555 in the 12S rRNA gene:evidence of heteroplasmy.Neurology,1997.48(2):453-456.
56.Chaig MR,Zernotti ME,Soria NW,Romero OF,Romero MF,Gerez NM.A mutation in mitochondrial 12S rRNA,A827G,in Argentinean family with hearing loss after aminoglycoside treatment.Biochem and Biophys Res Commun,2008.368(3):631-636.
57.Li Z,Li R,Chen J,Liao Z,et al.Mutational analysis of the mitochondrial 12S rRNA gene in Chinese pediatric subjects with aminoglycoside-induced and non-syndromic hearing loss.Hum Genet,2005.117(1):9-15.
58.Thyagarajan D,Bressman S,Bruno C,et al.A novel mitochondrial 12SrRNA point mutation in parkinsonism,deafness,and neuropathy.Ann Neurol,2000.48(5):730-736.
59.Wang Q,Li R,Zhao H,et al.Clinical and molecular characterization of a Chinese patient with auditory neuropathy associated with mitochondrial 12S rRNA T1095C mutation.Am J Med Genet A,2005.133A(1):27-30.
60.Mannervik B,Board PG,Hayes JD,et al.Nomenclature for human glutathione transferases.Biochem J,1992.282:305-306.
61.Strange RC,Spiteri MA,Ramachandran S,et al.Glutathione-S-transferase family of enzymes.Mutat Res,2001.482:21-26.
62.Unal M,Tamer L,Dogruer ZN,et al.N-Acetyltransferase 2 Gene Polymorphism and Presbycusis.Laryngoscope,2005.115(12):2238-2241.
63.McFadden SL,Ohlemiller KK,Ding D,et al.The influence of superoxide dismutase and glutathione peroxidase deficiencies on noise-induced hearing loss in mice.Noise Health,2001.3(11):49-64.
64.Fortunato G,Marciano E,Zarrilli F,et al.Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss.Clin Chem,2004.50(11):2012-2018.
65.Ohlemiller KK,McFadden SL,Ding DL,et al.Targeted mutation of the gene for cellular glutathione peroxidase(Gpxl) increases noise-induced hearing loss in mice.J Assoc Res Otolaryngol,2000.1(3):243-254.
66.Lautermann J,Crann SA,McLaren J,Schacht J.Glutathione-dependent antioxidant systems in the mammalian inner ear:effects of aging,ototoxic drugs and noise.Hear Res,1997.114(1-2):75-82.
67.Pemble S,Schroeder KR,Spencer SR,et al.Human glutathione S-transferase theta(GSTT1):cDNA cloning and the characterization of a genetic polymorphism.Biochem J,1994.300:271-276.
68.Rabinowitz PM,Pierce Wise J Sr,Hur Mobo B,Antonucci PG.Antioxidant status and hearing function in noise-exposed workers.Hear Res,2002.173(1-2):164-171.
69.Abdel-Rahman SZ,el-Zein RA,Anwar WA,Au WW.A multiplex PCR procedure for polymorphic analysis of GSTM1 and GSTT1 genes in population studies.Cancer Lett,1996.107(2):229-233.
70.Lee KA,Kim SH,Woo HY,et al.Increased frequencies of glutathione S-transferase(GSTM1 and GSTT1) gene deletions in Korean patients with acquired aplastic anemia.Blood,2001.98(12):3483-3485.
71.Ates NA,Unal M,Tamer L,et al.Glutathione S-transferase gene polymorphisms in presbycusis.Otol Neurotol,2005.26(3):392-397.
1.Fischel-Ghodsian N.Genetic factors in aminoglycoside toxicity.Pharmacogenomics,2005.6:27-36.
2.Li XF,Schwartz F,Yan Q,Friedman RA,Guan MX.Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness.Nucleic Acids Res,2004.32:867-877.
3.Zhao H,et al.Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.Am J Hum Genet,2004.74(1):139-52.
4.Zhao H,et al.,Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss.Nucleic Acids Res,2005.33(3):p.1132-9.
5.Estivill X,Barcelo'E,Perello'C.Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycoside.Am J Hum Genet,1998.62:27-35.
6.Matthijs G,Longo-Bbenza JJ,Cassiman.Nonsyndromic deafness associated with a mutation and a polymorphism in the mitochondrial 12S ribosomal RNA gene in a large Zairean pedigree.Eur J Hum Genet,1996.4:46-51.
7.Jacobs HT,Kappi T,Gillies G,Minkkinen K,Walker J,Thompson K,Rovio AT,Carella M.Mitochondrial DNA mutations in patients with postlingual,nonsyndromic hearing impairment.Eur J Hum Genet,2005.13:26-33.
8.Li R,Yan X,Cao XZ,Liu X,Guan MX.Cosegregation of C-insertion at position 961 with A1555G mutation of mitochondrial 12S rRNA gene in a large Chinese family with maternally inherited hearing loss.Am J Med Genet A,2004.124:113-117.
9.Yuan H,Xu Y,Cao J,Bai L,Shen W,Ji F,Zhang X.Cosegregation of the G7444A mutation in the mitochondrial COI/tRNASer(UCN) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside-induced and non-syndromic hearing loss.Am J Med Genet A, 2005.138:133-140.
10.Wang Q,et al.Clinical and molecular analysis of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss associated with the mitochondrial 12S rRNA C1494T mutation.Biochem Biophys Res Commun,2006.340:583-588.
11.Wang C,et al.mtDNA mutation C1494T,haplogroup A,and hearing loss in Chinese.Biochem Biophys Res Commun,2006.348:712-715.
12.Rieder MJ,Taylor SL,Tobe VO,Nickerson DA.Automating the identification of DNA variations using quality-based fluorescence resequencing:analysis of the human mitochondrial genome.Nucleic Acids Res,1998(26):967-973.
13.Andrews RM,Kubacka I,Chinnery PF,Lightowlers RN,Turnbull DM,Howell N.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA.Nat Genet,1999.23:147.
