Low penetrance of hearing loss in two Chinese families carrying the mitochondrial tRNASer(UCN) mutations
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- Published online on: April 30, 2020 https://doi.org/10.3892/mmr.2020.11100
- Pages: 77-86
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Copyright: © Peng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Hearing loss is a common communication disorder, affecting 1–3 newborns out of every 1,000 live births globally (1). Survey data from the World Health Organization (http://www.who.int) indicates that 32 million individuals out of 360 million with hearing loss are pediatric patients (2,3). Hearing loss can be caused by gene alterations and environmental factors, including ototoxic drugs such as aminoglycoside antibiotics (AmAn) (4). Genetic alterations in human mitochondrial DNA (mtDNA) are also associated with deafness (5). Moreover, A1555G and C1494T mtDNA mutations have been implicated in both AmAn-induced and non-syndromic hearing loss in patients worldwide (6–8). mt-transfer RNA(tRNA)Ser(UCN) gene pathogenic mutations are associated with hearing loss (9) and include A7445G (10), 7472insC (11), T7510C (12) and T7511C (13). Furthermore, mt-tRNA mutations may have structural and functional implications, such as affecting the processing of RNA precursors, nucleotide modification and aminoacylation (14). However, the molecular mechanism underlying mt-tRNASer(UCN) mutations and deafness are not fully understood.
To investigate the association between mt-tRNASer(UCN) mutations and non-syndromic hearing loss, and to facilitate early diagnosis and prevention of mitochondrial-associated deafness, the present study performed genetic analyses for deafness-associated mtDNA mutations. The clinical and molecular features of two Chinese families with hearing impairment were assessed. PCR and Sanger sequencing analyses results suggested the presence of cytochrome c oxidase 1 (CO1)/tRNASer(UCN) G7444A and tRNASer(UCN) C7492T mutations in these families. Mutations in gap junction β-2 (GJB2), solute Carrier Family 26 Member 4 (SLC26A4) and TRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) genes are the most prevalent deafness causing genetic modifications worldwide (15–17). To examine the potential role of GJB2, SLC26A4 and TRMU in deafness, mutational analyses of these genes were performed in the matrilineal relatives in the two Chinese families.
Materials and methods
Subjects and clinical examinations
In the present genetic screening program for deafness-associated mt-tRNASer(UCN) mutations, two Chinese families with hearing loss were recruited from The Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2018 and January 2019 (Fig. 1). There were 11 matrilineal relatives in Family 1 (5 males and 6 females), one of them (III-12) was the deaf patient. There were 8 matrilineal relatives in Family 2 (3 males and 5 females), one of them (II-9) was the deaf patient. Comprehensive medical histories and physical examination were assessed to identify any syndromic findings, history of AmAn use and genetic factors related to hearing impairment. An age-appropriate audiological examination was performed by an experienced audiologist, including pure-tone audiometry (PTA) and/or auditory brainstem response (ABR), immittance testing and distortion product otoacoustic emissions. PTA was calculated from the average of the audiometric thresholds at 500, 1,000, 2,000, 4,000 and 8,000 Hz. The severity of hearing impairment was classified into five grades: i) Normal, <26 decibel (dB); ii) mild =26–40 dB; iii) moderate =41–70 dB; iv) severe =71–90 dB; and v) profound >90 dB (18). The study was approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Signed written informed consent was obtained from the participants or their guardians. Control subjects (n=455; men, 200; women, 255; age, 20–45 years) were enrolled in the present study. The healthy subjects had normal hearing and did not have any mitochondrial disorders such as vision loss, neurological disorders, cancer or cardiovascular diseases. Subjects who had a family history of mitochondrial diseases or ongoing infectious disease, neoplastic disease, major surgery, severe liver dysfunction and inflammatory disease were excluded. Written informed consent was also provided by the control subjects.
