两个氨基糖甙类药物性耳聋家系的分子遗传学研究
|
摘要
目的:
探讨2个氨基糖甙类药物所致非综合征型耳聋中国家系的分子遗传学特征。
方法:
从2个氨基糖甙类药物性耳聋及非综合征型耳聋家系选择部分成员,包括7名母系成员及1名听力正常配偶,取外周血,提取基因组DNA。用遗传性耳聋基因检测芯片检测4个中国人中常见的耳聋相关基因中的9个热点突变,包括GJB2 ( 35delG,176del16bp,235delC及299delAT ),GJB3 ( C538T ),SLC26A4( IVS7-2A>G,A2168G )和线粒体DNA 12S rRNA ( A1555G,C1494T )。PCR扩增阳性突变基因并测序验证检测结果。然后,采用特定引物对两家系的先证者分别进行线粒体DNA全序列及核基因TRMU和MTO1编码区的PCR扩增,扩增产物经纯化后直接用ABI 3730型测序仪测序,并将测序结果与标准序列比对,识别有意义的碱基变异。
结果:
芯片检测发现,两家系的7名母系成员均存在同质性线粒体DNA12S rRNA基因C1494T突变。与修正的剑桥参考序列相比,两名先证者的线粒体DNA全序列分析共发现了53个碱基变异,但除已知的12S rRNA C1494T突变外,其余52个碱基变异均为已报道的多态性位点;两家系先证者线粒体单体型分别是D4和D5a。TRMU和MTO1基因序列分析无异常发现。
结论:
线粒体DNA 12S rRNA C1494T突变是这两个家系耳聋发生的主要分子基础,而氨基糖甙类抗生素的应用增强了该突变的表型表达;未能证实线粒体单体型以及核基因TRMU和MTO1对家系成员C1494T突变的表型具有修饰作用。
Objective:
To explore the molecular genetic characterization of two Chinese families withaminoglycoside-induced and nonsyndromic sensorineural hearing loss.
Methods:
Blood samples were obtained from 7 maternal members and 1 married-in spouseof the two Chinese families. Genomic DNA was isolated from the peripheralleukocytes of the subjects using the Puregene DNA Isolation Kits. Firstly, 9 hot spotsfor mutations in four most common pathologic genes, GJB2 (35delG, 176del16bp,235delC and 299delAT), GJB3 (C538T ), SLC26A4 (IVS7-2A>G, A2168G) andmitochondria 12S rRNA (A1555G, C1494T), were screened with the DNA microarrayto detect the deafness-associated mutations. The whole mitochondrial genomes andthe coding sequence of TRMU and MTO1 genes of two probands were then PCRamplified using specific primers. Each fragment was purified and subsequentlyanalyzed by direct sequencing in an Applied Biosystems 3730 automated DNAsequencer. The resultant sequence data were compared with the standard sequence toidentify base changes.
Results:
Mitochondrial 12S rRNA C1494T mutation was detected in all 7 maternalmembers of the two families. Sequence analysis of the complete mitochondrialgenomes in the two probands revealed the distinct sets of mitochondrial DNApolymorphism (52 other nucleotide changes), in addition to the identical 12S rRNAC1494T mutation. None of these 52 variants, however, were shown to be pathogenic.The whole mitochondrial genome of proband from each of the two families wasestablished that they belong to mitochondrial haplogroups D4 and D5a respectively.No mutations were identified in either TRMU gene or MTO1 gene.
Conclusions:
C1494T mutation in the mitochondrial 12S rRNA gene is the main molecularmechanism responsible for the hearing loss in the two pedigrees, and the use ofaminoglycoside antibiotics may enhance the phenotypic manifestation of deafness-associated mitochondrial C1494T mutation. Mitochondrial haplogroups and nucleargenes of TRMU and MTO1, however, seem not contribute to the phenotypicexpression of C1494T mutation in these two families.