14.Bibb MJ,Van Etten,Wright RA,Walberg CT,Clayton MW.Sequence and gene organization of mouse mitochondrial DNA.Cell,1981.26:167-180.
15.Gadaleta G,Pepe G,De CandiaG.,Quagliariello C,Sbisa E,Saccone C.The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome:cryptic signals revealed by comparative analysis between vertebrates.J Mol Evol,1989.28:497-516.
16.Roe A,Ma DP,Wilson RK,Wong JF.The complete nucleotide sequence of the Xenopus laevis mitochondrial genome.J Biol Chem,1985.260:9759-9774.
17.Tanaka M,et al.Mitochondrial genome variation in eastern Asia and the peopling of Japan.Genome Res,2004.14:1832-1850.
18.Han D,et al.The mitochondrial tRNA(Ala) T5628C variant may have a modifying role in the phenotypic manifestation of the 12S rRNA C1494T mutation in a large Chinese family with hearing loss.Biochem Biophys Res Commun,2007.357(2):554-60.
19.Chen J,et al.Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees.Gene,2007.401(1-2):4-11.
20.Yuan H,et al.Coexistence of mitochondrial 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigrees with aminoglycoside-induced and non-syndromic hearing loss.Biochem Biophys Res Commun,2007.362(1):94-100.
21.Cann R.Mitochondrial DNA and human evolution.Nature,1987.325:31-36.
22.Li R,Deng JH,Yang L,Tamagawa Y,Bai Y,Ichimura K,Guan MX.Maternally inherited nonsyndromic hearing loss is associated with the mitochondrial tRNASer(UCN) 7511C mutation in a Japanese family.Biochem Biophys Res Commun,2005.328:32-37.
23.Reid F,Vernham G,Jacobs H.A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness.Hum Mutat,1994.3:243-247.
24.Prezant T,et al.Mitochondrialribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness.Nat Genet,1993.4:289-294.
25.戴朴,刘新,于飞,等.全国18个聋校学生非综合征性聋分子病因学研究.中华耳科学杂志,2006.4:1-5.
26.Casano RMS,et al.Hearing Loss Due to the Mitochondrial A1555G Mutation in Italian Families.American Journal of Medical Genetics,1998.79:388-391.
27.Torroni A,et al.The A1555G mutation in the 12S rRNA gene of human mtDNA:recurrent origins and founder events in families affected by sensorineural deafness.Am J Hum Genet,1999.65:1349-1358.
28.Estivill X,et al.Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides.A m J Hum Genet,1998.62:27-35.
29.Torroni A,et al.Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484.Am J Hum Genet,1997.60:1107-1121.
1.Chang HP,Chou P,et al.Presbycusis among older Chinese people in Taipei,Taiwan:A community-based study.Int J Audiol,2007,46(12):738.
2.Dalton DS,et al.The impact of hearing loss on quality of life in older adults.Gerontologist,2003,43(5):661.
3.Viljanen A,Kaprio J,Pyykko I,et al.Genetic and environmental influences on hearing in older women.J.Gerontol.A Biol Sci Med Sci,2007,62:447.
4.Christensen K,Hoffman HJ,et al.Genetic and environmental influences on self-reported reduced hearing in the old and oldest old.J Am Geriatr Soc,2001,49:1512.
5.Gates GA,Myers RH,et al.Genetic associations in age-related hearing thresholds.Arch Otolaryngol Head Neck Surg,1999,125:654.
6.Dobie RA.The relative contributions of occupational noise and aging in individual cases of hearing loss.Ear Hear,1992,13:19.
7.Mills JH,Lee FS,Dubno JR,et al.Gender-specific effects of drugs on hearing levels of older persons.Ann.NY Acad Sci,1999,884:381.
8.Kurien M,Bhanu TS,et al.Hearing threshold in patients with diabetes mellitus.J Laryngol Otol,1989,103:164.
9.Gates GA,et al.The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors.Arch Otolaryngol Head Neck Surg,1993,119:156.
10.Tepass U,Truong K,et al.Cadherins in embryonic and neural morphogenesis.Nat Rev Mol Cell Biol,2000,1:91.
11.Di PF,Holme RH,et al.Mutations in Cdh23,encoding a new type of cadherin,cause stereocilia disorganization in waltzer,the mouse model for Usher syndrome type ID.Nat Genet,2001,27:103.
12.Siemen JL,et al.Cadherin 23 is a component of the tip link in hair-cell stereocilia.Nature,2004,428(6986):950.
13.Astuto LM,Weston MD,et al.CDH23 mutation and phenotype heterogeneity:a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness.Am J Hum Genet,2002,71:262.
14.Noben-Trauth K,Johnson KR,et al.Association of cadherin23 with polygenic inheritance and genetic modification of sensorineural hearing loss.Nat Genet,2003,35:21.
15.Davis RR,et al.Genetic influences in individual susceptibility to noise:a review.Noise Health,2003,5(20):19.
16.Johnson KR,et al.A major gene affecting age-related hearing loss is common to at least ten inbred strains of mice.Genomics,2000,70:171.
17.Bolz H,et al.Mutation of CDH23,encoding a new member of the cadherin gene family,causes Usher syndrome type 1D.Nat Genet,2001,27:108.
18.Kubisch C,Friedrich T,et al.KCNQ4,a novel potassium channel expressed in sensory outer hair cells,is mutated in dominant deafness.Cell,1999,96:437.
19.Kharkovets T,et al.KCNQ4,a K1 channel mutated in a form of dominant deafness,is expressed in the inner ear and the central auditory pathway.Proc Natl Acad Sci USA,2000,97:4333.
20.Kharkovets T,Maier H,et al.Mice with altered KCNQ4 K1 channels implicate sensory outer hair cells in human progressive deafness.EMBO J,2006,25:642.
21.Coucke PJ,Kelley PM,et al.Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.Hum Mol Genet,1999,8:1321.