Genetic screening for mtDNA mutations or variants
PCR and direct sequence analysis were performed to detect deafness related mtDNA mutations or variants. Blood samples (5 ml) from the family members (II-10, II-8 and II-5 in Family 1; I-2, II-6 and II-8 in Family 2; Fig. 1), as well as from 455 controls were collected. Genomic DNA was isolated from probands from the two families (III-12 and II-9) using the Puregene DNA Isolation kits (Gentra Systems, Inc.). DNA was preserved at 20°C. Amplification of complete mtDNA genes was performed as previously described (19). A PCR mixture containing 200 µM dNTPs, 10X buffer, Taq DNA polymerase and 15 mmol/l Mg2+ (Takara Biotechnology Co., Ltd.) was used for PCR, the primers' sequences are listed in Table I. The following PCR thermocycling conditions were used: Initial denaturation at 95°C for 5 min; 30 cycles of 94°C for 10 sec, 60°C for 30 sec and 72°C for 1 min; and a final extension at 72°C for 5 min. Subsequently, the 24 PCR products were purified and analyzed using Sanger sequence technology as previously described (20). The complete mtDNA genes of the matrilineal relatives from the two families (II-10, II-8 and II-5 in Family 1; I-2, II-6 and II-8 in Family 2) were also amplified by PCR and sequenced as above. Data were then compared with the revised Cambridge Reference sequences (rCRS) from GenBank database to detect mtDNA mutations (GenBank accession no. NC_001807) (21).
Conservation assessments
The sequence alignment was performed by using the ClustalW program version 2.0 (http;//www.ebi.ac.uk/Tools/msa/clustalw2/) (22). The conservation index (CI) of each mtDNA variants or mutations identified in these two families were analyzed as previously described (23). The CI was determined as the percentage of the sequence, from a list of 16 different vertebrates that possessed the wild-type nucleotide at the same position (24), these species included Bos Taurus, Cebus albifrons, Gorilla gorilla, Homo sapiens, Hylobates lar, Lemur catta, Macaca mulatta, Macaca sylvanus, Mus musculus, Nycticebus coucang, Pan paniscus, Pan troglodytes, Pongo pygmaeus, Pongo abelii, Papio hamadryas and Tarsius bancanus.
Screening for the GJB2, SLC26A4 and TRMU mutations
Mutations in GJB2, SLC26A4 and TRMU are associated with hearing impairment (15–17). To assess whether these nuclear genes play important roles in the clinical manifestation of hearing loss, a mutational screening for GJB2, SLC26A4 and TRMU was performed in the probands from these families (III-12 and II-9; Fig. 1). The primers used were as described previously (17,19,20). The primers for PCR amplification of GJB2 were: Forward, 5′-TATGACACTCCCCAGCACAG-3′ and reverse, 5′-GGGGCAATGCTTAAACTGGC-3′. The five primer sequences for SLC26A4 were: Forward, 5′-CGTGTAGCAGCAGGAAGTAT-3′ and reverse, 5′-TTAAATAAAAAAGACTGACT-3′; forward, 5′-TGGGGAAAAAGGATGGTGGT-3′ and reverse, 5′-CCAACCCCTTCTTTAGCTGA-3′; forward, 5′-GCAGGATAGCTCAAGGAATT-3′ and reverse, 5′-TCATCAGGGAAAGGAAATAA-3′; forward, 5′-TCTCCTTGATGTCTTGCTTA-3′ and reverse, 5′-CCCATGTATTTGCCCTGTTG-3′; and forward, 5′-CTGGGCAATAGAATGAGACT-3′ and reverse, 5′-ATCTGTAGAAAGGTTGAATA-3′. The primers for TRMU amplification were: Forward, 5′-ACAGCGCAGAAGAAGAGCAGT-3′ and reverse, 5′-ACAACGCCACGACGGACG-3′. The PCR products were analyzed by direct Sanger sequencing as mentioned in a previous study (19). The data were compared with published National Center for Biotechnology Information database sequences (https://www.ncbi.nlm.nih.gov/pubmed; GJB2, NM_004004; SLC26A4, NM_000441.1; TRMU, AF448221).