探讨2个氨基糖甙类药物所致非综合征型耳聋中国家系的分子遗传学特征。
方法:
从2个氨基糖甙类药物性耳聋及非综合征型耳聋家系选择部分成员,包括7名母系成员及1名听力正常配偶,取外周血,提取基因组DNA。用遗传性耳聋基因检测芯片检测4个中国人中常见的耳聋相关基因中的9个热点突变,包括GJB2 ( 35delG,176del16bp,235delC及299delAT ),GJB3 ( C538T ),SLC26A4( IVS7-2A>G,A2168G )和线粒体DNA 12S rRNA ( A1555G,C1494T )。PCR扩增阳性突变基因并测序验证检测结果。然后,采用特定引物对两家系的先证者分别进行线粒体DNA全序列及核基因TRMU和MTO1编码区的PCR扩增,扩增产物经纯化后直接用ABI 3730型测序仪测序,并将测序结果与标准序列比对,识别有意义的碱基变异。
结果:
芯片检测发现,两家系的7名母系成员均存在同质性线粒体DNA12S rRNA基因C1494T突变。与修正的剑桥参考序列相比,两名先证者的线粒体DNA全序列分析共发现了53个碱基变异,但除已知的12S rRNA C1494T突变外,其余52个碱基变异均为已报道的多态性位点;两家系先证者线粒体单体型分别是D4和D5a。TRMU和MTO1基因序列分析无异常发现。
结论:
线粒体DNA 12S rRNA C1494T突变是这两个家系耳聋发生的主要分子基础,而氨基糖甙类抗生素的应用增强了该突变的表型表达;未能证实线粒体单体型以及核基因TRMU和MTO1对家系成员C1494T突变的表型具有修饰作用。
Objective:
To explore the molecular genetic characterization of two Chinese families withaminoglycoside-induced and nonsyndromic sensorineural hearing loss.
Methods:
Blood samples were obtained from 7 maternal members and 1 married-in spouseof the two Chinese families. Genomic DNA was isolated from the peripheralleukocytes of the subjects using the Puregene DNA Isolation Kits. Firstly, 9 hot spotsfor mutations in four most common pathologic genes, GJB2 (35delG, 176del16bp,235delC and 299delAT), GJB3 (C538T ), SLC26A4 (IVS7-2A>G, A2168G) andmitochondria 12S rRNA (A1555G, C1494T), were screened with the DNA microarrayto detect the deafness-associated mutations. The whole mitochondrial genomes andthe coding sequence of TRMU and MTO1 genes of two probands were then PCRamplified using specific primers. Each fragment was purified and subsequentlyanalyzed by direct sequencing in an Applied Biosystems 3730 automated DNAsequencer. The resultant sequence data were compared with the standard sequence toidentify base changes.
Results:
Mitochondrial 12S rRNA C1494T mutation was detected in all 7 maternalmembers of the two families. Sequence analysis of the complete mitochondrialgenomes in the two probands revealed the distinct sets of mitochondrial DNApolymorphism (52 other nucleotide changes), in addition to the identical 12S rRNAC1494T mutation. None of these 52 variants, however, were shown to be pathogenic.The whole mitochondrial genome of proband from each of the two families wasestablished that they belong to mitochondrial haplogroups D4 and D5a respectively.No mutations were identified in either TRMU gene or MTO1 gene.
Conclusions:
C1494T mutation in the mitochondrial 12S rRNA gene is the main molecularmechanism responsible for the hearing loss in the two pedigrees, and the use ofaminoglycoside antibiotics may enhance the phenotypic manifestation of deafness-associated mitochondrial C1494T mutation. Mitochondrial haplogroups and nucleargenes of TRMU and MTO1, however, seem not contribute to the phenotypicexpression of C1494T mutation in these two families.
引文
1.第二次全国残疾人抽样调查办公室.第二次全国残疾人抽样调查主要数据库手册.北京:华夏出版社, 2007, 38.
2. Keats BJB, Berlin, CI, Gregory P. Epidemiology of Genetic Hearing Loss.Seminars in Hearing, 2006, 7(3): 136-147.
3. Kokotas H, Petersen MB, Willems PJ. Mitochondrial deafness. Clin Genet, 2007,71(5): 379-391.
4. hppt://hereditaryhearingloss.org. (Last update: February 24, 2011).
5. Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNAmutation associated with both antibiotic-induced and nonsyndromic deafness.Nat Genet, 1993, 4(3): 289-294.
6. Zhao H, Li RH, Wang QJ, et al. Maternally inherited aminoglycoside-inducedand nonsyndromic deafness is associated with the novel C1494T mutation in themitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet, 2004,74(1): 139-152.
7. Zhao L, Young WY, Li R, et al. Clinical evaluation and sequence analysis of thecomplete mitochondrial genome of three Chinese patients with hearingimpairment associated with the 12S rRNA T1095C mutation. Biochem BiophysRes Commun, 2004, 325(4): 1503-1508.
8. Xing G, Chen Z, Wei Q, et al. Maternally inherited non-syndromic hearing lossassociated with mitochondrial 12S rRNA A827G mutation in a Chinese family.Biochem Biophys Res Commun, 2006, 344(4): 1253-1257.
9. Chaig MR, Zernotti ME, Soria NW, et al. A mutation in mitochondrial 12S rRNA,A827G, in Argentinean family with hearing loss after aminoglycoside treatment.Biochem Biophys Res Commun, 2008, 368(3): 631-636.
