Generic placeholder image

Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Research Article

The Mitochondrial tRNAHis G12192A Mutation May Modulate the Clinical Expression of Deafness-Associated tRNAThr G15927A Mutation in a Chinese Pedigree

Author(s): Yu Ding, Yao-Shu Teng, Guang-Chao Zhuo, Bo-Hou Xia and Jian-Hang Leng*

Volume 19 , Issue 2 , 2019

Page: [136 - 146] Pages: 11

DOI: 10.2174/1566524019666190308121552

Price: $65


Background: Mutations in mitochondrial tRNA (mt-tRNA) genes have been found to be associated with both syndromic and non-syndromic hearing impairment. However, the pathophysiology underlying mt-tRNA mutations in clinical expression of hearing loss remains poorly understood.

Objective: The aim of this study was to explore the potential association between mttRNA mutations and hearing loss.

Methods and Results: We reported here the molecular features of a pedigree with maternally transmitted non-syndromic hearing loss. Among 12 matrilineal relatives, five of them suffered variable degree of hearing impairment, but none of them had any medical history of using aminoglycosides antibiotics (AmAn). Genetic screening of the complete mitochondrial genomes from the matrilineal relatives identified the coexistence of mt-tRNAHis G12192A and mt-tRNAThr G15927A mutations, together with a set of polymorphisms belonging to human mitochondrial haplogroup B5b1b. Interestingly, the G12192A mutation occurred 2-bp from the 3’ end of the TψC loop of mt-tRNAHis, which was evolutionarily conserved from various species. In addition, the well-known G15927A mutation, which disrupted the highly conserved C-G base-pairing at the anticodon stem of mt-tRNAThr, may lead to the failure in mt-tRNA metabolism.

Furthermore, a significant decreased in ATP production and an increased ROS generation were observed in polymononuclear leukocytes (PMNs) which were isolated from the deaf patients carrying these mt-tRNA mutations, suggested that the G12192A and G15927A mutations may cause mitochondrial dysfunction that was responsible for deafness. However, the absence of any functional mutations/variants in GJB2, GJB3, GJB6 and TRMU genes suggested that the nuclear genes may not play important roles in the clinical expression of non-syndromic hearing loss in this family.

Conclusion: Our data indicated that mt-tRNAHis G12192A mutation may increase the penetrance and expressivity of deafness-associated m-tRNAThr G15927A mutation in this family.

Keywords: Non-syndromic hearing loss, mt-tRNA mutations, G12192A, G15927A, clinical expression, pathophysiology.