Assessment of pathogenicity
The updated pathogenicity scoring system (25) was used to assess the pathogenic status of CO1/tRNASer(UCN) G7444A and tRNASer(UCN) C7492T mutations. Using this approach, a mutation was classified as a ‘neutral polymorphism’ with a score ≤6, as ‘possibly pathogenic’ with a score from 7–10 and ‘definitely pathogenic’ with a score ≥11. The status of G7444A and C7492T mutations were also searched on the MITOMAP database (www.mitomap.org) to confirm their pathogenicity (26).
Results
Clinical presentation of two families with hearing loss
The present study investigated deafness related mt-tRNASer(UCN) polymorphisms in two Chinese families with hearing impairment (Fig. 1). In Family 1, the proband (III-12) was a 15-year-old female patient who began to suffer bilateral hearing impairment at the age of 10 years old. No family members in Family 1 had a history of using AmAn. Audiological evaluation indicated that the 15-year-old female had profound hearing loss (118 and 110 dB for right and left ears, respectively; Fig. 2; Table II). Furthermore, clinical examination identified that no other matrilineal relatives in Family 1, including the mother of the patient (II-10), had hearing loss.
In Family 2, the proband (II-9) was a 38-year-old female who was treated at the Otology Clinic of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology for deafness. A comprehensive history and physical examination indicated that the proband (II-9) suffered bilateral hearing impairment at the age of 20 years old. Furthermore, the proband had profound hearing loss (103 and 99 dB for right and left ears, respectively; Table II). However, all matrilineal relatives in Family 2 had normal hearing and none had a history of AmAn use (Fig. 1).
Mitochondrial genome analysis
To investigate the molecular basis of hearing loss, mutational screening of mtDNA genes was performed in these families. First, the present study amplified the complete mitochondrial genomes of the probands in the families (III-12 and II-9) and the corresponding matrilineal relatives (II-10, II-8 and II-5 in Family 1; I-2, II-6 and II-8 in Family 2; Fig. 1). The resultant 24 PCR products were sequenced as previously described (20). By comparing the present results with previous data from the rCRS (21), a number of genetic variants were identified, in addition to the CO1/tRNASer(UCN) G7444A and tRNASer(UCN) C7492T mutations (Fig. 3; Table III). Moreover, ten variants were identified in the D-loop region, four known variants in 12S rRNA, four known variants in 16S rRNA and one 9-bp deletion in the non-coding region located between the CO2 and tRNALys genes (21). In addition, 26 variants were found in protein coding genes. These included five missense mutations: A8701G (Thr→Ala), A8860G (Thr→Ala) in ATP synthase membrane subunit 6, A10398G (Thr→Ala) in NADH-ubiquinone oxidoreductase chain 3 (ND3), C14766T (Thr→Ile) and A15326G (Thr→Ala) in Cytochrome B. Only the CO1/tRNASer(UCN) G7444A and tRNASer(UCN) C7492T mutations are highly conserved in various species, including humans (21), bovines (27), mice (28) and Xenopus laevis (29). The present phylogenetic analysis results indicated that none of the other identified variants were conserved, suggesting that the G7444A and C7492T mutations may have functional significance in deafness phenotype expression (Figs. 3 and 4). In addition, G7444A and C7492T mutations were not detected in 455 control subjects. Moreover, these mt-tRNASer(UCN) mutations were not found in the matrilineal relatives (II-10, II-8 and II-5 in Family 1; I-2, II-6 and II-8 in Family 2).
In fact, the C7492T mutation occurred at position 26 in the anticodon stem of tRNASer(UCN), nucleotide at that position was very conserved from different species (21), while the G7444A mutation was localized at the conjunction between CO1 and tRNASer(UCN) (21).
