Mitochondrial tRNAGlu 14693G variant may modulate the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in a Hah Chinese family

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 hearing 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 tRNAGlu 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 tRNAalu A14693G variant may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated AI555G mutation in this Chinese pedigree.     

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

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.     

Nuclear counterparts of the cytoplasmic mitochondrial 12S rRNA gene: A problem of ancient DNA and molecular phylogenies

Monkey mummy bones and teeth originating from the North Saqqara Baboon Galleries (Egypt), soft tissue from a mummified baboon in a museum collection, and nineteenth/twentieth-century skin fragments from mangabeys were used for DNA extraction and PCR amplification of part of the mitochondrial 12S rRNA gene. Sequences aligning with the 12S rRNA gene were recovered but were only distantly related to contemporary monkey mitochondrial 12S rRNA sequences. However, many of these sequences were identical or closely related to human nuclear DNA sequences resembling mitochondrial 12S rRNA (isolated from a cell line depleted in mitochondria) and therefore have to be considered contamination. Subsequently in a separate study we were able to recover genuine mitochondrial 12S rRNA sequences from many extant species of nonhuman Old World primates and sequences closely resembling the human nuclear integrations. Analysis of all sequences by the neighbor-joining (NJ) method indicated that mitochondrial DNA sequences and their nuclear counterparts can be divided into two distinct clusters. One cluster contained all temporary cytoplasmic mitochondrial DNA sequences and approximately half of the monkey nuclear mitochondriallike sequences. A second cluster contained most human nuclear sequences and the other half of monkey nuclear sequences with a separate branch leading to human and gorilla mitochondrial and nuclear sequences. Sequences recovered from ancient materials were equally divided between the two clusters. These results constitute a warning for when working with ancient DNA or performing phylogenetic analysis using mitochondrial DNA as a target sequence: Nuclear counterparts of mitochondrial genes may lead to faulty interpretation of results.Correspondence to: A.C. van der Kuyl     

Phylogeny of African monkeys based upon mitochondrial 12S rRNA sequences

The suborder Anthropoidea of the primates has traditionally been divided in three superfamilies: the Hominoidea (apes and humans) and the Cercopithecoidea (Old World monkeys), together comprising the infraorder Catarrhini, and the Ceboidea (New World monkeys) belonging to the infraorder Platyrrhini.We have sequenced an approximately 390-base-pair part of the mitochondrial 12S rRNA gene for 26 species of the major groups of African monkeys and apes and constructed an extensive phylogeny based upon DNA evidence. Not only is this phylogeny of great importance in classification of African guenons, but it also suggests rearrangements in traditional monkey taxonomy and evolution. Baboons and mandrills were found to be not directly related, while we could confirm that the known four superspecies of mangabeys do not form a monophyletic group, but should be separated into two genera, one clustering with baboons and the other with mandrills. Patas monkeys are clearly related to members of the genus Cercopithecus despite their divergence in build and habitat, while the talapoin falls outside the Cercopithecus clade (including the patas monkey). Correspondence to: A.C. van der Kuyl     

用12S rRNA基因序列研究斑腿蝗科二属六种的进化关系

采用DNA测序技术测定了中国斑腿蝗科昆虫6种和斑翅蝗科的红胫小车蝗线粒体12S rRNA基因长约345 bp片段的序列。在获得的345 bp的序列中,A+T约占71.8%,其中135个核苷酸位点存在变异 (约占39.1%)。PAUP4.0b数据分析软件构建该6种蝗虫的MP和NJ分子系统树显示,稻蝗属和蔗蝗属各为独立的一支。在稻蝗属一支中,中华稻蝗与山稻蝗关系很近,而与小稻蝗关系较远,这与形态学结果相吻合;在蔗蝗属一支中,异歧蔗蝗与斑角蔗蝗亲缘关系较近,而与等歧蔗蝗关系较远,这与形态学研究结果并不吻合,有待进一步的研究。     

Cochlear alterations in deaf and unaffected subjects carrying the deafness-associated A1555G mutation in the mitochondrial 12S rRNA gene

The A1555G mutation in the mitochondrial small ribosomal RNA gene (12S rRNA) has been associated with aminoglycoside-induced, nonsyndromic hearing loss. However, the clinical phenotype of A1555G carriers is extremely variable. In the present study, we have performed an audiological evaluation of a group of deaf patients and hearing carriers of mutation A1555G with the aim to assess the prevalence of the mutation and determine the associated cochlear alterations. Fifty-four patients affected of nonsyndromic hearing loss were screened for the presence of the A1555G mitochondrial mutation. Nine of the familial cases (21%) carried the A1555G mutation, whereas the mutation was not found in any of the sporadic cases. The positive cases and some of their family members underwent a clinical study consisting in a clinical evaluation and audiological testing. The phenotype of A1555G patients varied in age of onset and severity of hearing loss, ranging from profound deafness to completely normal hearing. The audiometric alterations showed bilateral hearing loss, being more severe at high frequencies. Otoacoustic emissions were absent in deaf A1555G carriers, and auditory brainstem response indicated a prolonged Wave I, suggesting a cochlear dysfunction without any effect of the auditory nerve. Moreover, all hearing carriers of A1555G also presented alterations in cochlear physiology. In conclusion, the A1555G mitochondrial mutation causes a cochlear form of deafness, characterized by a more severe loss of hearing at high frequencies. Although the expression of the mutation is variable, cochlear alterations are present in all carriers of mutation A1555G.     

从12S rRNA基因序列推测鹭科13种鸟类的系统发生关系

对鹭科12个种的线粒体12S rRNA基因全长约975bp的序列进行了测定,并从GenBank获得黄顶夜鹭12S rRNA基因全序列。比对后的序列长993bp,含363变异位点,288个多态位点,187个简约信息位点。使用邻接法和最大简约法重建的分子系统树将13种鹭聚为2支：第一支包括白鹭、中白鹭、大白鹭、池鹭、牛背鹭、苍鹭、草鹭、夜鹭、黄顶夜鹭,第二支由黄苇渴Gan、黑苇Gan、栗苇Gan、大麻Gan组成。结果提示将鹭科分为鹭亚科和Gan亚科的传统观点是合理的,不支持Payne将鹭科分为日鹭亚科(Ardeinae)、夜鹭亚科(Nycticracinae)、Gan亚科(Botaurinae)和虎鹭亚科(Tigrisomatinae)的观点。进一步的分析表明：白鹭在系统演化中要早于大白鹭和中白鹭分支出来,大白鹭和中白鹭与苍鹭、草鹭和牛背鹭间的亲缘关系较近,而与白鹭较远,支持Sibley(1990)将大白鹭和中白鹭作为独立的大白鹭属(Casmerodius)和中白鹭属(Mesophoyx)的建议;黑Gan、栗苇Gan与黄苇Gan在系统发生中构成一单系群,提示将黑Gan置于苇Gan属(Ixobrychus)是合适的[动物学报49(2)：205—210,2003]。     

Extremely low penetrance of deafness associated with the mitochondrial 12S rRNA mutation in 16 Chinese families: implication for early detection and prevention of deafness

Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report here the clinical, genetic, and molecular characterization of 16 Chinese pedigrees (a total of 246 matrilineal relatives) with aminoglycoside-induced impairment. Clinical evaluation revealed the variable phenotype of hearing impairment including audiometric configuration in these subjects, although these subjects share some common features: being bilateral and sensorineural hearing impairment. Strikingly, these Chinese pedigrees exhibited extremely low penetrance of hearing loss, ranging from 4% to 18%, with an average of 8%. In particular, nineteen of 246 matrilineal relatives in these pedigrees had aminoglycoside-induced hearing loss. Mutational analysis of the mtDNA in these pedigrees showed the presence of homoplasmic 12S rRNA A1555G mutation, which has been associated with hearing impairment in many families worldwide. The extremely low penetrance of hearing loss in these Chinese families carrying the A1555G mutation strongly supports the notion that the A1555G mutation itself is not sufficient to produce the clinical phenotype. Children carrying the A1555G mutation are susceptible to the exposure of aminoglycosides, thereby inducing or worsening hearing impairment, as in the case of these Chinese families. Using those genetic and molecular approaches, we are able to diagnose whether children carry the ototoxic mtDNA mutation. Therefore, these data have been providing valuable information and technology to predict which individuals are at risk for ototoxicity, to improve the safety of aminoglycoside therapy, and eventually to decrease the incidence of deafness.     

The ND4 G11696A mutation may influence the phenotypic manifestation of the deafness-associated 12S rRNA A1555G mutation in a four-generation Chinese family

We report here the clinical, genetic and molecular characterization of a large Han Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. The penetrance of hearing loss (affected matrilineal relatives/total matrilineal relatives) in this pedigree was 53%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrance of hearing loss in this pedigree was 42%. These matrilineal relatives exhibited a wide range of severity of hearing loss, varying from profound to normal hearing. Furthermore, these affected matrilineal relatives shared some common features: bilateral hearing loss of high frequencies and symmetries. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified the homoplasmic 12S rRNA A1555G mutation and other 35 variants belonging to Eastern Asian haplogroup D4. Of these, the V313I (G11696A) mutation in ND4 was associated with vision loss. However, the extremely low penetrance of visual loss, and the mild biochemical defect and the presence of one/167 Chinese controls indicted that the G11696A mutation is itself not sufficient to produce a clinical phenotype. Thus, the G11696A mutation may act in synergy with the primary deafness-associated 12S rRNA A1555G mutation in this Chinese family, thereby increasing the penetrance and expressivity of hearing loss in this Chinese pedigree.     

Mitochondrial 12S rRNA gene mutations affect RNA secondary structure and lead to variable penetrance in hearing impairment

Mutations in the mitochondrial DNA are one of the most important causes of sensorineural hearing loss, especially in the 12S ribosomal RNA (rRNA) gene. We have analyzed the mtDNA 12S rRNA gene in a cohort of 443 families with hearing impairment, and have identified the A1555G mutation in 69 unrelated cases. A1555G is not a fully penetrant change, since only 63% of subjects with this change have developed hearing impairment. In addition, only 22% of the 183 A1555G deaf subjects were treated with aminoglycosides. Two novel nucleotide changes (T1291C and T1243C) were identified. T1243C was found in five deafness cases and one control sample. Mutation T1291C was detected in all maternally related individuals of a pedigree and in none of 95 control samples. Conservation analysis and comparison of the 12S rRNA structure with the 16S rRNA of Escherichia coli showed that the T at nucleotide 1243 and A at nucleotide 1555 are conserved positions. Prediction of RNA secondary structure showed changes in all 12S rRNA variants, the most severe being for T1291C. The reported data confirm the high prevalence of mutation A1555G in deafness cases and the major role of the 12S rRNA gene in hearing. The two novel changes reported here might have different contributions as deafness-related variants. T1291C fulfills the criteria of a disease-causing change. As in the case of mutation A1555G, the underlying phenotype of T1291C is not homogeneous for all family members, providing evidence for the implication of environmental and/or additional genetic factors.     

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

We report here the clinical, genetic, and molecular characterization of a large Han Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. Two and 13 of 66 matrilineal relatives suffered from aminoglycoside-induced and nonsyndromic hearing loss, respectively. These matrilineal relatives exhibited a wide range of severity of hearing loss, varying from profound to normal hearing. In the absence of aminoglycosides, the age-at-onset of hearing impairment in these matrilineal relatives ranged from 13 to 50years. Furthermore, these affected matrilineal relatives shared some common features: bilateral hearing loss of high frequencies and symmetries. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified the homoplasmic 12S rRNA C1494T mutation and other 34 variants belonging to Eastern Asian haplogroup F1. Of these, the variant T5628C occurs at an extremely conserved nucleotide (A31) of tRNA(Ala). This variant converted a very conservative A-U to a G-U base-pairing at AC-stem of this tRNA. The disruption of this base-pairing in tRNAs by mtDNA mutations has been associated with several clinical abnormalities. The alteration of structure of the tRNA(Ala) by the T5628C mutation may lead to a failure in tRNA metabolism and lead to impairment of mitochondrial translation, thereby worsening mitochondrial dysfunctions, caused by the C1494T mutation. Therefore, this mtDNA mutation may influence the phenotypic manifestation of the 12S rRNA C1494T mutation in this Chinese pedigree.     

Species authentication of commercial beef jerky based on PCR-RFLP analysis of the mitochondrial 12S rRNA gene

In this study,we determined species-specific variations by analyzing the mitochondrial 12S rRNA gene sequence variation(～440 bp) in 17 newly obtained sequences and 90 published cattle,yak,buffalo,goat,and pig sequences,which represent 62 breeds and 17 geographic regions.Based on the defined species-specific variations,two endonucleases,Alu I and Bfa I,were selected for species authentication using raw meat/tissue samples and the PCR-RFLP method.Goat and pig were identified using the Alu I enzyme,while cattle,yak,and buffalo were identified by digestion with Bfa I.Our approach had relatively high detection sensitivity of cattle DNA in mixed cattle and yak products,with the lowest detectable threshold equaling 20% of cattle DNA in a mixed cattle/yak sample.This method was successfully used to type commercial beef jerky products,which were produced by different companies utilizing various processing technologies.Our results show that several yak jerky products might be implicated in commercial fraud by using cattle meat instead of yak meat.     

Isolation and characterization of the putative nuclear modifier gene MTO1 involved in the pathogenesis of deafness-associated mitochondrial 12 S rRNA A1555G mutation

The human mitochondrial 12 S rRNA A1555G mutation has been found to be associated with aminoglycoside-induced and non-syndromic deafness. However, putative nuclear modifier gene(s) have been proposed to regulate the phenotypic expression of this mutation. In yeast, the mutant alleles of MTO1, encoding a mitochondrial protein, manifest respiratory-deficient phenotype only when coupled with the mitochondrial 15 S rRNA P(R)454 mutation corresponding to human A1555G mutation. This suggests that the MTO1-like modifier gene may influence the phenotypic expression of human A1555G mutation. Here we report the identification of full-length cDNA and elucidation of genomic organization of the human MTO1 homolog. Human Mto1 is an evolutionarily conserved protein that implicates a role in the mitochondrial tRNA modification. Functional conservation of this protein is supported by the observation that isolated human MTO1 cDNA can complement the respiratory deficient phenotype of yeast mto1 cells carrying P(R)454 mutation. MTO1 is ubiquitously expressed in various tissues, but with a markedly elevated expression in tissues of high metabolic rates including cochlea. These observations suggest that human MTO1 is a structural and functional homolog of yeast MTO1. Thus, it may play an important role in the pathogenesis of deafness-associated A1555G mutation in 12 S rRNA gene or mutations in tRNA genes.     

浙江省非综合征型耳聋患者12SrRNA突变频谱分析

线粒体DNA(Mitochondrial DNA,mtDNA)突变是引起耳聋的重要原因之一。尤其是12S rRNA基因是药物性耳聋与非综合征型耳聋相关的突变热点区域。文章收集了浙江省各地区非综合征型及药物性耳聋患者标本318例,对其进行临床和分子遗传学评估。12S rRNA基因突变分析发现34个变异位点,已知的1555A>G、1494C>T和1095T>C突变分别占9.1%、0.6%和1.25%。结构和种系发生分析显示,839A>G和1452T>C突变位于12S rRNA基因的高度保守区域且未在449例正常对照组中发现,可能增加了耳毒性药物的敏感性。其他变异位点为多态性位点。文章数据支持了12S rRNA基因是耳毒性药物的作用靶点之一这一理论,为预测个体耳毒性的发生风险,提高氨基糖甙类药物治疗安全性提供了有价值的信息,以期降低耳聋的发生。     