10. Xing G, Chen Z, Cao X. Mitochondrial rRNA and tRNA and hearing function.Cell Res, 2007, 17(3): 227-239.
11. Guan MX. Molecular pathogenetic mechanism of maternally inherited deafness.Ann N Y Acad Sci, 2004, 1011: 259-271.
12. Guan MX, Yan Q, Li X, et al. Mutation in TRMU related to transfer RNAmodi?cation modulates the phenotypic expression of the deafness-associatedmitochondrial 12S ribosomal RNA mutations. Am J Hum Genet, 2006, 79(2):291-302.
13. Li X, Li R, Lin X, et al. Isolation and characterization of the putative nuclearmodifier gene MTO1 involved in the pathogenesis of deafness-associatedmitochondrial 12S rRNA A1555G mutation. J Biol Chem, 2002, 277(30): 27256-27264.
14. Li R, Xing G, Yan M, et al. Cosegregation of C-insertion at position 961 withA1555G mutation of mitochondrial 12S rRNA gene in a large Chinese familywith maternally inherited hearing loss. Am J Med Genet, 2004, 124A(2):113-117.
15. Xing G, Chen Z, Wei Q, et al. Mitochondrial 12S rRNA A827G mutation isinvolved in the genetic susceptibility to aminoglycoside ototoxicity. BiochemBiophys Res Commun, 2006, 346(4): 1131-1135.
16. Rieder MJ, Taylor SL, Tobe VO, et al. Automating the identification of DNAvariations using quality-based fluorescence re-sequencing: analysis of the humanmitochondrial genome. Nucleic Acids Res, 1998, 26(4): 967-973.
17. Guan MX. Prevalence of mitochondrial 12S rRNA mutations associated withaminoglycoside ototoxicity. Volta Rev, 2005, 105(3): 211-227.
18. Tessa A, Giannotti A, Tieri L, et al. Maternally inherited deafness associatedwith a T1095C mutation in the mtDNA. Eur J Hum Genet, 2001, 9(2): 147-149.
19. Wang Q, Li QZ, Han D, et al. Clinical and molecular analysis of a four-generation Chinese family with aminoglycoside-induced and nonsyndromichearing loss associated with the mitochondrial 12S rRNA C1494T mutation.Biochem Biophys Res Commun, 2006, 340(2): 583-588.
20. Chen J, Yang L, Yang A, et al. Maternally inherited aminoglycoside-induced andnonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation inthree Han Chinese pedigrees. Gene, 2007, 401(1-2): 4-11.
21. Han DY, Dai P, Zhu Q, et al. The mitochondrial tRNA(Ala) T5628C variant mayhave a modifying role in the phenotypic manifestation of the 12S rRNA C1494Tmutation in a large Chinese family with hearing loss. Biochem Biophys ResCommun, 2007, 357(2): 554-560.
22. Yuan H, Chen J, Liu X, et al. Coexistence of mitochondrial 12S rRNA C1494Tand CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigreeswith aminoglycoside-induced and non-syndromic hearing loss. Biochem BiophysRes Commun, 2007, 362(1), 94-100.
23. Rodr?′guez-Ballesteros M, Olarte M, Aguirre LA, et al. Molecular and clinicalcharacterisation of three Spanish families with maternally inherited non-syndromic hearing loss caused by the 1494C>T mutation in the mitochondrial12S rRNA gene. J Med Genet, 2006, 43(11): e54.
24. Zhu Y, Li Q, Chen Z, et al. Mitochondrial haplogroups and phenotype of 13Chinese families may suggest multi-original evolution of mitochondrial C1494Tmutation. Mitochondrion, 2009, 9(6): 418-428.
25.田古,刘玉和,马祎楠,等.中国人非综合征耳聋患者线粒体基因组C1494T突变筛查.中华医学遗传学杂志, 2007, 24(4): 464-466.
26. Zhao H, Young WY, Yan Q, et al. Functional characterization of themitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss. Nucleic Acids Res, 2005, 33(3):1132-1139.
27. Yuan H, Qian Y, Xu Y, et al. Cosegregation of the G7444A mutation in themitochondrial COI/tRNASer(UCN) genes with the 12S rRNA A1555G mutation in aChinese family with aminoglycoside-induced and nonsyndromic hearing loss.Am J Med Genet, 2005, 138A(2): 133-140.
28. Dai D, Lu Y, Chen Z, et al. Co-segregation of the T1095C with the A1555Gmutation of the mitochondrial 12S rRNA gene in a patient with non-syndromichearing loss. Biochem Biophys Res Commun, 2008, 377(4): 1152-1155.