Genotyping analysis of GJB2, SLC26A4 and TRMU genes
Previous studies showed that GJB2 (15), SCL26A4 (17) and TRMU (16) gene mutations are important causes of hereditary hearing loss. To investigate whether these nuclear genes played active roles in the phenotypic expression of deafness, mutational screening was performed. The present results suggested that no functional variants were identified in these nuclear genes.
G7444A and C7492T are ‘possibly pathogenic’ mutations associated with deafness
A pathogenicity scoring system (25) was used to evaluate the status of CO1/tRNASer(UCN) G7444A and tRNASer(UCN) C7492T mutations (Table IV). It was found that the total scores of G7444A and C7492T mutations were each nine points, and that these variants were ‘possibly pathogenic’ changes associated with hearing impairment.
Discussion
The present study investigated the molecular and genetic features of two Chinese family with deafness related mt-tRNASer(UCN) gene mutations. The mt-tRNASer(UCN) gene has been implicated as a key site for mutations and variants associated with hearing impairment (30–32). In a previous genetic screening program for mt-tRNASer(UCN) variants in 2,651 patients with deafness, the incidence rate of T7511C, T7505C and A7445C mutations were all 0.04% (9). It has been suggested that the primary defect in mt-tRNASer(UCN) mutations is tRNA metabolism failure, which affects mitochondrial translation and respiratory chain function (33).
Using PCR and direct sequencing analysis, the present results identified two potential pathogenic mutations in the two families with hearing loss; G7444A and C7492T. The CO1/tRNASer(UCN) G7444A mutation is on the mtDNA heavy strand and causes a read-through of the AGA stop codon in the CO1 gene. The CO1/tRNASer(UCN) G7444A mutation adds three amino acids, Lys-Gln-Lys, to the C-terminus of the polypeptide (34). In addition, the G7444A mutation is adjacent to the 3′ terminal endonucleolytic processing site of the L-strand RNA precursor, spanning tRNASer(UCN) and ND6 mRNA (35). Moreover, the deafness-associated A7445G mutation causes a significant decrease in the steady-state level of tRNASer(UCN) and ND6 mRNA (35,36). Thus, the G7444A mutation, which is similar to the A7445G mutation, may also cause impaired tRNASer(UCN) metabolism, which plays an important role in deafness (37). Kokotas et al (38) investigated a Greek family with hearing loss and identified the co-existence of the G7444A mutation and the GJB2 c.35delG mutation.
Furthermore, in the present study, the homoplasmic C7492T mutation was identified in Family 2. Structurally, this mutation is located at position 26 of the tRNASer(UCN) gene anticodon stem (39). The nucleotide at this position is highly conserved between species, indicating that it plays a critical role in tRNA stability and normal function. Moreover, the heteroplasmic T4295C mutation, located at the same position in the tRNAIle gene, is a pathogenic mutation causing chronic progressive external ophthalmoplegia (40). In addition, the C7492T mutation disrupts conserved base-pairing (A26-U44) and may cause the tRNA metabolism failure. The C7492T mutation is also associated with polycystic ovary syndrome (PCOS) (41) and hypertension (42). Thus, the present study hypothesized that the C7492T mutation may lead to mitochondrial dysfunction and may be involved in the pathogenesis of hearing loss. However, sequence analysis results for the complete mtDNA genes from the matrilineal relatives (II-10, II-8 and II-5 in Family 1; I-2, II-6 and II-8 in Family 2) indicated that the G7444A and C7492T mutations were only presented in the probands (III-12 in Family 1; II-9 in Family 2), but were absent in matrilineal relatives. Therefore, the present results suggested that G7444A and C7492T may be de novo mutations.