Han C, Someya S. Mouse models of age-related mitochondrial neurosensory hearing loss. Mol Cell Neurosci 2013; 55: 95-100.
Gates GA, Mills JH. Presbycusis. Lancet 2005; 366: 1111-20.
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. BMC Med Genet 2018; 19: 138.
Chan DK, Chang KW. GJB2-associated hearing loss: Systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope 2014; 124: E34-53.
Wu L, Li R, Chen J, et al. Analysis of mitochondrial A1555G mutation in infants with hearing impairment. Exp Ther Med 2018; 15: 5307-13.
Ding Y, Leng J, Fan F, et al. The role of mitochondrial DNA mutations in hearing loss. Biochem Genet 2013; 51: 588-602.
Young WY, Zhao L, Qian Y, et al. Extremely low penetrance of hearing loss in four Chinese families with the mitochondrial 12S rRNA A1555G mutation. Biochem Biophys Res Commun 2005; 328: 1244-51.
Chen J, Yang L, Yang A, 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: 4-11.
Zheng J, Ji Y, Guan MX. Mitochondrial tRNA mutations associated with deafness. Mitochondrion 2012; 12: 406-13.
Hoptasz M, Szczuciński A, Losy J. Heterogeneous phenotypic manifestations of maternally inherited deafness associated with the mitochondrial A3243G mutation. Case report. Neurol Neurochir Pol 2014; 48: 150-3.
Chen DY, Zhu WD, Chai YC, et al. Mutation in PCDH15 may modify the phenotypic expression of the 7511T>C mutation in MT-TS1 in a Chinese Han family with maternally inherited nonsyndromic hearing loss. Int J Pediatr Otorhinolaryngol 2015; 79: 1654-7.
Yan X, Wang X, Wang Z, et al. Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNAHis gene. J Med Genet 2011; 48: 682-90.
Wang M, Liu H, Zheng J, et al. A deafness- and diabetes-associated tRNA mutation causes deficient pseudouridinylation at position 55 in tRNAGlu and mitochondrial dysfunction. J Biol Chem 2016; 291: 21029-41.
Ding Y, Xia BH, Liu Q, et al. Allele-specific PCR for detecting the deafness-associated mitochondrial 12S rRNA mutations. Gene 2016; 591: 148-52.
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. Mol Genet Metab 2010; 100: 57-64.
Moassass F, Al-Halabi B, Nweder MS, et al. Investigation of the mtDNA mutations in Syrian families with non-syndromic sensorineural hearing loss. Int J Pediatr Otorhinolaryngol 2018; 113: 110-4.
Andrews RM, Kubacka I, Chinnery PF, et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 1999; 23: 147.
Zhang J, Lu B, Xia WW, et al. The mitochondrial transfer RNAAsp A7551G mutation may contribute to the clinical expression of deafness associated with the A1555G mutation in a pedigree with hearing impairment. Mol Med Rep 2019; 19: 1797-802.
Ming L, Wang Y, Lu W, et al. A mutational analysis of GJB2, SLC26A4, MT-RNA1, and GJB3 in children with nonsyndromic hearing loss in the Henan province of China. Genet Test Mol Biomarkers 2019; 23: 51-6.
Adhikary B, Ghosh S, Paul S, et al. Spectrum and frequency of GJB2, GJB6 and SLC26A4 gene mutations among nonsyndromic hearing loss patients in eastern part of India. Gene 2015; 573: 239-45.
Levin L, Zhidkov I, Gurman Y, et al. Functional recurrent mutations in the human mitochondrial phylogeny: Dual roles in evolution and disease. Genome Biol Evol 2013; 5: 876-90.
Ding Y, Xia BH, Zhang CJ, et al. Mitochondrial tRNALeu(UUR) C3275T, tRNAGln T4363C and tRNALys A8343G mutations may be associated with PCOS and metabolic syndrome. Gene 2018; 642: 299-306.
Ding Y, Xia BH, Zhang CJ, et al. Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome. Am J Transl Res 2017; 9: 2984-96.
Yarham JW, Al-Dosary M, Blakely EL, et al. A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations. Hum Mutat 2011; 32: 1319-25.
Kong QP, Bandelt HJ, Sun C, et al. Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations. Hum Mol Genet 2006; 15: 2076-86.
Bibb MJ, Van Etten RA, Wright CT, et al. Sequence and gene organization of mouse mitochondrial DNA. Cell 1981; 26: 167-80.
Gadaleta G, Pepe G, De Candia G, et al. 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.
Roe BA, Ma DP, Wilson RK, et al. The complete nucleotide sequence of the Xenopus laevis mitochondrial genome. J Biol Chem 1985; 260: 9759-74.
