Low penetrance of hearing loss in two Chinese families carrying the mitochondrial tRNASer(UCN) mutations

Peng,Wei; Zhong,Yi; Zhao,Xueyan; Yuan,Jie

doi:10.3892/mmr.2020.11100

Low penetrance of hearing loss in two Chinese families carrying the mitochondrial tRNASer(UCN) mutations

Authors:
- Wei Peng
- Yi Zhong
- Xueyan Zhao
- Jie Yuan
View Affiliations

Affiliations: Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: April 30, 2020 https://doi.org/10.3892/mmr.2020.11100
Pages: 77-86
Copyright: © Peng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mutations in mitochondrial DNA (mtDNA), especially in mitochondrial 12S rRNA and transfer RNA(tRNA)Ser(UCN) genes, are important causes of non‑syndromic hearing loss. However, the molecular mechanism underlying mt‑tRNA mutations in clinical hearing impairment are not fully understood. The present study assessed the molecular characterization of two Chinese families with non‑syndromic hearing loss, who both exhibited very low penetrance of deafness (9.1 and 12.5% for Family 1 and 2, respectively). Mutational analysis of the complete mtDNA genes identified the presence of cytochrome c oxidase 1/tRNASer(UCN) G7444A and tRNASer(UCN) C7492T mutations, together with polymorphisms belonging to human mitochondrial haplogroup D4 and G2b, respectively. Moreover, the G7444A and C7492T mutations occurred at highly conserved tRNASer(UCN) nucleotides and may cause tRNA metabolism failure, which is involved in mitochondrial translation defects. Therefore, the G7444A and C7492T mutations may lead to the mitochondrial dysfunction that responsible for deafness. However, the absence of any functional variants in Gap junction β‑2, Solute Carrier Family 26 Member 4 and TRNA 5‑methylaminomethyl‑2‑thiouridylate methyltransferase suggested that nuclear genes may not play active roles in the occurrence of deafness. In the present study, the observed incomplete penetrance of hearing loss and mild mitochondrial dysfunction indicated that mtDNA G7444A and C7492T mutations are insufficient to produce the deafness phenotype. Therefore, other risk factors such as environmental factors and epigenetic regulation may be involved in the pathogenesis of hearing loss in the families recruited in the present study.

View Figures

View References

1	Kral A and O'Donoghue GM: Profound deafness in childhood. N Engl J Med. 363:1438–1450. 2010. View Article : Google Scholar : PubMed/NCBI
2	Humes LE: Examining the validity of the world health organization's long-standing hearing impairment grading system for unaided communication in age-related hearing loss. Am J Audiol. 28:810–818. 2019. View Article : Google Scholar : PubMed/NCBI
3	Kenna MA: Acquired hearing loss in children. Otolaryngol Clin North Am. 48:933–953. 2015. View Article : Google Scholar : PubMed/NCBI
4	Morton CC: Genetics, genomics and gene discovery in the auditory system. Hum Mol Genet. 11:1229–1240. 2002. View Article : Google Scholar : PubMed/NCBI
5	Fischel-Ghodsian N: Genetic factors in aminoglycoside toxicity. Pharmacogenomics. 6:27–36. 2005. View Article : Google Scholar : PubMed/NCBI
6	Ou YH, Chen AW, Fan JY, Cheng WL, Lin TT, Chen MK and Liu CS: Aminoglycoside-associated nonsyndromic deafness and speech disorder in mitochondrial A1555G mutation in a family: A case report. Medicine (Baltimore). 97:e128782018. View Article : Google Scholar : PubMed/NCBI
7	Zhao H, Li R, Wang Q, Yan Q, Deng JH, Han D, Bai Y, Young WY and Guan MX: Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am J Hum Genet. 74:139–152. 2004. View Article : Google Scholar : PubMed/NCBI
8	Wu L, Li R, Chen J, Chen Y, Yang M and Wu Q: Analysis of mitochondrial A1555G mutation in infants with hearing impairment. Exp Ther Med. 15:5307–5313. 2018.PubMed/NCBI
9	Tang X, Zheng J, Ying Z, Cai Z, Gao Y, He Z, Yu H, Yao J, Yang Y, Wang H, et al: Mitochondrial tRNA(Ser(UCN)) variants in 2651 Han Chinese subjects with hearing loss. Mitochondrion. 23:17–24. 2015. View Article : Google Scholar : PubMed/NCBI
10	Reid FM, Vernham GA and Jacobs HT: A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mutat. 3:243–247. 1994. View Article : Google Scholar : PubMed/NCBI
11	Jacobs HT, Hutchin TP, Kappi T, Gillies G, Minkkinen K, Walker J, Thompson K, Rovio AT, Carella M, Melchionda S, et al: Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment. Eur J Hum Genet. 13:26–33. 2005. View Article : Google Scholar : PubMed/NCBI
12	Hutchin TP, Parker MJ, Young ID, Davis AC, Pulleyn LJ, Deeble J, Lench NJ, Markham AF and Mueller RF: A novel mutation in the mitochondrial tRNA(Ser(UCN)) gene in a family with non-syndromic sensorineural hearing impairment. J Med Genet. 37:692–694. 2000. View Article : Google Scholar : PubMed/NCBI
13	Sue CM, Tanji K, Hadjigeorgiou G, Andreu AL, Nishino I, Krishna S, Bruno C, Hirano M, Shanske S, Bonilla E, et al: Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser(UCN)) gene. Neurology. 52:1905–1908. 1999. View Article : Google Scholar : PubMed/NCBI
14	Suzuki T, Nagao A and Suzuki T: Human mitochondrial diseases caused by lack of taurine modification in mitochondrial tRNAs. Wiley Interdiscip Rev RNA. 2:376–386. 2011. View Article : Google Scholar : PubMed/NCBI
15	Dai P, Yu F, Han B, Liu X, Wang G, Li Q, Yuan Y, Liu X, Huang D, Kang D, et al: GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. J Transl Med. 7:262009. View Article : Google Scholar : PubMed/NCBI
16	Guan MX, Yan Q, Li X, Bykhovskaya Y, Gallo-Teran J, Hajek P, Umeda N, Zhao H, Garrido G, Mengesha E, et al: Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet. 79:291–302. 2006. View Article : Google Scholar : PubMed/NCBI
17	Wang QJ, Zhao YL, Rao SQ, Guo YF, Yuan H, Zong L, Guan J, Xu BC, Wang DY, Han MK, et al: A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China. Clin Genet. 72:245–254. 2007. View Article : Google Scholar : PubMed/NCBI
18	Oosterloo BC, Homans NC, Baatenburg de Jong RJ, Ikram MA, Nagtegaal AP and Goedegebure A: Assessing hearing loss in older adults with a single question and person characteristics; Comparison with pure tone audiometry in the rotterdam study. PLoS One. 15:e02283492020. View Article : Google Scholar : PubMed/NCBI
19	Ding Y, Teng YS, Zhuo GC, Xia BH and Leng JH: The mitochondrial tRNAHis G12192A mutation may modulate the clinical expression of deafness-associated tRNAThr G15927A mutation in a Chinese pedigree. Curr Mol Med. 19:136–146. 2019. View Article : Google Scholar : PubMed/NCBI
20	Zhang J, Lu B, Xia WW, Fang B, Ding XX and Hu GW: 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. 19:1797–1802. 2019.PubMed/NCBI
21	Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM and Howell N: Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet. 23:1471999. View Article : Google Scholar : PubMed/NCBI
22	Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, et al: Clustal W and Clustal X version 2.0. Bioinformatics. 23:2947–2948. 2007. View Article : Google Scholar : PubMed/NCBI
23	Ding Y, Xia BH, Liu Q, Li MY, Huang SX and Zhuo GC: Allele-specific PCR for detecting the deafness-associated mitochondrial 12S rRNA mutations. Gene. 591:148–152. 2016. View Article : Google Scholar : PubMed/NCBI
24	Zarrouk-Mahjoub S, Mehri S, Ouarda F, Finsterer J and Boussaada R: Mitochondrial tRNA glutamine variant in hypertrophic cardiomyopathy. Herz. 40:436–441. 2015. View Article : Google Scholar : PubMed/NCBI
25	Yarham JW, Al-Dosary M, Blakely EL, Alston CL, Taylor RW, Elson JL and McFarland R: A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations. Hum Mutat. 32:1319–1325. 2011. View Article : Google Scholar : PubMed/NCBI
26	Brandon MC, Lott MT, Nguyen KC, Spolim S, Navathe SB, Baldi P and Wallace DC: MITOMAP: A human mitochondrial genome database-2004 update. Nucleic Acids Res. 33:D611–D613. 2005. View Article : Google Scholar : PubMed/NCBI
27	Gadaleta G, Pepe G, De Candia G, Quagliariello C, Sbisà E and Saccone C: The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome: Cryptic signals revealed by comparative analysis between vertebrates. J Mol Evol. 28:497–516. 1989. View Article : Google Scholar : PubMed/NCBI
28	Bibb MJ, Van Etten RA, Wright CT, Walberg MW and Clayton DA: Sequence and gene organization of mouse mitochondrial DNA. Cell. 26:167–180. 1981. View Article : Google Scholar : PubMed/NCBI
29	Roe BA, Ma DP, Wilson RK and Wong JF: The complete nucleotide sequence of the Xenopus laevis mitochondrial genome. J Biol Chem. 260:9759–9774. 1985.PubMed/NCBI
30	Ding Y, Leng J, Fan F, Xia B and Xu P: The role of mitochondrial DNA mutations in hearing loss. Biochem Genet. 51:588–602. 2013. View Article : Google Scholar : PubMed/NCBI
31	Rydzanicz M, Wróbel M, Cywińska K, Froehlich D, Gawecki W, Szyfter W and Szyfter K: Screening of the general Polish population for deafness-associated mutations in mitochondrial 12S rRNA and tRNA Ser(UCN) genes. Genet Test Mol Biomarkers. 13:167–172. 2009. View Article : Google Scholar : PubMed/NCBI
32	Jin L, Yang A, Zhu Y, Zhao J, Wang X, Yang L, Sun D, Tao Z, Tsushima A, Wu G, et al: Mitochondrial tRNASer(UCN) gene is the hot spot for mutations associated with aminoglycoside-induced and non-syndromic hearing loss. Biochem Biophys Res Commun. 361:133–139. 2007. View Article : Google Scholar : PubMed/NCBI
33	Boczonadi V, Ricci G and Horvath R: Mitochondrial DNA transcription and translation: Clinical syndromes. Essays Biochem. 62:321–340. 2018. View Article : Google Scholar : PubMed/NCBI
34	Liu Q, Liu P, Ding Y, Dong XJ, Wang ZX, Qian YE, Wang Q and Yang GC: Mitochondrial COI/tRNASer(UCN) G7444A mutation may be associated with aminoglycoside-induced and non-syndromic hearing impairment. Mol Med Rep. 12:8176–8178. 2015. View Article : Google Scholar : PubMed/NCBI
35	Guan MX, Enriquez JA, Fischel-Ghodsian N, Puranam RS, Lin CP, Maw MA and Attardi G: The deafness-associated mitochondrial DNA mutation at position 7445, which affects tRNASer(UCN) precursor processing, has long-range effects on NADH dehydrogenase subunit ND6 gene expression. Mol Cell Biol. 18:5868–5879. 1998. View Article : Google Scholar : PubMed/NCBI
36	Li X, Zhang LS, Fischel-Ghodsian N and Guan MX: Biochemical characterization of the deafness-associated mitochondrial tRNASer(UCN) A7445G mutation in osteosarcoma cell cybrids. Biochem Biophys Res Commun. 328:491–498. 2005. View Article : Google Scholar : PubMed/NCBI
37	Yuan H, Chen J, Liu X, Cheng J, Wang X, Yang L, Yang S, Cao J, Kang D, Dai P, et al: 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. Biochem Biophys Res Commun. 362:94–100. 2007. View Article : Google Scholar : PubMed/NCBI
38	Kokotas H, Grigoriadou M, Yang L, Lodahl M, Rendtorff ND, Gyftodimou Y, Korres GS, Ferekidou E, Kandiloros D, Korres S, 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. 75:89–94. 2011. View Article : Google Scholar : PubMed/NCBI
39	Pütz J, Dupuis B, Sissler M and Florentz C: Mamit-tRNA, a database of mammalian mitochondrial tRNA primary and secondary structures. RNA. 13:1184–1190. 2007. View Article : Google Scholar : PubMed/NCBI
40	Silvestri G, Servidei S, Rana M, Ricci E, Spinazzola A, Paris E and Tonali P: A novel mitochondrial DNA point mutation in the tRNA (Ile) gene is associated with progressive external ophtalmoplegia. Biochem Biophys Res Commun. 220:623–627. 1996. View Article : Google Scholar : PubMed/NCBI
41	Ding Y, Xia BH, Zhang CJ and Zhuo GC: Mutations in mitochondrial tRNA genes may be related to insulin resistance in women with polycystic ovary syndrome. Am J Transl Res. 9:2984–2996. 2017.PubMed/NCBI
42	Liu Y, Li Y, Wang X, Ma Q, Zhu C, Li Z, Yin T, Yang J, Chen Y and Guan M: Mitochondrial tRNA mutations in Chinese hypertensive individuals. Mitochondrion. 28:1–7. 2016. View Article : Google Scholar : PubMed/NCBI
43	Ouyang XM, Yan D, Yuan HJ, Pu D, Du LL, Han DY and Liu XZ: The genetic bases for non-syndromic hearing loss among Chinese. J Hum Genet. 54:131–140. 2009. View Article : Google Scholar : PubMed/NCBI
44	Cohn ES and Kelley PM: Clinical phenotype and mutations in connexin 26 (DFNB1/GJB2), the most common cause of childhood hearing loss. Am J Med Genet. 89:130–136. 1999. View Article : Google Scholar : PubMed/NCBI
45	Mishra S, Pandey H, Srivastava P, Mandal K and Phadke SR: Connexin 26 (GJB2) mutations associated with non-syndromic hearing loss (NSHL). Indian J Pediatr. 85:1061–1066. 2018. View Article : Google Scholar : PubMed/NCBI
46	Zheng J, Ying Z, Cai Z, Sun D, He Z, Gao Y, Zhang T, Zhu Y, Chen Y and Guan MX: GJB2 mutation spectrum and genotype-phenotype correlation in 1067 han Chinese subjects with non-syndromic hearing loss. PLoS One. 10:e01286912015. View Article : Google Scholar : PubMed/NCBI
47	Wu CC, Tsai CY, Lin YH, Chen PY, Lin PH, Cheng YF, Wu CM, Lin YH, Lee CY, Erdenechuluun J, et al: Genetic epidemiology and clinical features of hereditary hearing impairment in the Taiwanese population. Genes (Basel). 10:E7722019. View Article : Google Scholar : PubMed/NCBI
48	Adhikary B, Ghosh S, Paul S, Bankura B, Pattanayak AK, Biswas S, Maity B and Das M: Spectrum and frequency of GJB2, GJB6 and SLC26A4 gene mutations among nonsyndromic hearing loss patients in eastern part of India. Gene. 573:239–245. 2015. View Article : Google Scholar : PubMed/NCBI
49	Kato T, Fuku N, Noguchi Y, Murakami H, Miyachi M, Kimura Y, Tanaka M and Kitamura K: Mitochondrial DNA haplogroup associated with hereditary hearing loss in a Japanese population. Acta Otolaryngol. 132:1178–1182. 2012. View Article : Google Scholar : PubMed/NCBI
50	Ying Z, Zheng J, Cai Z, Liu L, Dai Y, Yao J, Wang H, Gao Y, Zheng B, Tang X, et al: Mitochondrial haplogroup B increases the risk for hearing loss among the Eastern Asian pedigrees carrying 12S rRNA 1555A>G mutation. Protein Cell. 6:844–848. 2015. View Article : Google Scholar : PubMed/NCBI
51	Lu J, Qian Y, Li Z, Yang A, Zhu Y, Li R, Yang L, Tang X, Chen B, Ding Y, et al: Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 12S rRNA 1555A>G mutation. Mitochondrion. 10:69–81. 2010. View Article : Google Scholar : PubMed/NCBI
52	Kong QP, Bandelt HJ, Sun C, Yao YG, Salas A, Achilli A, Wang CY, Zhong L, Zhu CL, Wu SF, et al: Updating the East Asian mtDNA phylogeny: A prerequisite for the identification of pathogenic mutations. Hum Mol Genet. 15:2076–2086. 2006. View Article : Google Scholar : PubMed/NCBI
53	Bandelt HJ, Salas A, Taylor RW and Yao YG: Exaggerated status of ‘novel’ and ‘pathogenic’ mtDNA sequence variants due to inadequate database searches. Hum Mutat. 30:191–196. 2009. View Article : Google Scholar : PubMed/NCBI