22.Van Eyken E,Fransen E,et al.KCNQ4:a gene for age-related hearing impairment?.Hum Mutat,2006,27:1007.
23.Lefebvre PP,et al.Cormexins,hearing and deafness:clinical aspects of mutations in the connexin 26 gene.Brain Res Brain Res Rev,2000,32:159.
24.Kikuchi T,Paul DL,et al.Gap junction systems in the mammalian cochlea.Brain Res Brain Res Rev,2000,32:163.
25.Gasparini P,Rabionet R,et al.High carrier frequency of the 35delG deafness mutation in European populations.European Journal of Human Genetics,2000,8:19.
26.Liu XZ,Xia XJ,et al.The prevalence of connexin 26(GJB2) mutations in the Chinese population.Hum Genet,2002,11:394.
27.Kelsell DP,Stevens HP,et al.Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.Nature,1997,387(6628):80.
28.肖自安,冯永,等：非综合征性耳聋患者连接蛋白26基因突变的研究。中华耳鼻咽喉科杂志,2000,35(3)：188．
29.Murgia A,Polli R,et al.Cx26 deafness:mutation analysis and clinical variability.J Med Genet,1999,36:829.
30.Van Eyken E,et al.The Contribution of GJB2(Connexin 26) 35delG to Age-Related Hearing Impairment and Noise-Induced Hearing Loss.Otology & Neurotology,2007,28(7):970.
31.Van Laer L,et al.The grainyhead like 2 gene(GRHL2),alias TFCP2L3,is associated with age-related hearing impairment.Human Molecular Genetics,2008,17(2):159.
32.Wilanowski T,Tuckfield A,et al.A highly conserved novel family of mammalian developmental transcription factors related to Drosophila grainyhead.Mech Dev,2002,114(1-2):37.
33.Ting SB,et al.The identification and characterization of human Sister-of-Mammalian Grainyhead(SOM) expands the grainyhead-like family of developmental transcription factors.Biochem J,2003,370(3):953.
34.Auden A,et al.Spatial and temporal expression of the Grainyhead-like transcription factor family during murine development.Gene Expr Patterns,2006,6(8):964.
35.Seidman MD,Khan MJ,et al.Association of mitochondrial DNA deletions and cochlear pathology:a molecular biologic tool.Laryngoscope,1996,106:777.
36.Seidman MD,Dolan D,et al.Age-related differences in cochlear microcirculation and auditory brain stem response.Arch Otolaryngol Head Neck Surg,1996,122:1221.
37.韩维举,韩东一,等：人听觉器官线粒体DNA4977缺失与老年聋的关系．中华耳鼻咽喉科杂志,2000,35：416．
38.Dai P,Jiang S,Gu R,et al.Correlation of cochlear blood supply with mitochondrial DNA common deletion in presbyacusis.Acta Otolaryngol,2004,124:130.
39.Unal M,et al.N-Acetyltransferase 2 Gene Polymorphism and Presbycusis.Laryngoscope,2005,115(12):2238.
40.Mannervik B,Board PG,et al.Nomenclature for human glutathione transferases.Biochem J,1992,282:305.
41.Strange RC,et al.Glutathione-S-transferase family of enzymes.Mutat Res,2001,482:21.
42.Pemble S,Spencer SR,et al.Human glutathione S-transferase theta(GSTT1):cDNA cloning and the characterization of a genetic polymorphism.Biochem J,1994,300:271.
43.Rabinowitz PM,et al.Antioxidant status and hearing function in noise-exposed workers.Hear Res,2002,173:164.
44.McFadden SL,et al.The influence of superoxide dismutase and glutathione peroxidase deficiencies on noise-induced hearing loss in mice.Noise Health,2001,3:49.
45.Fortunato G,Zarrilli F,Mazzaccara C,et al.Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss.Clin Chem, 2004,50:2012.
46.Ohlemiller KK,et al.Targeted mutation of the gene for cellular glutathione peroxidase(Gpxl) increases noise-induced hearing loss in mice.Assoc Res Otolaryngol,2000,1:243.
2.Hughes AL,Welch R,Puff V,et al.Genome-wide SNP typing reveals signatures of population history.Genomics,2008.92(1):1-8.
3.Cann R.Mitochondrial DNA and human evolution.Nature,1987.325:31-36.
4.Maciejewski JP,Mufti GJ.Whole genome scanning as a cytogenetic tool in hematologic malignancies.Blood,2008.112(4):965-974.
1.Beckstead WA,Bjork BC,Stottmann RW,et al.SNP2RFLP:a computational tool to facilitate genetic mapping using benchtop analysis of SNPs.Mamm Genome,2008.19(10-12):687-690.
2.Van Laer L,Cryns K,Smith RJ,et al.Nonsyndromic Heating Loss.Ear Hear,2003.24:275-288.
3.Su MC,Yang JJ,Su CC,Hsin CH,Li SY.Identification of novel variants in the Myosin ⅦA gene of patients with nonsyndromic heating loss from Taiwan.Int J Pediatr Otorhinolaryngol,2009.17.
4.Weil D,Blanchard S,Kaplan J,Guilford P,Gibson F,Walsh J,Mburu P,Varela A,Levilliers J,Weston MD,et al.Defective myosin ⅦA gene responsible for Usher syndrome type 1B.Nature,1995.374(6517):60-61.
5.International Organization for Standardization Acoustics:reference zero for the calibration of audiometric equipment - part 1:reference equivalent threshold sound pressure levels for pure tones and supra - aural earphones,BS EN ISO 389 - 1.International Organization for Standardization,Geneva,Switzerland,2000.
6.International Organization for Standardization Acoustics:audiometric test methods,Ⅰ:basic pure tone air and bone conduction threshold audiometry,ISO 8253-1.International Organization for Standardization,Geneva,Switzerland,1998.
7.孙开来,熊第志,译。医学遗传学原理[M]．北京：科学出版社,2001：190-197．
8.Abecasis GR,Cherny SS,Cookson WO,et al.Merlin-rapid analysis of dense genetic maps using sparse gene flow trees.Nat Genet,2002.30:97-101.