29. Yan Q, Bykhovskaya Y, Li R, et al. Human TRMU encoding the mitochondrial5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclearmodifier gene for the phenotypic expression of the deafness-associated 12SrRNA mutations. Biochem Biophys Res Commun, 2006, 342(4): 1130-1136.
30. Finnila S, Majamaa K. Lack of a modulative factor in locus 8p23 in a Finnishfamily with nonsyndromic sensorineural hearing loss associated with the1555A>G mitochondrial DNA mutation . Eur J Hum Genet, 2003, 11(9):652-658.
31. Sousa de Moraes VC, Alexandrino F, Andrade PB, et al. Study of modifiersfactors associated to mitochondrial mutations in individuals with hearingimpairment. Biochem Biophys Res Commun, 2009, 381(2): 210-213.
1. Morton ME. Genetic epidemiology of hearing impairment. Ann NY Acad Sci,1991, 630: 16-31.
2. Petit C, Levilliers J, Hardelin JP. Molecular genetics of hearing loss. Annu RevGenet, 2001, 35: 589-646
3. Xing G, Chen Z, Cao X. Mitochondrial rRNA and tRNA and hearing function.Cell Res, 2007, 17(3): 227-239.
4. Guan MX. Prevalence of mitochondrial 12S rRNA mutations associated withaminoglycoside ototoxicity . Volta Rev, 2005, 105(3): 211–227.
5. Fischel-Ghodsian N. Genetic factors in aminoglycoside toxicity.Pharmacogenomics, 2005, 6(1):27–36.
6. Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNAmutation associated with both antibiotic-induced and non-syndromic deafness [J].Nat Genet, 1993, 4(3): 289–294.
7. Li R, Xing G, Yan M, et al. Cosegregation of C-insertion at position 961 withA1555G mutation of mitochondrial 12S rRNA gene in a large Chinese familywith maternally inherited hearing loss. Am J Med Genet, 2004, 124A(2):113–117.
8. Tessa A, Giannotti A, Tieri L, et al. Maternally inherited deafness associated witha T1095C mutation in the mtDNA. Eur J Hum Genet, 2001, 9(2):147–149.
9. Xing G, Chen Z, Wei Q, et al. Maternally inherited non-syndromic hearing lossassociated with mitochondrial 12S rRNA A827G mutation in a Chinese family.Biochem Biophys Res Commun, 2006, 344(4): 1253-1257.
10. Zhao H, Li R, Wang Q, et al. Maternally inherited aminoglycoside-induced andnonsyndromic deafness is associated with the novel C1494T mutation in themitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet, 2004,74(1): 139–152.
11. Bacino C, Prezant TR, Bu X, et al. Susceptibility mutations in the mitochondrialsmall ribosomal RNA gene in aminoglycoside induced deafness. Pharmaco-genetics, 1995, 5(3): 165–172.
12. Casano RA, Johnson DF, Bykhovskaya Y, et al. Inherited susceptibility toaminoglycoside ototoxicity: Genetic heterogeneity and clinical implications.Am J Otolaryngol, 1999, 20(3): 151–156.
13. Reid FM, Vernham GA, Jacobs HT, et al. A novel mitochondrial point mutationin a maternal pedigree with sensorineural deafness. Hum Mut, 1994, 3(3):243–247.
14. Verhoeven K, Ensink RJ, Tiranti V, et al. Hearing impairment andneurological dysfunction associated with a mutation in the mitochondrialtRNASer(UCN) gene. Eur J Hum Genet, 1999, 7(1): 45–51.
15. Jacobs HT, Hutchin TP, Kappi T, et al. Mitochondrial DNA mutations in patientswith postlingual, nonsyndromic hearing impairment. Eur J Hum Genet, 2005,13(1): 26–33.
16. Hutchin T, Parker MJ, Young ID, et al. A novel mutation in the mitochondrialtRNASer(UCN) gene in a family with nonsyndromic sensorineural hearingimpairment. J Med Genet, 2000, 37(9): 692–694.
17. Li R, Ishikawa K, Deng JH, et al. Maternally inherited nonsyndromic hearingloss is associated with the T7511C mutation in the mitochondrial tRNASer(UCN)gene in a Japanese family. Biochem Biophys Res Commun, 2005, 328(1): 32–37.
