台州地区耳聋相关的线粒体12S rRNA C1494T突变筛查
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摘要
目的探讨线粒体12SrRNA基因C1494T突变和耳聋的相关性,为了耳聋的防治提供理论依据。方法在台州地区收集耳聋患者200例以及100例性别和年龄相仿的正常对照,使用聚合酶链反应(PCR)和测序法筛选线粒体C1494T突变,并进行临床和分子遗传学的评估。结果测序结果显示有2名耳聋患者携带同质性的C1494T突变,检出率为1%,其中只有1位患者具有明显的家族遗传。该家系的外显率较高,线粒体全基因组测序发现携带tRNASer(UCN)T7505C突变,该突变在进化上高度保守,可能会引起线粒体功能损伤,进而加剧了耳聋的外显率和表现度。结论线粒体C1494T突变是药物性耳聋相关的重要分子基础,继发突变T7505C可能会影响C1494T突变的表型表达,因此,本研究对耳聋的防治有重要的临床指导意义。
Objective:To explore the influence of mitochondrial 12 S rRNA C1494 T mutations in the clinical expression of maternally inherited aminoglycoside-induced deafness,and provided valuable information for prevention and diagnosis of hearing loss. Methods:We enrolled 200 deaf patients and 100 age and gender-matched healthy controls from Taizhou area,we further used PCR and sequence analysis to screen the mitochondrial C1494 T mutation,in addition,we performed the clinical and molecular characterization of the C1494 T deaf patients. Results:Sequence data indicated that there were 2 deafness patients carrying the homoplasmic C1494 T mutation(1%). However,only one patient has the family history of hearing loss. This Chinese pedigree exhibited a high penetrance of hearing loss,analysis of the complete mitochondrial genome showed the presence of tRNASer(UCN)T7505 C mutation,which was very conserved between different species,and may cause the mitochondrial dysfunction,therefore,increase the penetrance and expressivity of hearing loss-associated C1494 T mutation. Conclusions:Mitochondrial C1494 T mutation may be the important molecular basis for hearing loss,secondary T7505 C mutation may influence the clinical manifestation of C1494 T mutation,thus,our study is very useful for prevention and treatment of hearing loss.
Objective:To explore the influence of mitochondrial 12 S rRNA C1494 T mutations in the clinical expression of maternally inherited aminoglycoside-induced deafness,and provided valuable information for prevention and diagnosis of hearing loss. Methods:We enrolled 200 deaf patients and 100 age and gender-matched healthy controls from Taizhou area,we further used PCR and sequence analysis to screen the mitochondrial C1494 T mutation,in addition,we performed the clinical and molecular characterization of the C1494 T deaf patients. Results:Sequence data indicated that there were 2 deafness patients carrying the homoplasmic C1494 T mutation(1%). However,only one patient has the family history of hearing loss. This Chinese pedigree exhibited a high penetrance of hearing loss,analysis of the complete mitochondrial genome showed the presence of tRNASer(UCN)T7505 C mutation,which was very conserved between different species,and may cause the mitochondrial dysfunction,therefore,increase the penetrance and expressivity of hearing loss-associated C1494 T mutation. Conclusions:Mitochondrial C1494 T mutation may be the important molecular basis for hearing loss,secondary T7505 C mutation may influence the clinical manifestation of C1494 T mutation,thus,our study is very useful for prevention and treatment of hearing loss.
引文
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[14] Guan MX,Enriquez JA,Fischel-Ghodsian N,et al. The deafnessassociated mitochondrial DNA mutation at position 7445,which affects tRNASer(UCN)precursor processing,has long-range effects on NADH dehydrogenase subunit ND6 gene expression[J].Mol Cell Biol, 1998,18(10):5868-5879.
[15] Li X,Fischel‐Ghodsian N,Schwartz F,et al. Biochemical characterization of the mitochondrial tRNASer(UCN)T7511C mutation associated with nonsyndromic deafness[J]. Nucleic Acids Res,2004,32(3):867.
[16] Verma A,Piccoli DA,Bonilla E,et al. A novel mitochondrial G8313A mutation associated with prominent initial gastrointestinal symptoms and progressive encephaloneuropathy[J]. Pediatr Res,1997,42(4):448-454.
[2]Morton CC,Nance WE. Newborn hearing screening-a silent revolution[J]. N Engl J Med,2006,354(20):2151-2164.
[3]孙喜斌,于丽玫,曲成毅,等.中国听力残疾构成特点及康复对策[J].中国听力学语言康复科学杂志,2008,27(2):21-24.
[4]Prezant TR,Agapian JV,Bohlman MC,et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness[J]. Nat Genet,1993,4(3):289-294.
[5]ZhaoH,LiR,WangQ,etal.Maternallyinherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family[J]. Am J Hum Genet,2004,74(1):139-152.
[6]Andrews RM,Kubacka I,Chinnery PF,et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA[J]. Nat Genet,1999,23(2):147.
[7]Zytsar MV,Barashkov NA,Bady-Khoo MS,et al. Updated carrier rates for c.35delG(GJB2)associated with hearing loss in Russia and common c.35delG haplotypes in Siberia[J]. BMC Med Genet,2018,19(1):138.
[8]Tang X,Li R,Zheng J,et al. Maternally inherited hearing loss is associated with the novel mitochondrial tRNA Ser(UCN)7505T> C mutation in a Han Chinese family[J]. Mol Genet Metab,2010,100(1):57-64.
[9]Zhu Y,Li Q,Chen Z,et al. Mitochondrial haplotype and phenotype of 13 Chinese families may suggest multi-original evolution of mitochondrial C1494T mutation[J]. Mitochondrion,2009,9(6):418-428.
[10] ChenJ,YangL,YangA,etal.Maternallyinherited aminoglycoside-induced and nonsyndromic hearing loss is associated with the 12S rRNA C1494T mutation in three Han Chinese pedigrees[J]. Gene,2007,401(1-2):4-11.
[11] Rodriguez-Ballesteros M,Olarte M,Aguirre LA,et al. Molecular and clinical characterisation of three Spanish families with maternally inherited non-syndromic hearing loss caused by the1494C-> T mutation in the mitochondrial 12S rRNA gene[J]. J Med Genet,2006,43(11):e54.
[12] Zhao H,Young WY,Yan Q,et al. Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss[J].Nucleic Acids Res,2005,33(3):1132-1139.
[13] Lu J,Li Z,Zhu Y,et al. Mitochondrial 12S rRNA variants in 1642Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss[J]. Mitochondrion,2009,10(4):380-390.
[14] Guan MX,Enriquez JA,Fischel-Ghodsian N,et al. The deafnessassociated mitochondrial DNA mutation at position 7445,which affects tRNASer(UCN)precursor processing,has long-range effects on NADH dehydrogenase subunit ND6 gene expression[J].Mol Cell Biol, 1998,18(10):5868-5879.
[15] Li X,Fischel‐Ghodsian N,Schwartz F,et al. Biochemical characterization of the mitochondrial tRNASer(UCN)T7511C mutation associated with nonsyndromic deafness[J]. Nucleic Acids Res,2004,32(3):867.
[16] Verma A,Piccoli DA,Bonilla E,et al. A novel mitochondrial G8313A mutation associated with prominent initial gastrointestinal symptoms and progressive encephaloneuropathy[J]. Pediatr Res,1997,42(4):448-454.