中国沙塘鳢属鱼类线粒体12S rRNA基因序列分析

沙塘鳢属鱼类为东亚特有的小型淡水经济鱼类,中国产沙塘鳢属鱼类分类问题长期存在争议。本文测定了中国产沙塘鳢属鱼类全部种类的线粒体12S rRNA基因部分序列,结合GenBank中下载的2种日本沙塘鳢属鱼类和塘鳢科鱼类同源序列,探讨中国产4种沙塘鳢属鱼类的物种有效性,分析沙塘鳢属鱼类的系统发育关系。作者所使用的同源序列长度为690bp,其中变异位点258个,简约信息位点201个,包括插入/缺失位点34个,转换/颠换平均值为3.0,表明12S rRNA基因是研究沙塘鳢属鱼类系统发育关系的合适分子标记。基于p-distance模型的6种沙塘鳢属鱼类种内遗传距离为0.000—0.024,种间遗传距离为0.058—0.064,支持暗色沙塘鳢和中华沙塘鳢为不同种,中国产沙塘鳢属鱼类包括中华沙塘鳢、河川沙塘鳢、海丰沙塘鳢、鸭绿江沙塘鳢4个种的观点;至于中国还有没有新的沙塘鳢属鱼类,尚有待进一步研究。系统发育分析表明海丰海塘鳢是河川沙塘鳢的姐妹群,暗色沙塘鳢与O.hikimius的亲缘关系最为密切,而同属其余类群之间的系统发育关系则由于自展数据支持率较低而尚不明确。中国产沙塘鳢和日本产沙塘鳢并未单独分群,推测沙塘鳢属鱼类的共同原始祖先可能广泛分布于中国、朝鲜和日本等东亚地区,约在4.9—6.5百万年前的上新世开始分化,系统发育过程比较适合离散假说。     

Phylogenetic relationships within caniform carnivores based on analyses of the mitochondrial 12S rRNA gene

The complete 12S rRNA gene of 32 carnivore species, including four feliforms and 28 caniforms, was sequenced. The sequences were aligned on the basis of their secondary structures and used in phylogenetic analyses that addressed several evolutionary relationships within the Caniformia. The analyses showed an unresolved polytomy of the basic caniform clades; pinnipeds, mustelids, procyonids, skunks,Ailurus (lesser panda), ursids, and canids. The polytomy indicates a major diversification of caniforms during a relatively short period of time. The lesser panda was distinct from other caniforms, suggesting its inclusion in a monotypic family, Ailuridae. The giant panda and the bears were joined on the same branch. The skunks are traditionally included in the family Mustelidae. The present analysis, however, showed a less close molecular relationship between the skunks and the remaining Mustelidae (sensu stricto) than between Mustelidae (sensu stricto) and Procyonidae, making Mustelidae (sensu lato) paraphyletic. The results suggest that the skunks should be included in a separate family, Mephitidae. Within the Pinnipedia, the grouping of walrus, sea lions, and fur seals was strongly supported. Analyses of a combined set of 12S rRNA and cytochromeb data were generally consistent with the findings based on each gene.     

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

We report here the clinical, genetic, and molecular characterization of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. Five of nine matrilineal relatives had aminoglycoside-induced hearing loss. These matrilineal relatives exhibited variable severity and audiometric configuration of hearing impairment, despite sharing some common features: being bilateral and having sensorineural hearing impairment. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified 16 variants and the homoplasmic 12S rRNA C1494T mutation, which was associated with hearing loss in the other large Chinese family. In fact, the occurrence of the C1494T mutation in these genetically unrelated pedigrees affected by hearing impairment strongly indicated that this mutation is involved in the pathogenesis of aminoglycoside-induced and nonsyndromic hearing loss. However, incomplete penetrance of hearing loss indicated that the C1494T mutation itself is not sufficient to produce a clinical phenotype but requires the involvement of modifier factors for the phenotypic expression. Those mtDNA variants, showing no evolutional conservation, may not have a potential modifying role in the pathogenesis of the C1494T mutation. However, nuclear background seems to contribute to the phenotypic variability of matrilineal relatives in this family. Furthermore, aminoglycosides modulate the expressivity and penetrance of deafness associated with the C1494T mutation in this family.     