In total >130 genes have been associated with hearing loss (43). GJB2 encodes a gap junction protein that is expressed in the cochlea and is thought to be important for recycling potassium ions that flow into sensory hair cells as part of the transduction current (44). Mutations in the GJB2 gene are a major cause of non-syndromic hearing loss (45). Among these mutations, c.235delC and c.167delT are the most frequent variants among Eastern Asian populations (46). Furthermore, SLC26A4 mutations contribute to non-syndromic enlarged vestibular aqueduct (MIM 600791) and Pendred syndrome (MIM 274600) (47). Moreover, c.919>2A>G is the most frequent SLC26A4 gene mutation associated with non-syndromic hearing loss (48). The TRMU gene, which encodes the mitochondrial tRNA-specific 2-thiouridylase, is regarded as a nuclear modified gene for the phenotypic manifestation of deafness-associated 12S rRNA mutations (16). In a previous study, the A10S mutation in TRMU exon 1 was found to modulate the clinical expression of deafness related A1555G mutation in an Arab-Israel family (16). However, in the present study, the absence of GJB2, SLC26A4 and TRMU variants in the two families suggested that these genes may not play a role in the clinical expression of hearing impairments.
Mitochondrial haplogroups may influence the phenotypic expression of hearing loss associated with mtDNA pathogenic mutations (49). Mitochondrial haplogroup B may increase the risk for hearing impairment among patients with the A1555G mutation (50). In addition, mitochondrial haplogroup specific variants including G15927A of haplogroup B5b, T12338C of haplogroup F2, T5802C, T10454C, C12224T and G11696A of haplogroup D4, G5821A of haplogroup C, A14693G of haplogroups Y2 and F, and T15908C of haplogroup Y2 may enhance the penetrance of hearing loss carrying the 12S rRNA A1555G mutation (51). Sequence characterization of mitochondrial genomes in the present study identified sets of genetic polymorphisms belonging to the D4 and G2b Eastern Asian haplogroups (52). However, phylogenetic conservation analysis showed that, except for the G7444A and C7492T mutations, the variants were not conserved. Collectively, the present results suggested that the mitochondrial genetic background may not play a significant role in the expression of deafness-associated pathogenic mtDNA mutations. Moreover, the pathogenicity scoring system indicated that the total scores of G7444A and C7492T mutations were both nine points, and belonged to the ‘possibly pathogenic’ classification associated with deafness; however, scoring needs to be examined using cybrid cells carrying the G7444A or C7492T mutation in future studies. Furthermore, data from the MITOMAP suggested that the C7492T mutation was likely benign. However, MITOMAP reports the published data on human mtDNA mutations or variants and does not analyze functions (53). The C7492T mutation had been reported to be associated with PCOS (41) and hypertension (42), thus C7492T is a disease-associated mutation. However, in the present study, the incomplete penetrance of hearing loss and mild mitochondrial dysfunction indicated that G7444A and C7492T mutations are insufficient to produce the observed clinical phenotypes. Therefore, environmental factors and epigenetic modification may contribute to the expression of the deafness phenotype.
There are several limitations in the present study. Functional analysis was not performed for the C7492T and G7444A mutations, and the small sample size is major limitation. Further studies, including more patients with deafness and using trans-mitochondrial cybrid cells are required to investigate the present results in more depth.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.
Authors' contributions
WP and YZ designed the studies, XZ collected the samples and performed the clinical analysis of two pedigrees, JY performed the molecular analysis of mitochondrial genomes. WP and YZ wrote the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Signed written informed consent was obtained from the participants or their guardians.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
Kral A and O'Donoghue GM: Profound deafness in childhood. N Engl J Med. 363:1438–1450. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
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 | |
|
Kenna MA: Acquired hearing loss in children. Otolaryngol Clin North Am. 48:933–953. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Morton CC: Genetics, genomics and gene discovery in the auditory system. Hum Mol Genet. 11:1229–1240. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Fischel-Ghodsian N: Genetic factors in aminoglycoside toxicity. Pharmacogenomics. 6:27–36. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 |