Suzuki T, Nagao A, Suzuki T. Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu Rev Genet 2011; 45: 299-329.
Pütz J, Dupuis B, Sissler M, et al. Mamit-tRNA, a database of mammalian mitochondrial tRNA primary and secondary structures. RNA 2007; 13: 1184-90.
Wang X, Lu J, Zhu Y, et al. Mitochondrial tRNAThr G15927A mutation may modulate the phenotypic manifestation of ototoxic 12S rRNA A1555G mutation in four Chinese families. Pharmacogenet Genomics 2008; 18: 1059-70.
Rybalka E, Timpani CA, Cooke MB, et al. Defects in mitochondrial ATP synthesis in dystrophin-deficient mdx skeletal muscles may be caused by complex I insufficiency. PLoS One 2014; 9: e115763.
Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev 2014; 94: 909-50.
Mimaki M, Ikota A, Sato A, et al. A double mutation (G11778A and G12192A) in mitochondrial DNA associated with Leber’s hereditary optic neuropathy and cardiomyopathy. J Hum Genet 2003; 48: 47-50.
Ueda T, Yotsumoto Y, Ikeda K, et al. The T-loop region of animal mitochondrial tRNA(Ser)(AGY) is a main recognition site for homologous seryl-tRNA synthetase. Nucleic Acids Res 1992; 20: 2217-22.
Meng F, He Z, Tang X, et al. Contribution of the tRNAIle 4317A→G mutation to the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA 1555A→G mutation. J Biol Chem 2018; 293: 3321-34.
Valente L, Piga D, Lamantea E, et al. Identification of novel mutations in five patients with mitochondrial encephalo-myopathy. Biochim Biophys Acta 2009; 1787: 491-501.
Zhang J, Ji Y, Liu X, et al. Leber’s hereditary optic neuro-pathy caused by a mutation in mitochondrial tRNAThr in eight Chinese pedigrees. Mitochondrion 2018; 42: 84-91.
Jia Z, Wang X, Qin Y, et al. Coronary heart disease is associated with a mutation in mitochondrial tRNA. Hum Mol Genet 2013; 22: 4064-73.
Yano T, Nishio SY, Usami S. Deafness Gene Study Consortium Frequency of mitochondrial mutations in non-syndromic hearing loss as well as possibly responsible variants found by whole mitochondrial genome screening. J Hum Genet 2014; 59: 100-6.
Dai P, Yu F, Han B, et al. GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. J Transl Med 2009; 7: 26.
Li TC, Kuan YH, Ko TY, et al. Mechanism of a novel missense mutation, p.V174M, of the human connexin31 (GJB3) in causing nonsyndromic hearing loss. Biochem Cell Biol 2014; 92: 251-7.
Oh SK, Choi SY, Yu SH, et al. Evaluation of the pathogenicity of GJB3 and GJB6 variants associated with nonsyndromic hearing loss. Biochim Biophys Acta 2013; 1832: 285-91.
Meng F, Cang X, Peng Y, et al. Biochemical evidence for a nuclear modifier allele (A10S) in TRMU (Methylaminomethyl-2-thiouridylate-methyltransferase) related to mitochondrial tRNA modification in the phenotypic manifestation of deafness-associated 12S rRNA mutation. J Biol Chem 2017; 292: 2881-92.
Ying Z, Zheng J, Cai Z, et al. Mitochondrial haplogroup B increases the risk for hearing loss among the Eastern Asian pedigrees carrying 12S rRNA 1555A>G mutation. Protein Cell 2015; 6: 844-8.
Bai Y, Wang Z, Dai W, et al. A six-generation Chinese family in haplogroup B4C1C exhibits high penetrance of 1555A>G-induced hearing Loss. BMC Med Genet 2010; 11: 129.
Chen X, Nie Z, Wang F, et al. Late onset nonsyndromic hearing loss in a Dongxiang Chinese family is associated with the 593T>C variant in the mitochondrial tRNAPhe gene. Mitochondrion 2017; 35: 111-8.
Wu Y, Liang LZ, Xiao HL, et al. Hearing loss may be associated with the novel mitochondrial tRNA(Asp) A7551G mutation in a Chinese family. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2013; 48: 978-84. [Article in Chinese].
Kokotas H, Grigoriadou M, Yang L, et al. Homoplasmy of the G7444A mtDNA and heterozygosity of the GJB2 c.35delG mutations in a family with hearing loss. Int J Pediatr Otorhinolaryngol 2011; 75: 89-94.
Kamogashira T, Fujimoto C, Yamasoba T. Reactive oxygen species, apoptosis, and mitochondrial dysfunction in hearing loss. BioMed Res Int 2015; 2015: 617207.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy