Variants in mitochondrial tRNAGlu, tRNAArg, and tRNAThr may influence the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in three Han Chinese families with hearing loss

We report here on the clinical, genetic, and molecular characterization of three Han Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing loss. Clinical evaluation revealed the variable phenotype of hearing loss including severity, age-at-onset, audiometric configuration in these subjects. Penetrances of hearing loss in BJ107, BJ108, and BJ109 pedigrees are 35%, 63%, and 67%, respectively. Mutational analysis of the complete mitochondrial genomes in these pedigrees showed the identical homoplasmic A1555G mutation and distinct sets of mitochondrial DNA (mtDNA) variants belonging to haplogroups N, F, and M, respectively. Of these variants, the A14693G mutation in the tRNA(Glu), the T15908C mutation in the tRNA(Thr), and the T10454C mutation in the tRNA(Arg) are of special interest as these mutations occur at positions which are highly evolutionarily conserved nucleotides of corresponding tRNAs. These homoplasmic mtDNA mutations were absent among 156 unrelated Chinese controls. The A14693G and T10454C mutations occur at the highly conserved bases of the TpsiC-loop of tRNA(Glu) and tRNA(Arg), respectively. Furthermore, the T15908C mutation in the tRNA(Thr) disrupts a highly conserved A-U base-pairing at the D-stem of this tRNA. The alteration of structure of these tRNAs by these mtDNA mutations may lead to a failure in tRNA metabolism, thereby causing impairment of mitochondrial translation. Thus, mitochondrial dysfunctions, caused by the A1555G mutation, would be worsened by these mtDNA mutations. Therefore, these mtDNA mutations may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated 12S rRNA A1555G mutation in those Chinese pedigrees.     

五个母系遗传非综合征性耳聋和药物性耳聋的中国汉族家系

目的 通过对母系遗传非综合征性耳聋家系临床和分子遗传学特征分析,进一步探讨线粒体12S rRNA基因对母系遗传药物性耳聋的影响.方法 收集5个非综合征性耳聋患者家系,提取基因组DNA,然后进行线粒体DNA全序列和间隙连接蛋白β2(gap junction protein beta 2,GJB2)基因扩增并测序分析.结果 5个家系内和家系间的母系成员在听力损失、发病年龄和听力曲线上存在较大差异.5个家系耳聋发生的外显率分别为17.6%、50.0%、66.7%、31.3%和23.1%,平均外显率是37.7%.线粒体全序列显示家系间存在已知的1555A＞G突变和不同的多态性位点,分别属于东亚人群D4b2b、B4c1b1、F3、C1、D5a单倍型.这5个家系没有携带已知的线粒体DNA继发突变,但发现了2个保守性较高的ND1L89T和CO3 A200T突变.而且,GJB2基因上未发现与耳聋相关的突变.结论 这5个母系遗传非综合征性耳聋家系中,线粒体DNA继发突变、GJB2基因可能没有影响1555A＞G的表型表达.然而,氨基糖甙类抗生素、线粒体DNA多态性及其他核修饰基因可能对这5个耳聋家系的表型表达起到修饰作用.     

Cosegregation of the G7444A mutation in the mitochondrial COI/tRNA(Ser(UCN)) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside-induced and nonsyndromic hearing loss

We report here on the characterization of a three-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing impairment. Ten of 17 matrilineal relatives exhibited bilateral and sensorineural hearing impairment. Of these, nine matrilineal relatives, who had a history of exposure to aminoglycosides, exhibited variable severity and audiometric configuration of hearing loss. The dose and age at the time of drug administration seemed to be correlated with the severity of the hearing loss experienced by affected individuals. Sequence analysis of the complete mitochondrial genome in the pedigree showed the presence of homoplasmic A1555G mutation and 37 variants belonging to haplogroup D4a. Of those variants, the G7444A mutation is of special interest as the mutation at this position results in a read-through of the stop condon AGA of the COI message, thereby adding three amino acids (Lys-Gln-Lys) to the C-terminal of the polypeptide. Alternatively, the G7444A mutation is adjacent to the site of 3' end endonucleolytic processing of L-strand RNA precursor, spanning tRNA(Ser(UCN)) and ND6 mRNA. Thus, the G7444A mutation, similar to the deafness-associated A7445G mutation, may lead to a defect in the processing of the L-strand RNA precursor, thus influencing the phenotypic expression of the A1555G mutation. These data also imply that nuclear background plays a role in the aminoglycoside ototoxicity associated with the A1555G mutation in this Chinese pedigree.     

The contribution of the mitochondrial COI/tRNA(Ser(UCN)) gene mutations to non-syndromic and aminoglycoside-induced hearing loss in Polish patients

Mutations in mitochondrial DNA have been implicated in both, non-syndromic and aminoglycoside-induced hearing loss. In the present study, we have performed the systematic mutation screening of the COI/tRNA(Ser(UCN)) genes in 250 unrelated Polish subjects with hearing impairment. Three different homoplasmic sequence variants were identified, including one common polymorphism m.7476 C>T in tRNA(Ser(UCN)) and two mutations, m.7444 G>A and m.7445 A>G localized in the COI/precursor of tRNA(Ser(UCN)). The incidence of m.7444 G>A substitution was estimated at 1.6% (4/250), however variable penetrance of hearing loss, age of onset and hearing thresholds among m.7444 G>A carriers was observed. Two subjects had the positive history of aminoglycoside exposure and one of them harbored both m.7444 G>A and 12S rRNA m.1555 A>G mutations. Those suggest that m.7444 G>A itself is not sufficient to produce a clinical phenotype and additional modifier factors are required for pathogenic manifestation of m.7444 G>A substitution. Moreover, we have described the first Polish family with non-syndromic hearing loss, harboring m.7445 A>G mutation. The penetrance of hearing loss in this pedigree was 58% when aminoglycoside-induced hearing impairment was included, and 8% when ototoxic effect was excluded. This finding strongly suggests the possible role of m.7445 A>G in susceptibility to aminoglycoside induced-hearing loss.     

两个非综合征型耳聋家系中线粒体DNA 12S rRNA基因A827G突变

目的探讨线粒体DNA（mitochondrial DNA，mtDNA）12S rRNA基因与中国人非综合征型遗传性耳聋的关系。方法对两个母系遗传性的非综合征型耳聋家系中20名成员及32例散发耳聋患者外周血DNA进行12S rRNA、tRNA^ser（UCN）以及GJB2基因PCR扩增，产物通过限制性片段多态性分析及基因测序，进行突变检测和分析。结果所有研究对象的基因区域均扩增成功。12S rRNA全序列测定发现两家系中所有受检的母系成员（包括12例耳聋患者）均存在nt827A→G转换，并表现为同质性突变。而非母系成员该位点序列正常。32例散发耳聋中有1例A827G突变阳性。未检测到GJB2基因、tRN^ser（UCN） A7445G及12S rRNA A1555G突变。结论再次验证了mtDNA 12S rRNA基因突变在母系遗传性非综合征型耳聋发病中的重要性。首次发现mt DNA 12S rRNA nt827A→G转换是导致两个中国家系耳聋遗传易感性的分子基础。     

线粒体tRNAThr A15951G可能是与Leber遗传性视神经病变相关的基因突变

目的 进一步分析中国汉族Leber遗传性视神经病变(Leber's hereditary optic neuropathy,LHON)家系的临床和分子遗传学特征,阐明LHON的分子致病机制.方法 对2例具有典型LHON临床特征的先证者和家系其他成员进行眼科学及其临床检查.对这2个家系先证者使用24对有部分重叠的引物进行线粒体DNA(mitochondrial DNA,mtDNA)全序列扩增分析.结果 检查发现这些家系成员中视力损害的外显率分别为5.3％(1/19)、18.2％(4/22).经mtDNA测序分析,并没有发现mtDNA G11778A、G3460A和T14484C 3个常见的突变,在tRNAThr上发现了A15951G同质性突变位点.线粒体DNA全序列分析显示2个家系呈现mtDNA多态性,都属于东亚单倍型D4b1.A15951G突变位于线粒体tRNAThr高度保守区(通用位点为71位),可能导致tRNA空间结构和稳定性发生改变,线粒体蛋白合成功能受损,最终发生视力损害.结论 线粒体tRNAThr A15951G可能是与Leber遗传性视神经病变相关的致病性线粒体基因突变.     