9.Du C,Fang M,Li Y,et al.DFNA60,a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.Cell,2000.102(1):33-42.
10.Verhagen AM,Ekert PG,Pakusch M,et al.Identification of DFNA60,a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.Cell,2000.102(1):43-53.
11.Lalwani AK,Castelein CM.Cracking the auditory genetic code:nonsyndromic hereditary hearing impairment.Am J Otol,1999.20:115-132.
12.Greene CC,McMillan PM,Barker SE,Kurnool P,Lomax MI,Burmeister M,Lesperance MM.DFNA25,a novel locus for dominant nonsyndromic hereditary hearing impairment,maps to 12q21-24.Am J Hum Genet,2001.68(1):254-260.
13.Ruel J,Emery S,Nouvian R,et al.Impairment of SLC17A8 encoding vesicular glutamate transporter-3,VGLUT3,underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice.Am J Hum Genet,2008.83(2):278-292.
14.Blanton SH,Liang CY,Cai MW,Pandya A,Du L,Landa B,Mummalanni S,Li KS,Chen ZY,Qin XN,Liu YF,Balkany T,Nance WE,Liu XZ.A novel locus for autosomal dominant non-syndromic deafness(DFNA41) maps to chromosome 12q24-qter.J Med Genet,2002.39:567-570.
15.D'Adamo P,Pinna M,Capobianco S,Cesarini A,D'Eustacchio A,Fogu P,Carella M,Seri M,Gasparini P.A novel autosomal dominant non-syndromic deafness locus(DFNA48) maps to 12q13-q14 in a large Italian family.Hum Genet,2003.112:319-320.
16.Donaudy F,Ferrara A,Esposito L,Hertzano R,Ben-David O,Bell RE,Melchionda S,Zelante L,Avraham KB,Gasparini P.Multiple mutations of MYO1A,a cochlear-expressed gene,in sensorineural hearing loss.Am J Hum Genet,2003.72:1571-1577.
17.Smith RJ,Steel KP,Barkway C,Soucek S,Michaels L.A histologic study of nonmorphogenetic forms of hereditary hearing impairment.Arch Otolaryngol Head Neck Surg,1992.118(10):1085-1094.
18.Chai J,Du C,Wu JW,et al.Structural and biochemical basis of apoptotic activation by DFNA60.Nature,2000.406(6798):855-862.
19.Wu G,Chai J,Suber TL,Wu JW,Du C,Wang X,Shi Y.Structural basis of IAP recognition by DFNA60.Nature,2000.408:1008-1012.
20.Takasawa R,Tanuma S.Sustained release of DFNA60 from mitochondria commits to undergo UVB induced apoptosis.Apoptosis,2003.8(3):291-299.
21.Orrenius S,Gogvadze V,Zhivotovsky B.Mitochondrial oxidative stress:implications for cell death.Annu Rev Pharmacol Toxicol,2007.47:143-183.
22.Roberts DL,Merrion W,MacFarlane M,et al.The inhibitor of apoptosis protein-binding domain of DFNA60 is not essential for its proapoptotic activity.J Cell Biol,2001.153(1):221-228.
23.Adrain C,Creagh EM,Martin SJ.Apoptosis-associated release of DFNA60 from mitochondria requires active caspases and is blocked by Bcl-2.Embo J,2001.20(23):6627-6636.
24.Yoo NJ,Kim HS,Kim SY,et al.Immunohistochemical analysis of DFNA60 expression in human carcinomas and sarcomas.APMIS,2003.111(3):382-388.
25.郑丽瑞,陶凯雄,等。DFNA60基因过表达对胃癌细胞株MKN245化疗敏感性的影响。癌症,2004,23(4)：361。
26.Li R,Ruttinger D,Urba W,Fox BA,Hu HM.Targeting and amplificatim of immune killing of tumor cells by pro-DFNA60.Int J Cancer,2004.109(1):85-94.
27.Jia L,Patwari Y,Kelsey SM,et al.Role of DFNA60 in human leukaemic cell apoptosis and proliferation.Oncogene,2003.22(11):1589-1599.
28.Arnt CR,Chiorean MV,Heldebrant MP,Gores GJ,Kaufmann SH.Synthetic DFNA60 peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ.Biol Chem,2002.277(46):44236-44243.
1.Gates GA,Couropmitree NN,Myers RH.Genetic associations in age-related hearing thresholds.Arch Otolaryngol Head Neck Surg,1999.125:654-659.
2.Viljanen A,Era P,Kaprio J,et al.Genetic and environmental influences on hearing in older women.J Gerontol A Biol Sci Med Sci,2007.62:447-452.
3.Christensen K,Frederiksen H,Hoffman HJ.Genetic and environmental influences on self-reported reduced hearing in the old and oldest old.J Am Geriatr Soc,2001.49(11):1512-1517.
4.Dalton DS,Cruickshanks KJ,Klein BE,et al.The impact of hearing loss on quality of life in older adults.Gerontologist,2003.43(5):661-668.
5.Dobie RA.The relative contributions of occupational noise and aging in individual cases of hearing loss.Ear Hear,1992.13(1):19-27.
6.Mills JH,Matthews LJ,Lee FS,et al.Gender-specific effects of drugs on hearing levels of older persons.Ann NY Acad Sci,1999.884:381-388.
7.Kurien M,Thomas K,Bhanu TS.Hearing threshold in patients with diabetes mellitus.J Laryngol Otol,1989.103(2):164-168.
8.Gates GA,Cobb JL,D'Agostino RB,Wolf PA.The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors.Arch Otolaryngol Head Neck Surg,1993.119(2):156-161.
9.Risch N,Merikangas K.The future of genetic studies of complex human diseases.Science,1996.273(5281):1516-1517.
10.John H,Mills PRL.Otorhinolaryngology Head and Neck Surgery-Sixteenth Edition.Presbyacusis.2003.443.
