A six-generation Chinese family in haplogroup B4C1C exhibits high penetrance of 1555A &gt; G-induced hearing Loss

Bai, Yan; Wang, Zhengmin; Dai, Wenjia; Chen, Guoling; Cong, Ning; Guan, Min‐Xin; Li, Huawei

doi:10.1186/1471-2350-11-129

Cited by 9 publications

(4 citation statements)

References 32 publications

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“…Compared with previous studies, if the AmAn was included, the penetrances of mitochondrial A1555G-induced hearing loss ranged from 13.0% to 71.4%, with an average of 45.75%. While the AmAn was excluded, the penetrances of A1555G-induced deafness ranged from 8.0% to 51.5%, with an average of 23.85% (Table 6) [34][35][36][37][38][39]. Whereas in other seven families with C1494T mutation, the penetrances of hearing loss ranged from 6.3% to 42.8% (with AmAn, average: 18.8%).…”

Section: Discussionmentioning

confidence: 99%

Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method

et al. 2020

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Mitochondrial 12S rRNA A1555G and C1494T mutations are the major contributors to hearing loss. As patients with these mutations are sensitive to aminoglycosides, mutational screening for 12S rRNA is therefore recommended before the use of aminoglycosides. Most recently, we developed a novel multiplex allele-specific PCR (MAS-PCR) that can be used for detecting A1555G and C1494T mutations. In the present study, we employed this MAS-PCR to screen the 12S rRNA mutations in 500 deaf patients and 300 controls from 5 community hospitals. After PCR and electrophoresis, two patients with A1555G and one patient with C1494T were identified, this was consistent with Sanger sequence results. We further traced the origin of three Chinese pedigrees. Clinical evaluation revealed variable phenotypes of hearing loss including severity, age at onset and audiometric configuration in these patients. Sequence analysis of the mitochondrial genomes from matrilineal relatives suggested the presence of three evolutionarily conserved mutations: tRNACys T5802C, tRNALys A8343G and tRNAThr G15930A, which may result the failure in tRNAs metabolism and lead to mitochondrial dysfunction that was responsible for deafness. However, the lack of any functional variants in GJB2, GJB3, GJB6 and TRMU suggested that nuclear genes may not play active roles in deafness expression. Hence, aminoglycosides and mitochondrial genetic background may contribute to the clinical expression of A1555G/C1494T-induced deafness. Our data indicated that the MAS-PCR was a fast, convenience method for screening the 12S rRNA mutations, which was useful for early detection and prevention of mitochondrial deafness.

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Section: Discussionmentioning

confidence: 99%

Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method

et al. 2020

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“…These mutations are not pathogenic. Of these mutations, m.195T>C, m.310T>CCTC, m.514delC and m.515delA have been observed in subjects of Chinese pedigrees who had the m.1555A>G mutation Bai et al, 2010).…”

Section: T>c (Mt-nd5) All These Mutations Observed Inmentioning

confidence: 99%

Complete Mitochondrial Genome Analysis and Clinical Documentation of a Five-Generational Indian Family with Mitochondrial 1555A>G Mutation and Postlingual Hearing Loss

Subathra

Selvakumari

Ramesh

et al. 2014

Annals of Human Genetics

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SummaryHearing loss is the most common sensory disorder and is genetically heterogeneous. Apart from nuclear gene mutations, a number of inherited mitochondrial mutations have also been implicated. The m.1555A>G mutation in the mitochondrial MT-RNR1 gene is reported as the most common mutation causing nonsyndromic hearing loss in various ethnic populations. We report here for the first time the clinical, genetic and molecular characterisation of a single large five-generational Tamil-speaking South Indian family with maternally inherited nonsyndromic postlingual hearing loss. Molecular analysis led to identification of m.1555A>G in 28 maternal relatives with variable degree of phenotypic expression. The penetrance of hearing loss among the maternal relatives in this family was 55%. Sequence analysis of the complete mitochondrial genome in 36 members of this pedigree identified 25 known variants and one novel variant co-transmitted along with m.1555A>G mutation. The mtDNA haplotype analysis revealed that the maternal relatives carry the R * T 2 haplotype similar to Europeans and South Asians. Sequencing of the coding exon of GJB2 nuclear gene did not show any pathogenic mutations. The results suggest that other nuclear or environmental modifying factors could have played a role in the differential expression of mutation m.1555A>G in postlingual hearing loss in this family.

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“…Without the usage of AmAn, subjects with the m.1555A>G mutation exhibited a wide range of clinical phenotypes that ranged from mild to severe hearing loss, and even normal hearing, indicating that while the m.1555A>G mutation is a major risk factor for hearing loss, by itself it is not sufficient to produce the phenotype [ 49 ], for which it requires other factors such as nuclear genes, AmAn or mtDNA secondary variants [ 50 , 51 ]. In particular, mtDNA haplogroup B4C1C exhibited a higher penetrance and expressivity of m.1555A>G-induced deafness [ 52 ]. Recent experimental studies indicate that mitochondrial haplogroup B enhances the risk for hearing impairment in Chinese patients carrying the m.1555A>G mutation [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial tRNAGln 4394C>T Mutation May Contribute to the Clinical Expression of 1555A>G-Induced Deafness

Ding

Teng

Guo

et al. 2022

Genes

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The mitochondrial 1555A>G mutation plays a critical role in aminoglycoside-induced and non-syndromic hearing loss (AINSHL). Previous studies have suggested that mitochondrial secondary variants may modulate the clinical expression of m.1555A>G-induced deafness, but the molecular mechanism has remained largely undetermined. In this study, we investigated the contribution of a deafness-associated tRNAGln 4394C>T mutation to the clinical expression of the m.1555A>G mutation. Interestingly, a three-generation family with both the m.1555A>G and m.4394C>T mutations exhibited a higher penetrance of hearing loss than another family harboring only the m.1555A>G mutation. At the molecular level, the m.4394C>T mutation resides within a very conserved nucleotide of tRNAGln, which forms a new base-pairing (7T-66A) and may affect tRNA structure and function. Using trans-mitochondrial cybrid cells derived from three subjects with both the m.1555A>G and m.4394C>T mutations, three patients with only the m.1555A>G mutation and three control subjects without these primary mutations, we observed that cells with both the m.1555A>G and m.4394C>T mutations exhibited more severely impaired mitochondrial functions than those with only the m.1555A>G mutation. Furthermore, a marked decrease in mitochondrial RNA transcripts and respiratory chain enzymes was observed in cells harboring both the m.1555A>G and m.4394C>T mutations. Thus, our data suggest that the m.4394C>T mutation may play a synergistic role in the m.1555A>G mutation, enhancing mitochondrial dysfunctions and contributing to a high penetrance of hearing loss in families with both mtDNA pathogenic mutations.

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A six-generation Chinese family in haplogroup B4C1C exhibits high penetrance of 1555A > G-induced hearing Loss

Cited by 9 publications

References 32 publications

Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method

Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method

Complete Mitochondrial Genome Analysis and Clinical Documentation of a Five-Generational Indian Family with Mitochondrial 1555A>G Mutation and Postlingual Hearing Loss

Mitochondrial tRNAGln 4394C>T Mutation May Contribute to the Clinical Expression of 1555A>G-Induced Deafness

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