九种绢丝昆虫线粒体12S rRNA基因的序列特征和系统发育分析

为探讨鳞翅目中绢丝昆虫之间的系统发育关系和分子进化特征,本研究测定了中国柞蚕Antheraea pernyi野生型和放养型的线粒体12S rRNA基因的部分序列,结合来自GenBank数据库的17条序列,对总共9种绢丝昆虫（2科3属）的12S rRNA基因序列进行了分析。利用软件MEGA 3.1进行碱基组成、变异位点的统计和分子进化分析,分别用类平均聚类法（UPGMA）、邻接法（NJ）、最小进化法（ME）、最大简约法（MP）重建系统发生树。测定的中国柞蚕野生型的12S rRNA基因序列（427 bp）与放养型“豫早1号”的序列完全一致。序列对齐后共鉴定80个变异位点,50个简约信息位点。碱基组成分析显示在科属间具有明显差异,AT含量蚕蛾科高于大蚕蛾科;在A和T碱基的使用上,大蚕蛾科偏好使用T,而蚕蛾科则偏好使用A。与动物中常见的以转换为主的碱基替换模式不同,所分析的9种昆虫中除桑蚕属内部为转换与颠换基本一致外,其余物种间均是颠换多于转换。进化分析支持柞蚕属、樗蚕属和桑蚕属的单系。基于UPGMA法的进化树支持琥珀蚕是柞蚕属的较原始类型,而NJ、ME和MP法则支持印度柞蚕是较原始的类型,因此,柞蚕属种间的进化关系尚需进一步研究。     

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

Mutations in mitochondrial DNA are one of the important causes of hearing loss. We report here the clinical, genetic, and molecular characterization of two Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the wide range of severity, age-at-onset, and audiometric configuration of hearing impairment in matrilineal relatives in these families. The penetrances of hearing loss in these pedigrees were 20% and 18%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees were 10% and 15%. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations. Their distinct sets of mtDNA polymorphism belonged to Eastern Asian haplogroup C4a1, while other previously identified six Chinese mitochondrial genomes harboring the C1494T mutation belong to haplogroups D5a2, D, R, and F1, respectively. This suggested that the C1494T or G7444A mutation occurred sporadically and multiplied through evolution of the mitochondrial DNA (mtDNA). The absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in their mtDNA suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in those Chinese families. However, aminoglycosides and other nuclear modifier genes play a modifying role in the phenotypic manifestation of the C1494T mutation in these Chinese families.     

Study of modifiers factors associated to mitochondrial mutations in individuals with hearing impairment

Hearing impairment is the most prevalent sensorial deficit in the general population. Congenital deafness occurs in about 1 in 1000 live births, of which approximately 50% has hereditary cause in development countries. Non-syndromic deafness can be caused by mutations in both nuclear and mitochondrial genes. Mutations in mtDNA have been associated with aminoglycoside-induced and non-syndromic deafness in many families worldwide. However, the nuclear background influences the phenotypic expression of these pathogenic mutations. Indeed, it has been proposed that nuclear modifier genes modulate the phenotypic manifestation of the mitochondrial A1555G mutation in the MTRNR1 gene. The both putative nuclear modifiers genes TRMU and MTO1 encoding a highly conserved mitochondrial related to tRNA modification. It has been hypothesizes that human TRMU and also MTO1 nuclear genes may modulate the phenotypic manifestation of deafness-associated mitochondrial mutations. The aim of this work was to elucidate the contribution of mitochondrial mutations, nuclear modifier genes mutations and aminoglycoside exposure in the deafness phenotype. Our findings suggest that the genetic background of individuals may play an important role in the pathogenesis of deafness-associated with mitochondrial mutation and aminoglycoside-induced.