18. Rodr?′guez-Ballesteros M, Olarte M, Aguirre LA, et al. Molecular and clinicalcharacterisation of three Spanish families with maternally inheritednon-syndromic hearing loss caused by the 1494C>T mutation in themitochondrial 12S rRNA gene. J Med Genet, 2006, 43(11): e54
19. Zhao H, Young WY, Yan QF, et al. Functional characterization of themitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss. Nucleic Acids Res, 2005, 33(3):1132-1139
20. Wang Q, Li QZ, Han D, et al. Clinical and molecular analysis of afour-generation Chinese family with aminoglycoside-induced and nonsyndromichearing loss associated with the mitochondrial 12S rRNA C1494T mutation.Biochem Biophys Res Commun, 2006, 340(2): 583-588.
21. Chen J, Yang L, Yang A, et al. Maternally inherited aminoglycoside-induced andnonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation inthree Han Chinese pedigrees. Gene, 2007, 401(1-2): 4-11
22. Han DY, Dai P, Zhu Q, et al. The mitochondrial tRNA(Ala) T5628C variant mayhave a modifying role in the phenotypic manifestation of the 12S rRNA C1494Tmutation in a large Chinese family with hearing loss. Biochem Biophys ResCommun, 2007, 357(2): 554-560.
23. Zhu Y, Li Q, Chen Z, et al. Mitochondrial haplogroups and phenotype of 13Chinese families may suggest multi-original evolution of mitochondrial C1494Tmutation. Mitochondrion, 2009, 9(6): 418-428
24.田古,刘玉和,马祎楠,等.中国人非综合征耳聋患者线粒体基因组C1494T突变筛查[J].中华医学遗传学杂志, 2007, 24(4): 464-466.
25. Kokotas H, Petersen MB, Willems PJ. Mitochondrial deafness. Clin Genet, 2007,71(5): 379-391.
26. Guan MX, Yan Q, Li X, et al. Mutation in TRMU related to transfer RNAmodi?cation modulates the phenotypic expression of the deafness-associatedmitochondrial 12S ribosomal RNA mutations. Am J Hum Genet, 2006, 79(2):291-302.
27. Finnila S, Majamaa K. Lack of a modulative factor in locus 8p23 in a Finnishfamily with nonsyndromic sensorineural hearing loss associated with the1555A>G mitochondrial DNA mutation. Eur J Hum Genet, 2003, 11(9):652-658.
28. Fourmy D, Recht MI, Puglisi JD. Binding of neomycin-class aminoglycosideantibiotics to A-site of 16S rRNA. J Mol Bio, 1998, 277(2): 347-362
29. Spangler EA, Blackburn EH. The nucleotide sequence of the 17S ribosomal RNAgene of Tetrahymena thermophila and the identification of point mutationsresulting in resistance to the antibiotics paromycin and hygromycin. J Biol Chem,1985, 260(10): 6334-6340
30. Li X, Guan MX. A human mitochondrial GTP binding protein related to tRNAmodi?cation may modulate the phenotypic expression of the deafness-associatedmitochondrial 12S rRNAmutation. Mol Cell Biol, 2002, 22(21): 7701–7711.
31. Li X, Li R, Lin X, et al. Isolation and characterization of the putative nuclearmodi?er gene MTO1 involved in the pathogenesis of deafness-associatedmitochondrial 12S rRNA A1555G mutation. J Biol Chem, 2002, 277(30),27256–27264.
32. Bykhovskaya Y, Shohat M, Ehrenman K, et al. Evidence for complex nuclearinheritance in a pedigree with nonsyndromic deafness due to a homoplasmicmitochondrial mutation. Am J Med Genet, 1998, 77(5): 421–426.
33. Yan Q, Li X, Faye G, et al. Mutations in MTO2 related to tRNA modi?cationimpair mitochondrial gene expression and protein synthesis in the presence of aparomomycin resistance mutation in mitochondrial 15S rRNA. J Biol Chem,2005, 280(32): 29151–29157.
34. Yuan H, Chen J, Liu X, et al. Coexistence of mitochondrial 12S rRNA C1494Tand CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigreeswith aminoglycoside-induced and non-syndromic hearing loss. Biochem BiophysRes Commun, 2007, 362(1): 94–100.
2. Keats BJB, Berlin, CI, Gregory P. Epidemiology of Genetic Hearing Loss.Seminars in Hearing, 2006, 7(3): 136-147.
3. Kokotas H, Petersen MB, Willems PJ. Mitochondrial deafness. Clin Genet, 2007,71(5): 379-391.
4. hppt://hereditaryhearingloss.org. (Last update: February 24, 2011).
5. Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNAmutation associated with both antibiotic-induced and nonsyndromic deafness.Nat Genet, 1993, 4(3): 289-294.
6. Zhao H, Li RH, Wang QJ, et al. Maternally inherited aminoglycoside-inducedand nonsyndromic deafness is associated with the novel C1494T mutation in themitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet, 2004,74(1): 139-152.