11.赫尔辛基宣言,第52届世界医学大会,2000,10,苏格兰,爱丁堡。
12.世界人类基因组与人权宣言,联合国教科文组织第29届大会,1997,11,11,巴黎。
13.HUGO Ethics Committee:Statement on DNA Sampling:Control and Access,GD,1999,6(1):8-9.
14.Van Camp G.Hereditary Hearing Loss Homepage.
15.Kelsell DP,Dunlop J,Stevens HP,et al.Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.Nature,1997.387(6628):80-83.
16.肖自安,冯永,等:非综合征性耳聋患者连接蛋白26基因突变的研究。中华耳鼻咽喉科杂志,2000,35(3):188-191.
17.Murgia A,Orzan E,Polli R,et al.Cx26 deafness:mutation analysis and clinical variability.J Med Genet,1999.36:829-832.
18.Petersen MB,Willems PJ.Non-syndromic,autosomal-recessive deafness.Clin Genet,2006.69(5):371-92.
19.Engel-Yeger B,Zaaroura S,Zlotogora J,et al.The effects of a connexin 26mutation--35delG--on oto-acoustic emissions and brainstem evoked potentials:homozygotes and carriers.Hear Res,2002.163(1-2):93-100.
20.Wilcox SA,Saunders K,Osborn AH,et al.High frequency heating loss correlated with mutations in the GJB2 gene.Hum Genet,2000.106:399-405.
21.Franz(?) A,et al.Audiometric evaluation of carriers of the connexin 26mutation 35delG.Eur Arch Otorhinolaryngol,2005.262:921-924.
22.Lefebvre PP,Van De Water TR.Connexins,hearing and deafness:clinical aspects of mutations in the connexin 26 gene.Brain Res Brain Res Rev,2000.32(1):159-162.
23.Kikuchi T,Kimura RS,Paul DL,et al.Gap junction systems in the mammalian cochlea.Brain Res Brain Res Rev,2000.32:163-166.
24.Gasparini P,Rabionet R,Barbujani G,et al.High carrier frequency of the 35delG deafness mutation in European populations.European Journal of Human Genetics,2000.8(1):19-23.
25.Liu XZ,Xia X J,Ke XM,et al.The prevalence of connexin 26(GJB2)mutations in the Chinese population.Hum Genet,2002.111(4-5):394-397.
26.Kelley PM,Harris DJ,Comer BC,et al.Novel mutations in the connexin 26gene(GJB2) that cause autosomal recessive(DFNB1) hearing loss.Am J Hum Genet,1998.62(4):792-799.
27.Wilcox SA,Saunders K,Oshorn AH,et al.High-frequency hearing Loss correlated with mutations in the GJB2 gene.Hum Genet,2000.106:399-405.
28.Troen BR.The biology of aging.Mt Sinai J Med,2003.70(1):3-22.
29.Seidman MD,Ahmad N,Bai U.Molecular mechanisms of age-related hearing loss.Ageing Res Rev,2002.1(3):331-343.
30.韩维举,韩东一,等:人听觉器官线粒体DNA4977缺失与老年聋的关系.中华耳鼻咽喉科杂志,2000.35:416.
31.Dai P,Yang W,Jiang S,et al.Correlation of cochlear blood supply with mitochondrial DNA common deletion in presbyacusis.Acta Otolaryngol,2004.124(2):130-136.
32.Staecker H,Zheng QY,Van De Water TR.Oxidative stress in aging in the C57B 16/J mouse cochlea.Acta Otolaryngol,2001.121(6):666-672.
33.Goto Y,Nonaka I,Horai S.A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.Nature,1990.348(6302):651-653.
34.Bacino C,Prezant TR,Bu X,Fournier P,Fischel-Ghodsian N.Susceptibility mutations in the mitochondrial small ribosomal RNA gene in aminoglycoside induced deafness.Pharmacogenetics,1995.5(3):165-172.
35.Zhao H,Li R,Wang Q,et al.Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.Am J Hum Genet,2004.74(1):139-152.
36.Reid FM,Vernham GA,Jacobs HT.A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness.Hum Mutat,1994.3:243-247.
37.Tiranti V,Chariot P,Carella F,et al.Maternally inherited hearing loss,ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNA~(Ser(UCN))gene.Hum Mol Genet,1995.4(8):1421-1427.
38.Verhoeven K,Ensink RJ,Tiranti V,et al.Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNA~(Ser(UCN)) gene.Eur J Hum Genet,1999.7(1):45-51.
39.Hutchin TP,Parker MJ,Young ID,et al.A novel mutation in the mitochondrial tRNA(Ser(UCN))gene in a family with non-syndromic sensorineural hearing impairment.J Med Genet,2000.37(9):692-694.
40.Castillo FJ,Moreno-Pelayo MA,et al.Maternally inherited non-syndromal hearing impariment in a Spanish family with the 7510T＞C mutation in the mitochondrial tRNA(Ser(UCN))gene.J Med Genet,2002.39:82.
41.Sue CM,Tanji K,Hadjigeorgiou G,et al.Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser(UCN))gene.Neurol,1999.52(9):1905-1908.
42.Chapiro E,Feldmann D,Denoyelle F,et al.Two large French pedigrees with nonsyndromic sensorineural deafness and the mitochondrial DNA T7511C mutation:evidence for a modulatory factor.Eur J Hum Genet,2002.10(12):851-856.
43.Jaksch M,Klopstock T,Kurlemann G,et al.Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA(Ser(UCN)gene.Ann Neurol,1998.44(4):635-640.
44.Majamaa K,Moilanen JS,Uimonen S,et al.Epidemiology of A3243G,the mutation for mitochondrial encephalomyopathy,lactic acidosis,and stroke-like episodes:prevalence of the mutation in an adult population.Am J Hum Genet,1998.63(2):447-454.
45.Li R,Ishikawa K,Deng JH,et al.Maternally inherited nonsyndromic hearing loss is associated with the mitochondrial tRNA~(ser(UCN)) T7511C mutation in a Japanese family.Biochem Biophys Res Commun,2005.328(1):32-37.