非综合征型遗传性耳聋两家系线粒体基因突变分析

目的 探讨母系遗传非综合征型耳聋发病机理及7445^G点突变在这类家系及散发感音神经性耳聋病例中的发生率，为建立相应的基因诊断方法提供依据。方法 收集两个母系遗传非综合征型耳聋家系和14个感音神经性耳聋散发病例；抽外周血标本，从白细胞中提取DNA；聚合酶链反应扩增线粒体DNA（mitochondrial DNA,mtDNA）目的片段，分别以Alw 26Ⅰ、ApaⅠ及XbaⅠ限制性内切酶检测1555^G、3243^G及7445^G点突变；行mtDNA 12S r RNA、tRNA^Leu(UUR)、tRNA^Ser(UCN)基因测序。结果 经酶切检测，两家系中12例为7445^G点突变阳性，其余6例及14例散发病例均为阴性，所有病例1555^G、3243^G点突变均阴性；7445^G点突变呈母系遗传。mtDNA测序显示，所有病例1555^G、3243^G点突变均阴性；酶切显示为7445^G突变阳性病例经基因测序均发现有（nt)7445A→G替换。结论 7445^G点突变在母系遗传非综合征型耳聋家系中有较高的发生率，而在散发病例中发生率很低；7445^G结合1555^G点7突变筛查对这类耳聋的诊断有重要意义。     

12个非综合征型遗传性耳聋家系mtDNA12SrRNA，tRNA^Leu（UUR）,tRNA^Ser（UCN）及16SrRNA基因序列分析

目的 探讨mtDNA突变与遗传性耳聋的关系。以及突变家系对氨基糖甙类抗生素（aminoglycoside antibiotic,AmAn)耳毒敏感性差异的原因。方法 调查了12个非综合征型耳聋家系;抽取外周血,提取DNA;PCR扩增线粒体DNA9mitochondrialDNA,mtDNA)目的片段,分别以Alw26Ⅰ、ApaⅠ及XbaⅠ限制性内切酶检测1555^G、3243^G及7445^G点突变,行mtDNA12SrRNA,tRNA^Leu(UUR)、tRNA^Ser(UCN)及16SrRNA基因序列测定。结果 经酶切及测序证实12个家系具有mtDNA突变,形式为：1555^G突变家系10个,7445^G突变家系2个,示发现3243^G突变家系,基因测序显示mtDNA16SrRNA基因6序列变化形式为：2230^G点突变,2230^AG插入,2243^AG插入及2230^AA插入突变,它们在家族性AmAn耳毒敏感性家系中被发现,且呈母系遗传;在AmAn不敏感家系中未被发现,结论 单纯1555^G或7445^G突变家系表现为无诱因的渐进性遗传性耳聋或先天性聋;1555^G或7445^G突变合并16SrRNA基因突变者对AmAn高度敏感,表现为家族性敏感致聋。ⅠⅠ     

氨基糖甙类抗生素耳毒性相关的线粒体DNA突变

线粒体12S rRNA基因是引起氨基糖甙类抗生素耳毒性和非综合征型耳聋的突变热点区域。其中,位于高度保守的12S rRNA基因解码区的同质性1555A＞G和1494C＞T突变,可导致部分患者对氨基糖甙类抗生素超敏感。当发生1555A＞G或1494C＞T突变时,12S rRNA高度保守的A位就会形成新的1494C-G1555或1494U-A1555碱基配对,使得人类线粒体核糖体的结构与细菌核糖体更加相似,以致氨基糖甙类抗生素与12S rRNA的结合更加容易,从而解释了为何携带这些突变的个体在使用了氨基糖甙类抗生素后会出现或加重耳聋表型。相关功能研究表明,无论是否存在氨基糖甙类抗生素的作用,携带1555A＞G或1494C＞T突变的细胞均会出现线粒体蛋白合成缺陷,并随之引发细胞呼吸功能障碍。此外,携带这些突变的家系,其母系成员听力损失程度、发病年龄和外显率均存在较大差异,提示核修饰基因、线粒体单体型以及氨基糖甙类抗生素等对12S rRNA 1555A＞G和1494C＞T突变的表型表达起着修饰作用。这些研究成果为以下三个方面提供了科学依据：①预测个体耳毒性风险;②提高氨基糖甙类抗生素治疗的安全性;③降低耳聋发生率。     

Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation

We report here the clinical, genetic and molecular characterization of four Han Chinese families with Leber's hereditary optic neuropathy (LHON). The penetrances of optic neuropathy in these Chinese pedigrees were 38%, 38%, 44% and 56%. This observation is in contrast with the previously identified 14 Chinese families with very low penetrance of LHON. The age-at-onset for visual impairment in matrilineal relatives in these Chinese families varied from 18 to 30 years. Furthermore, the ratios between affected male and female matrilineal relatives in these families were 3:0, 3:0, 3:1 and 2:3, respectively. Molecular analysis of mitochondrial genomes identified the known ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M9a. Of these, the ND1 T3394C mutation caused the substitution of a highly conserved histidine for tyrosine (Y30H) at amino acid position 30. This mutation was associated with LHON in other families with low penetrance of optic neuropathy and other clinical abnormalities. The presence of both G11778A and T3394C mutations appears to contribute to higher penetrance of optic neuropathy in these four Chinese families than other Chinese families carrying only the G11778A mutation. Therefore, the mitochondrial haplogroup M9a specific variant T3394C may modulate the phenotypic manifestation of LHON-associated G11778A mutation in these Chinese pedigrees.     

七个非综合征型耳聋家系患者的mtDNA A1555G突变性质与特点

目的 探讨非综合征型耳聋家系患者mtDNA A1555G突变性质及其特点,探索临床表型多样性的分子遗传学基础.方法 应用聚合酶链反应-限制性片段长度多态和实时荧光-扩增阻碍突变系统-定量PCR(real time-amplification refractory mutation system-quantitative PCR,RT-ARMS-qPCR)检测7个非综合征型耳聋家系71个成员的mtDNA A1555G突变,并收集、分析其临床资料.结果 7个家系中所有受检的母系成员mtDNA A1555G突变均为阳性,突变性质含同质性和异质性两种;非母系成员及配偶该突变为阴性.7个家系mtDNA A1555G同质性突变的拷贝数与耳聋轻重程度相关(R=0.341,P=0.022);mtDNA A1555G异质性突变的拷贝数与耳聋轻重程度相关(R=0.85,P=0.015).结论 mtDNA A1555G突变可导致非综合征型耳聋和氨基糖甙类抗生素致聋,其突变性质含同质性和异质性两种,且含mtDNA A1555G位点的突变型与野生型的比例与耳聋的严重程度密切相关.     

修饰因子对线粒体DNA突变致聋的影响

线粒体DNA突变是引起感音神经性耳聋的重要原因之一,这些突变主要位于线粒体12SrRNA和tRNA基因上.其中12S rRNA基因上的同质性A1555G和C1494T突变与氨基糖甙类抗生素造成的耳聋相关.携带这两个突变的个体对耳毒性药物高度敏感,导致临床上常见的"一针致聋"现象.但携带A1555G或C1494T突变的个体在没用药的情况下也能产生非综合征型耳聋,而且同一家系内和不同家系间的母系成员在听力损失程度、发病年龄及听力曲线上存在很大差异.这些数据表明A1555G或C1494T突变是导致非综合征型耳聋发生的首要因子,其他修饰因子包括氨基糖甙类抗生素、线粒体DNA单倍型和核修饰基因等,在线粒体12S rRNA A1555G或C1494T突变相关的耳聋表型表达上起协同作用.作者简要介绍了这些因素对线粒体DNA突变致聋的影响以及母系遗传性耳聋发生的可能致病机制.

Abstract：

Mutations in the mitochondrial DNA have been found to be one of the most important causes of sensorineural hearing loss. In particular, these mutations often occur in the mitochondrial 12S rRNA and tRNA genes. Of these, the homoplasmic A1555G and C1494T mutations in the 12S rRNA have been associated with both aminoglycoside induced and nonsyndromic hearing impairment in many families worldwide. Children carrying the A1555G or C1494T mutation are susceptible to the exposure of ototoxic drugs, thereby inducing or worsening hearing loss. Individuals harboring A1555G or C1494T mutation can also develop hearing loss even in the absence of aminoglycoside exposure. However, matrilineal relatives of intra-families or inter-families carrying the A1555G or C1494T mutation exhibit a wide range of severity,age-at-onset, and audiometric configuration of hearing impairment. These indicate that the A1555G or C1494T mutation is a primary factor underlying the development of deafness but insufficient to produce the clinical phenotype. Thus, other modifier factors, such as aminoglycoside (s), mitochondrial DNA haplotype(s) or nuclear modifier gene(s), play a role in the phenotypic expression of the deafness-associated mitochondrial 12S rRNA A1555G or C1494T mutation. In this review, we summarize the modifier factors for the phenotypic expression of deafness-associated 12S rRNA A1555G and C1494T mutations and propose the molecular pathogenetic mechanism of maternally inherited deafness.     

修饰因子对线粒体DNA突变致聋的影响

线粒体DNA突变是引起感音神经性耳聋的重要原因之一,这些突变主要位于线粒体12SrRNA和tRNA基因上.其中12S rRNA基因上的同质性A1555G和C1494T突变与氨基糖甙类抗生素造成的耳聋相关.携带这两个突变的个体对耳毒性药物高度敏感,导致临床上常见的"一针致聋"现象.但携带A1555G或C1494T突变的个体在没用药的情况下也能产生非综合征型耳聋,而且同一家系内和不同家系间的母系成员在听力损失程度、发病年龄及听力曲线上存在很大差异.这些数据表明A1555G或C1494T突变是导致非综合征型耳聋发生的首要因子,其他修饰因子包括氨基糖甙类抗生素、线粒体DNA单倍型和核修饰基因等,在线粒体12S rRNA A1555G或C1494T突变相关的耳聋表型表达上起协同作用.作者简要介绍了这些因素对线粒体DNA突变致聋的影响以及母系遗传性耳聋发生的可能致病机制.     

修饰因子对线粒体DNA突变致聋的影响

线粒体DNA突变是引起感音神经性耳聋的重要原因之一,这些突变主要位于线粒体12SrRNA和tRNA基因上.其中12S rRNA基因上的同质性A1555G和C1494T突变与氨基糖甙类抗生素造成的耳聋相关.携带这两个突变的个体对耳毒性药物高度敏感,导致临床上常见的"一针致聋"现象.但携带A1555G或C1494T突变的个体在没用药的情况下也能产生非综合征型耳聋,而且同一家系内和不同家系间的母系成员在听力损失程度、发病年龄及听力曲线上存在很大差异.这些数据表明A1555G或C1494T突变是导致非综合征型耳聋发生的首要因子,其他修饰因子包括氨基糖甙类抗生素、线粒体DNA单倍型和核修饰基因等,在线粒体12S rRNA A1555G或C1494T突变相关的耳聋表型表达上起协同作用.作者简要介绍了这些因素对线粒体DNA突变致聋的影响以及母系遗传性耳聋发生的可能致病机制.     

中国Leber遗传性视神经病变G11696A突变两个家系分析

目的对两个中国Leber遗传性视神经病变(Leber’shereditary optic neuropathy,LHON)家系的临床和分子遗传学特征进行分析。方法眼科临床检查发现在这两个家系中只有先证者1人出现视力障碍,发病年龄分别为10岁和17岁。对这两个家系先证者使用24对有部分重叠的引物进行线粒体DNA(mitochondrial DNA,mtDNA)全序列扩增分析。结果没有发现mtDNAG11778A、G3460A和T14484C3个常见的突变位点,而发现了与LHON相关的ND4G11196A同质性突变位点的存在,在167名正常对照只发现1例G11696A突变。结论线粒体DNA全序列分析发现两个家系呈现独特的mtDNA多态性,都属于东亚单体型D4。不完全外显率和正常对照频率(1/167)表明G11696A突变本身不足以导致LHON的发生,说明其它因素在这两个LHON家系的表型表达中也起一定的作用。在这些家系mtDNA中缺乏影响重要功能突变位点的存在,排除了线粒体背景对LHON临床表型的影响。因此,核修饰基因、环境因素可能对两个中国G11696A突变家系的外显率和发病严重程度起促进作用。     

Maternally inherited hearing impairment in a family with the mitochondrial DNA A7445G mutation

Despite the increasing number of reports of families with hearing impairment and mitochondrial DNA (mtDNA) mutations, the frequency of these mutations as causes of non-syndromic sensorineural hearing impairment (NSSHI) remains unknown. Mutations such as A1555G, A7445G and 7472insC have been found in several unrelated families implying they are more frequent than initially thought. We describe a family with NSSHI due to the presence of the homoplasmic mtDNA A7445G mutation in the tRNASer(UCN) gene. This is the fourth such family described with this mutation, all of different genetic backgrounds. Our study also demonstrates the difficulties sometimes encountered in establishing mitochondrial inheritance of hearing impairment in some families.     