7. Zhao L, Young WY, Li R, et al. Clinical evaluation and sequence analysis of thecomplete mitochondrial genome of three Chinese patients with hearingimpairment associated with the 12S rRNA T1095C mutation. Biochem BiophysRes Commun, 2004, 325(4): 1503-1508.
8. Xing G, Chen Z, Wei Q, et al. Maternally inherited non-syndromic hearing lossassociated with mitochondrial 12S rRNA A827G mutation in a Chinese family.Biochem Biophys Res Commun, 2006, 344(4): 1253-1257.
9. Chaig MR, Zernotti ME, Soria NW, et al. A mutation in mitochondrial 12S rRNA,A827G, in Argentinean family with hearing loss after aminoglycoside treatment.Biochem Biophys Res Commun, 2008, 368(3): 631-636.
10. Xing G, Chen Z, Cao X. Mitochondrial rRNA and tRNA and hearing function.Cell Res, 2007, 17(3): 227-239.
11. Guan MX. Molecular pathogenetic mechanism of maternally inherited deafness.Ann N Y Acad Sci, 2004, 1011: 259-271.
12. Guan MX, Yan Q, Li X, et al. Mutation in TRMU related to transfer RNAmodi?cation modulates the phenotypic expression of the deafness-associatedmitochondrial 12S ribosomal RNA mutations. Am J Hum Genet, 2006, 79(2):291-302.
13. Li X, Li R, Lin X, et al. Isolation and characterization of the putative nuclearmodifier gene MTO1 involved in the pathogenesis of deafness-associatedmitochondrial 12S rRNA A1555G mutation. J Biol Chem, 2002, 277(30): 27256-27264.
14. Li R, Xing G, Yan M, et al. Cosegregation of C-insertion at position 961 withA1555G mutation of mitochondrial 12S rRNA gene in a large Chinese familywith maternally inherited hearing loss. Am J Med Genet, 2004, 124A(2):113-117.
15. Xing G, Chen Z, Wei Q, et al. Mitochondrial 12S rRNA A827G mutation isinvolved in the genetic susceptibility to aminoglycoside ototoxicity. BiochemBiophys Res Commun, 2006, 346(4): 1131-1135.
16. Rieder MJ, Taylor SL, Tobe VO, et al. Automating the identification of DNAvariations using quality-based fluorescence re-sequencing: analysis of the humanmitochondrial genome. Nucleic Acids Res, 1998, 26(4): 967-973.
17. Guan MX. Prevalence of mitochondrial 12S rRNA mutations associated withaminoglycoside ototoxicity. Volta Rev, 2005, 105(3): 211-227.
18. Tessa A, Giannotti A, Tieri L, et al. Maternally inherited deafness associatedwith a T1095C mutation in the mtDNA. Eur J Hum Genet, 2001, 9(2): 147-149.
19. Wang Q, Li QZ, Han D, et al. Clinical and molecular analysis of a four-generation Chinese family with aminoglycoside-induced and nonsyndromichearing loss associated with the mitochondrial 12S rRNA C1494T mutation.Biochem Biophys Res Commun, 2006, 340(2): 583-588.
20. Chen J, Yang L, Yang A, et al. Maternally inherited aminoglycoside-induced andnonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation inthree Han Chinese pedigrees. Gene, 2007, 401(1-2): 4-11.
21. Han DY, Dai P, Zhu Q, et al. The mitochondrial tRNA(Ala) T5628C variant mayhave a modifying role in the phenotypic manifestation of the 12S rRNA C1494Tmutation in a large Chinese family with hearing loss. Biochem Biophys ResCommun, 2007, 357(2): 554-560.
22. Yuan H, Chen J, Liu X, et al. Coexistence of mitochondrial 12S rRNA C1494Tand CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigreeswith aminoglycoside-induced and non-syndromic hearing loss. Biochem BiophysRes Commun, 2007, 362(1), 94-100.
23. Rodr?′guez-Ballesteros M, Olarte M, Aguirre LA, et al. Molecular and clinicalcharacterisation of three Spanish families with maternally inherited non-syndromic hearing loss caused by the 1494C>T mutation in the mitochondrial12S rRNA gene. J Med Genet, 2006, 43(11): e54.
24. Zhu Y, Li Q, Chen Z, et al. Mitochondrial haplogroups and phenotype of 13Chinese families may suggest multi-original evolution of mitochondrial C1494Tmutation. Mitochondrion, 2009, 9(6): 418-428.
25.田古,刘玉和,马祎楠,等.中国人非综合征耳聋患者线粒体基因组C1494T突变筛查.中华医学遗传学杂志, 2007, 24(4): 464-466.