46.Tessa A,Giannotti A,Tieri L,et al.Maternally inherited deafness associated with a T1095C mutation in the mDNA.Eur J Hum Genet,2001.9:147-149.
47.HARMAN D.Aging:a theory based on free radical and radiation chemistry.J Gerontol,1956.11(3):298-300.
48.Richter C,Park JW,Ames BN.Normal oxidative damage to mitochondrial and nuclear DNA is extensive.Proc Natl Acad Sci U S A,1988.85(17):6465-6467.
49.Hayakawa M,Torii K,Sugiyama S,et al.Age-associated accumulation of 8-hydroxydeoxyguanosine in mitochondrial DNA of human diaphragm.Biochem Biophys Res Commum,1991.179(2):1023-1029.
50.Hayakawa M,Hattori K,Sugiyama S,Ozawa T.Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts.Biochem Biophys Res Comm,1992.189(2):979-985.
51.Mecocci P,MacGarvey U,Kaufman AE,et al.Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain.Ann Neurol,1993.34(4):609-616.
52.Zhao L,Young WY,Li R,Wang Q,Qian Y,Guan MX.Clinical evaluation and sequence analysis of the complete mitochondrial genome of three Chinese patients with hearing impairment associated with the 12S rRNA T1095C mutation.Biochem Biophys Res Commun,2004.325(4):1503-1538.
53.Reid FM,Vernham GA,Jacobs HT.A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness.Hum Mutat,1994.3:243-247.
54.del Castillo FJ,Rodriguez-Ballesteros M,Martin Y,et al.Heteroplasmy for the 1555A＞G mutation in the mitochondrial 12S rRNA gene in six Spanish families with non-syndromic hearing loss.J Med Genet,2003.40:632-636.
55.el-Schahawi M,Lopez de Munain A,Sarrazin AM,et al.Two large Spanish pedigrees with nonsyndromic sensorineural deafness and the mtDNA mutation at nt1555 in the 12S rRNA gene:evidence of heteroplasmy.Neurology,1997.48(2):453-456.
56.Chaig MR,Zernotti ME,Soria NW,Romero OF,Romero MF,Gerez NM.A mutation in mitochondrial 12S rRNA,A827G,in Argentinean family with hearing loss after aminoglycoside treatment.Biochem and Biophys Res Commun,2008.368(3):631-636.
57.Li Z,Li R,Chen J,Liao Z,et al.Mutational analysis of the mitochondrial 12S rRNA gene in Chinese pediatric subjects with aminoglycoside-induced and non-syndromic hearing loss.Hum Genet,2005.117(1):9-15.
58.Thyagarajan D,Bressman S,Bruno C,et al.A novel mitochondrial 12SrRNA point mutation in parkinsonism,deafness,and neuropathy.Ann Neurol,2000.48(5):730-736.
59.Wang Q,Li R,Zhao H,et al.Clinical and molecular characterization of a Chinese patient with auditory neuropathy associated with mitochondrial 12S rRNA T1095C mutation.Am J Med Genet A,2005.133A(1):27-30.
60.Mannervik B,Board PG,Hayes JD,et al.Nomenclature for human glutathione transferases.Biochem J,1992.282:305-306.
61.Strange RC,Spiteri MA,Ramachandran S,et al.Glutathione-S-transferase family of enzymes.Mutat Res,2001.482:21-26.
62.Unal M,Tamer L,Dogruer ZN,et al.N-Acetyltransferase 2 Gene Polymorphism and Presbycusis.Laryngoscope,2005.115(12):2238-2241.
63.McFadden SL,Ohlemiller KK,Ding D,et al.The influence of superoxide dismutase and glutathione peroxidase deficiencies on noise-induced hearing loss in mice.Noise Health,2001.3(11):49-64.
64.Fortunato G,Marciano E,Zarrilli F,et al.Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss.Clin Chem,2004.50(11):2012-2018.
65.Ohlemiller KK,McFadden SL,Ding DL,et al.Targeted mutation of the gene for cellular glutathione peroxidase(Gpxl) increases noise-induced hearing loss in mice.J Assoc Res Otolaryngol,2000.1(3):243-254.
66.Lautermann J,Crann SA,McLaren J,Schacht J.Glutathione-dependent antioxidant systems in the mammalian inner ear:effects of aging,ototoxic drugs and noise.Hear Res,1997.114(1-2):75-82.
67.Pemble S,Schroeder KR,Spencer SR,et al.Human glutathione S-transferase theta(GSTT1):cDNA cloning and the characterization of a genetic polymorphism.Biochem J,1994.300:271-276.
68.Rabinowitz PM,Pierce Wise J Sr,Hur Mobo B,Antonucci PG.Antioxidant status and hearing function in noise-exposed workers.Hear Res,2002.173(1-2):164-171.
69.Abdel-Rahman SZ,el-Zein RA,Anwar WA,Au WW.A multiplex PCR procedure for polymorphic analysis of GSTM1 and GSTT1 genes in population studies.Cancer Lett,1996.107(2):229-233.
70.Lee KA,Kim SH,Woo HY,et al.Increased frequencies of glutathione S-transferase(GSTM1 and GSTT1) gene deletions in Korean patients with acquired aplastic anemia.Blood,2001.98(12):3483-3485.
71.Ates NA,Unal M,Tamer L,et al.Glutathione S-transferase gene polymorphisms in presbycusis.Otol Neurotol,2005.26(3):392-397.
1.Fischel-Ghodsian N.Genetic factors in aminoglycoside toxicity.Pharmacogenomics,2005.6:27-36.
2.Li XF,Schwartz F,Yan Q,Friedman RA,Guan MX.Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness.Nucleic Acids Res,2004.32:867-877.
3.Zhao H,et al.Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.Am J Hum Genet,2004.74(1):139-52.
4.Zhao H,et al.,Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss.Nucleic Acids Res,2005.33(3):p.1132-9.
5.Estivill X,Barcelo'E,Perello'C.Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycoside.Am J Hum Genet,1998.62:27-35.
6.Matthijs G,Longo-Bbenza JJ,Cassiman.Nonsyndromic deafness associated with a mutation and a polymorphism in the mitochondrial 12S ribosomal RNA gene in a large Zairean pedigree.Eur J Hum Genet,1996.4:46-51.
7.Jacobs HT,Kappi T,Gillies G,Minkkinen K,Walker J,Thompson K,Rovio AT,Carella M.Mitochondrial DNA mutations in patients with postlingual,nonsyndromic hearing impairment.Eur J Hum Genet,2005.13:26-33.
8.Li R,Yan X,Cao XZ,Liu X,Guan MX.Cosegregation of C-insertion at position 961 with A1555G mutation of mitochondrial 12S rRNA gene in a large Chinese family with maternally inherited hearing loss.Am J Med Genet A,2004.124:113-117.
9.Yuan H,Xu Y,Cao J,Bai L,Shen W,Ji F,Zhang X.Cosegregation of the G7444A mutation in the mitochondrial COI/tRNASer(UCN) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside-induced and non-syndromic hearing loss.Am J Med Genet A, 2005.138:133-140.
10.Wang Q,et al.Clinical and molecular analysis of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss associated with the mitochondrial 12S rRNA C1494T mutation.Biochem Biophys Res Commun,2006.340:583-588.
11.Wang C,et al.mtDNA mutation C1494T,haplogroup A,and hearing loss in Chinese.Biochem Biophys Res Commun,2006.348:712-715.
12.Rieder MJ,Taylor SL,Tobe VO,Nickerson DA.Automating the identification of DNA variations using quality-based fluorescence resequencing:analysis of the human mitochondrial genome.Nucleic Acids Res,1998(26):967-973.
13.Andrews RM,Kubacka I,Chinnery PF,Lightowlers RN,Turnbull DM,Howell N.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA.Nat Genet,1999.23:147.
14.Bibb MJ,Van Etten,Wright RA,Walberg CT,Clayton MW.Sequence and gene organization of mouse mitochondrial DNA.Cell,1981.26:167-180.
15.Gadaleta G,Pepe G,De CandiaG.,Quagliariello C,Sbisa E,Saccone C.The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome:cryptic signals revealed by comparative analysis between vertebrates.J Mol Evol,1989.28:497-516.
16.Roe A,Ma DP,Wilson RK,Wong JF.The complete nucleotide sequence of the Xenopus laevis mitochondrial genome.J Biol Chem,1985.260:9759-9774.
17.Tanaka M,et al.Mitochondrial genome variation in eastern Asia and the peopling of Japan.Genome Res,2004.14:1832-1850.
18.Han D,et al.The mitochondrial tRNA(Ala) T5628C variant may have a modifying role in the phenotypic manifestation of the 12S rRNA C1494T mutation in a large Chinese family with hearing loss.Biochem Biophys Res Commun,2007.357(2):554-60.
19.Chen J,et al.Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees.Gene,2007.401(1-2):4-11.
20.Yuan H,et al.Coexistence of mitochondrial 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigrees with aminoglycoside-induced and non-syndromic hearing loss.Biochem Biophys Res Commun,2007.362(1):94-100.
21.Cann R.Mitochondrial DNA and human evolution.Nature,1987.325:31-36.
22.Li R,Deng JH,Yang L,Tamagawa Y,Bai Y,Ichimura K,Guan MX.Maternally inherited nonsyndromic hearing loss is associated with the mitochondrial tRNASer(UCN) 7511C mutation in a Japanese family.Biochem Biophys Res Commun,2005.328:32-37.
23.Reid F,Vernham G,Jacobs H.A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness.Hum Mutat,1994.3:243-247.
24.Prezant T,et al.Mitochondrialribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness.Nat Genet,1993.4:289-294.
25.戴朴,刘新,于飞,等.全国18个聋校学生非综合征性聋分子病因学研究.中华耳科学杂志,2006.4:1-5.
26.Casano RMS,et al.Hearing Loss Due to the Mitochondrial A1555G Mutation in Italian Families.American Journal of Medical Genetics,1998.79:388-391.
27.Torroni A,et al.The A1555G mutation in the 12S rRNA gene of human mtDNA:recurrent origins and founder events in families affected by sensorineural deafness.Am J Hum Genet,1999.65:1349-1358.
28.Estivill X,et al.Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides.A m J Hum Genet,1998.62:27-35.
29.Torroni A,et al.Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484.Am J Hum Genet,1997.60:1107-1121.
1.Chang HP,Chou P,et al.Presbycusis among older Chinese people in Taipei,Taiwan:A community-based study.Int J Audiol,2007,46(12):738.
2.Dalton DS,et al.The impact of hearing loss on quality of life in older adults.Gerontologist,2003,43(5):661.
3.Viljanen A,Kaprio J,Pyykko I,et al.Genetic and environmental influences on hearing in older women.J.Gerontol.A Biol Sci Med Sci,2007,62:447.
4.Christensen K,Hoffman HJ,et al.Genetic and environmental influences on self-reported reduced hearing in the old and oldest old.J Am Geriatr Soc,2001,49:1512.
5.Gates GA,Myers RH,et al.Genetic associations in age-related hearing thresholds.Arch Otolaryngol Head Neck Surg,1999,125:654.
6.Dobie RA.The relative contributions of occupational noise and aging in individual cases of hearing loss.Ear Hear,1992,13:19.
7.Mills JH,Lee FS,Dubno JR,et al.Gender-specific effects of drugs on hearing levels of older persons.Ann.NY Acad Sci,1999,884:381.
8.Kurien M,Bhanu TS,et al.Hearing threshold in patients with diabetes mellitus.J Laryngol Otol,1989,103:164.
9.Gates GA,et al.The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors.Arch Otolaryngol Head Neck Surg,1993,119:156.