The A1555G mtDNA mutation in Danish hearing-impaired patients: frequency and clinical signs

The A1555G mutation of the mtDNA is associated with both aminoglycoside-induced and non-syndromic hearing loss. The A1555G is relatively frequent in the Spanish and some Asian populations, but has only been reported rarely in other populations, possibly because of ascertainment bias. We studied 85 Danish patients with varying degrees of hearing impairment and found two patients with the A1555G mutation (2.4%). Neither had received aminoglycosides. Our study indicates that the mutation might not be uncommon in Danish patients with hearing impairment.     

线粒体基因组A1555G突变在中国非综合征性聋患者中的流行病学分析

目的检测线粒体基因组12SrRNA、基因A1555G突变在中国非综合征性聋患者中的携带频率,探讨中国非综合征性聋的分子病因的流行病学意义。方法提取中国人群中22例氨基糖甙类药物致聋患者、158例散发的非综合征性聋患者以及60例非综合征性聋家系先证者的DNA,以聚合酶链反应结合限制性内切酶酶解分析法检测线粒体基因组A1555G突变的发生情况。结果线粒体基因组A1555G阳性患者占所有耳聋患者的4.2%,散发病例组中A1555G阳性率为1.3%,非综合征性聋家系组中A1555G阳性率为13.3%,22例氨基糖甙类药物致聋患者中未发现A1555G突变。结论线粒体基因组A1555G的突变发生率略高于以往报道,是非综合征性聋家系中致聋的主要病因之一,这对于中国人群耳聋的病因学研究有积极意义。     

氨基糖甙类抗生素致聋患者线粒体DNA 1555G点突变分析

目的考察１５５５Ｇ点突变在氨基糖甙类抗生素致聋家系及散发病例中的发生率,为建立相应的基因诊断方法提供依据。方法收集有明确氨基糖甙类抗生素应用史的两个母系遗传耳聋家系和７个散发病例,以及部分亲属２６人的外周静脉血标本,从白细胞中提取ＤＮＡ,多聚酶链反应扩增线粒体ＤＮＡ目的片段,Ａｌｗ２６Ⅰ限制性内切酶检测１５５５Ｇ点突变。结果两个家系的１４份样品为１５５５Ｇ点突变阳性,散发病例及部分亲属的１２份样品全部为１５５５Ｇ点突变阴性。结论１５５５Ｇ点突变在氨基糖甙类抗生素致聋家系中的发生率较高,在散发病例中的发生率低。１５５５Ｇ点突变筛查有潜在的临床应用价值。     

120例非综合征性耳聋患者线粒体A1555G和Cl494T突变分析

目的分析温州地区120例耳聋患者的致聋原因,并探讨线粒体ONA（mitochondrial DNA,mtDNA）12S rRNA基因A1555G和C1494T突变与耳聋之间的关系。方法对我院收集的120例耳聋患者进行分子流行病学的调查,并针对线粒体1555和1494位点进行引物设计,通过PCR扩增,产物Sanger测序后比对标准序列,检测A1555G和C1494T突变的频率以及和患者使用氨基糖苷类抗生素的相关性。结果在120例重度耳聋患者中具有氨基糖苷类抗生素用药史的有66例（55％）,家族性遗传耳聋有22例（18．3％）,近亲结婚可能致聋有10例（8．3％）,不明原因的耳聋有22例（18．3％）;我们还发现,有9例患者携带线粒体A1555G突变,突变的阳性率为7．5％,1例携带C1494T突变,阳性率为0．83％,这10例患者均有用药史。结论遗传因素和氨基糖苷类用药史是导致耳聋的重要原因,其中Al555G突变和C1494T突变是耳聋较为常见的线粒体DNA突变,这对早期诊断和预防药物性耳聋具有一定的临床意义。