26. Zhao H, Young WY, Yan Q, et al. Functional characterization of themitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss. Nucleic Acids Res, 2005, 33(3):1132-1139.
27. Yuan H, Qian Y, Xu Y, et al. Cosegregation of the G7444A mutation in themitochondrial COI/tRNASer(UCN) genes with the 12S rRNA A1555G mutation in aChinese family with aminoglycoside-induced and nonsyndromic hearing loss.Am J Med Genet, 2005, 138A(2): 133-140.
28. Dai D, Lu Y, Chen Z, et al. Co-segregation of the T1095C with the A1555Gmutation of the mitochondrial 12S rRNA gene in a patient with non-syndromichearing loss. Biochem Biophys Res Commun, 2008, 377(4): 1152-1155.
29. Yan Q, Bykhovskaya Y, Li R, et al. Human TRMU encoding the mitochondrial5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclearmodifier gene for the phenotypic expression of the deafness-associated 12SrRNA mutations. Biochem Biophys Res Commun, 2006, 342(4): 1130-1136.
30. Finnila S, Majamaa K. Lack of a modulative factor in locus 8p23 in a Finnishfamily with nonsyndromic sensorineural hearing loss associated with the1555A>G mitochondrial DNA mutation . Eur J Hum Genet, 2003, 11(9):652-658.
31. Sousa de Moraes VC, Alexandrino F, Andrade PB, et al. Study of modifiersfactors associated to mitochondrial mutations in individuals with hearingimpairment. Biochem Biophys Res Commun, 2009, 381(2): 210-213.
1. Morton ME. Genetic epidemiology of hearing impairment. Ann NY Acad Sci,1991, 630: 16-31.
2. Petit C, Levilliers J, Hardelin JP. Molecular genetics of hearing loss. Annu RevGenet, 2001, 35: 589-646
3. Xing G, Chen Z, Cao X. Mitochondrial rRNA and tRNA and hearing function.Cell Res, 2007, 17(3): 227-239.
4. Guan MX. Prevalence of mitochondrial 12S rRNA mutations associated withaminoglycoside ototoxicity . Volta Rev, 2005, 105(3): 211–227.
5. Fischel-Ghodsian N. Genetic factors in aminoglycoside toxicity.Pharmacogenomics, 2005, 6(1):27–36.
6. Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNAmutation associated with both antibiotic-induced and non-syndromic deafness [J].Nat Genet, 1993, 4(3): 289–294.
7. Li R, Xing G, Yan M, et al. Cosegregation of C-insertion at position 961 withA1555G mutation of mitochondrial 12S rRNA gene in a large Chinese familywith maternally inherited hearing loss. Am J Med Genet, 2004, 124A(2):113–117.
8. Tessa A, Giannotti A, Tieri L, et al. Maternally inherited deafness associated witha T1095C mutation in the mtDNA. Eur J Hum Genet, 2001, 9(2):147–149.
9. Xing G, Chen Z, Wei Q, et al. Maternally inherited non-syndromic hearing lossassociated with mitochondrial 12S rRNA A827G mutation in a Chinese family.Biochem Biophys Res Commun, 2006, 344(4): 1253-1257.
10. Zhao H, Li R, Wang Q, et al. Maternally inherited aminoglycoside-induced andnonsyndromic deafness is associated with the novel C1494T mutation in themitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet, 2004,74(1): 139–152.
11. Bacino C, Prezant TR, Bu X, et al. Susceptibility mutations in the mitochondrialsmall ribosomal RNA gene in aminoglycoside induced deafness. Pharmaco-genetics, 1995, 5(3): 165–172.
12. Casano RA, Johnson DF, Bykhovskaya Y, et al. Inherited susceptibility toaminoglycoside ototoxicity: Genetic heterogeneity and clinical implications.Am J Otolaryngol, 1999, 20(3): 151–156.
13. Reid FM, Vernham GA, Jacobs HT, et al. A novel mitochondrial point mutationin a maternal pedigree with sensorineural deafness. Hum Mut, 1994, 3(3):243–247.
14. Verhoeven K, Ensink RJ, Tiranti V, et al. Hearing impairment andneurological dysfunction associated with a mutation in the mitochondrialtRNASer(UCN) gene. Eur J Hum Genet, 1999, 7(1): 45–51.
15. Jacobs HT, Hutchin TP, Kappi T, et al. Mitochondrial DNA mutations in patientswith postlingual, nonsyndromic hearing impairment. Eur J Hum Genet, 2005,13(1): 26–33.
16. Hutchin T, Parker MJ, Young ID, et al. A novel mutation in the mitochondrialtRNASer(UCN) gene in a family with nonsyndromic sensorineural hearingimpairment. J Med Genet, 2000, 37(9): 692–694.