10.Tepass U,Truong K,et al.Cadherins in embryonic and neural morphogenesis.Nat Rev Mol Cell Biol,2000,1:91.
11.Di PF,Holme RH,et al.Mutations in Cdh23,encoding a new type of cadherin,cause stereocilia disorganization in waltzer,the mouse model for Usher syndrome type ID.Nat Genet,2001,27:103.
12.Siemen JL,et al.Cadherin 23 is a component of the tip link in hair-cell stereocilia.Nature,2004,428(6986):950.
13.Astuto LM,Weston MD,et al.CDH23 mutation and phenotype heterogeneity:a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness.Am J Hum Genet,2002,71:262.
14.Noben-Trauth K,Johnson KR,et al.Association of cadherin23 with polygenic inheritance and genetic modification of sensorineural hearing loss.Nat Genet,2003,35:21.
15.Davis RR,et al.Genetic influences in individual susceptibility to noise:a review.Noise Health,2003,5(20):19.
16.Johnson KR,et al.A major gene affecting age-related hearing loss is common to at least ten inbred strains of mice.Genomics,2000,70:171.
17.Bolz H,et al.Mutation of CDH23,encoding a new member of the cadherin gene family,causes Usher syndrome type 1D.Nat Genet,2001,27:108.
18.Kubisch C,Friedrich T,et al.KCNQ4,a novel potassium channel expressed in sensory outer hair cells,is mutated in dominant deafness.Cell,1999,96:437.
19.Kharkovets T,et al.KCNQ4,a K1 channel mutated in a form of dominant deafness,is expressed in the inner ear and the central auditory pathway.Proc Natl Acad Sci USA,2000,97:4333.
20.Kharkovets T,Maier H,et al.Mice with altered KCNQ4 K1 channels implicate sensory outer hair cells in human progressive deafness.EMBO J,2006,25:642.
21.Coucke PJ,Kelley PM,et al.Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.Hum Mol Genet,1999,8:1321.
22.Van Eyken E,Fransen E,et al.KCNQ4:a gene for age-related hearing impairment?.Hum Mutat,2006,27:1007.
23.Lefebvre PP,et al.Cormexins,hearing and deafness:clinical aspects of mutations in the connexin 26 gene.Brain Res Brain Res Rev,2000,32:159.
24.Kikuchi T,Paul DL,et al.Gap junction systems in the mammalian cochlea.Brain Res Brain Res Rev,2000,32:163.
25.Gasparini P,Rabionet R,et al.High carrier frequency of the 35delG deafness mutation in European populations.European Journal of Human Genetics,2000,8:19.
26.Liu XZ,Xia XJ,et al.The prevalence of connexin 26(GJB2) mutations in the Chinese population.Hum Genet,2002,11:394.
27.Kelsell DP,Stevens HP,et al.Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.Nature,1997,387(6628):80.
28.肖自安,冯永,等：非综合征性耳聋患者连接蛋白26基因突变的研究。中华耳鼻咽喉科杂志,2000,35(3)：188．
29.Murgia A,Polli R,et al.Cx26 deafness:mutation analysis and clinical variability.J Med Genet,1999,36:829.
30.Van Eyken E,et al.The Contribution of GJB2(Connexin 26) 35delG to Age-Related Hearing Impairment and Noise-Induced Hearing Loss.Otology & Neurotology,2007,28(7):970.
31.Van Laer L,et al.The grainyhead like 2 gene(GRHL2),alias TFCP2L3,is associated with age-related hearing impairment.Human Molecular Genetics,2008,17(2):159.
32.Wilanowski T,Tuckfield A,et al.A highly conserved novel family of mammalian developmental transcription factors related to Drosophila grainyhead.Mech Dev,2002,114(1-2):37.
33.Ting SB,et al.The identification and characterization of human Sister-of-Mammalian Grainyhead(SOM) expands the grainyhead-like family of developmental transcription factors.Biochem J,2003,370(3):953.
34.Auden A,et al.Spatial and temporal expression of the Grainyhead-like transcription factor family during murine development.Gene Expr Patterns,2006,6(8):964.
35.Seidman MD,Khan MJ,et al.Association of mitochondrial DNA deletions and cochlear pathology:a molecular biologic tool.Laryngoscope,1996,106:777.
36.Seidman MD,Dolan D,et al.Age-related differences in cochlear microcirculation and auditory brain stem response.Arch Otolaryngol Head Neck Surg,1996,122:1221.
37.韩维举,韩东一,等：人听觉器官线粒体DNA4977缺失与老年聋的关系．中华耳鼻咽喉科杂志,2000,35：416．
38.Dai P,Jiang S,Gu R,et al.Correlation of cochlear blood supply with mitochondrial DNA common deletion in presbyacusis.Acta Otolaryngol,2004,124:130.
39.Unal M,et al.N-Acetyltransferase 2 Gene Polymorphism and Presbycusis.Laryngoscope,2005,115(12):2238.
40.Mannervik B,Board PG,et al.Nomenclature for human glutathione transferases.Biochem J,1992,282:305.
41.Strange RC,et al.Glutathione-S-transferase family of enzymes.Mutat Res,2001,482:21.
42.Pemble S,Spencer SR,et al.Human glutathione S-transferase theta(GSTT1):cDNA cloning and the characterization of a genetic polymorphism.Biochem J,1994,300:271.
43.Rabinowitz PM,et al.Antioxidant status and hearing function in noise-exposed workers.Hear Res,2002,173:164.
44.McFadden SL,et al.The influence of superoxide dismutase and glutathione peroxidase deficiencies on noise-induced hearing loss in mice.Noise Health,2001,3:49.
45.Fortunato G,Zarrilli F,Mazzaccara C,et al.Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss.Clin Chem, 2004,50:2012.
46.Ohlemiller KK,et al.Targeted mutation of the gene for cellular glutathione peroxidase(Gpxl) increases noise-induced hearing loss in mice.Assoc Res Otolaryngol,2000,1:243.