17. Li R, Ishikawa K, Deng JH, et al. Maternally inherited nonsyndromic hearingloss is associated with the T7511C mutation in the mitochondrial tRNASer(UCN)gene in a Japanese family. Biochem Biophys Res Commun, 2005, 328(1): 32–37.
18. Rodr?′guez-Ballesteros M, Olarte M, Aguirre LA, et al. Molecular and clinicalcharacterisation of three Spanish families with maternally inheritednon-syndromic hearing loss caused by the 1494C>T mutation in themitochondrial 12S rRNA gene. J Med Genet, 2006, 43(11): e54
19. Zhao H, Young WY, Yan QF, et al. Functional characterization of themitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss. Nucleic Acids Res, 2005, 33(3):1132-1139
20. Wang Q, Li QZ, Han D, et al. Clinical and molecular analysis of afour-generation Chinese family with aminoglycoside-induced and nonsyndromichearing loss associated with the mitochondrial 12S rRNA C1494T mutation.Biochem Biophys Res Commun, 2006, 340(2): 583-588.
21. Chen J, Yang L, Yang A, et al. Maternally inherited aminoglycoside-induced andnonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation inthree Han Chinese pedigrees. Gene, 2007, 401(1-2): 4-11
22. Han DY, Dai P, Zhu Q, et al. The mitochondrial tRNA(Ala) T5628C variant mayhave a modifying role in the phenotypic manifestation of the 12S rRNA C1494Tmutation in a large Chinese family with hearing loss. Biochem Biophys ResCommun, 2007, 357(2): 554-560.
23. Zhu Y, Li Q, Chen Z, et al. Mitochondrial haplogroups and phenotype of 13Chinese families may suggest multi-original evolution of mitochondrial C1494Tmutation. Mitochondrion, 2009, 9(6): 418-428
24.田古,刘玉和,马祎楠,等.中国人非综合征耳聋患者线粒体基因组C1494T突变筛查[J].中华医学遗传学杂志, 2007, 24(4): 464-466.
25. Kokotas H, Petersen MB, Willems PJ. Mitochondrial deafness. Clin Genet, 2007,71(5): 379-391.
26. Guan MX, Yan Q, Li X, et al. Mutation in TRMU related to transfer RNAmodi?cation modulates the phenotypic expression of the deafness-associatedmitochondrial 12S ribosomal RNA mutations. Am J Hum Genet, 2006, 79(2):291-302.
27. Finnila S, Majamaa K. Lack of a modulative factor in locus 8p23 in a Finnishfamily with nonsyndromic sensorineural hearing loss associated with the1555A>G mitochondrial DNA mutation. Eur J Hum Genet, 2003, 11(9):652-658.
28. Fourmy D, Recht MI, Puglisi JD. Binding of neomycin-class aminoglycosideantibiotics to A-site of 16S rRNA. J Mol Bio, 1998, 277(2): 347-362
29. Spangler EA, Blackburn EH. The nucleotide sequence of the 17S ribosomal RNAgene of Tetrahymena thermophila and the identification of point mutationsresulting in resistance to the antibiotics paromycin and hygromycin. J Biol Chem,1985, 260(10): 6334-6340
30. Li X, Guan MX. A human mitochondrial GTP binding protein related to tRNAmodi?cation may modulate the phenotypic expression of the deafness-associatedmitochondrial 12S rRNAmutation. Mol Cell Biol, 2002, 22(21): 7701–7711.
31. Li X, Li R, Lin X, et al. Isolation and characterization of the putative nuclearmodi?er gene MTO1 involved in the pathogenesis of deafness-associatedmitochondrial 12S rRNA A1555G mutation. J Biol Chem, 2002, 277(30),27256–27264.
32. Bykhovskaya Y, Shohat M, Ehrenman K, et al. Evidence for complex nuclearinheritance in a pedigree with nonsyndromic deafness due to a homoplasmicmitochondrial mutation. Am J Med Genet, 1998, 77(5): 421–426.
33. Yan Q, Li X, Faye G, et al. Mutations in MTO2 related to tRNA modi?cationimpair mitochondrial gene expression and protein synthesis in the presence of aparomomycin resistance mutation in mitochondrial 15S rRNA. J Biol Chem,2005, 280(32): 29151–29157.
34. Yuan H, Chen J, Liu X, et al. Coexistence of mitochondrial 12S rRNA C1494Tand CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigreeswith aminoglycoside-induced and non-syndromic hearing loss. Biochem BiophysRes Commun, 2007, 362(1): 94–100.