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Title: Aminoglycoside-induced and non-syndromic hearing loss is associated with the G7444A mutation in the mitochondrial COI/tRNA{sup Ser(UCN)} genes in two Chinese families

Abstract

We report here the clinical, genetic, and molecular characterization of two Chinese families with aminoglycoside induced and non-syndromic hearing impairment. Clinical and genetic evaluations revealed the variable severity and age-of-onset in hearing impairment in these families. Strikingly, there were extremely low penetrances of hearing impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical G7444A mutation associated with hearing loss. Indeed, the G7444A mutation in the CO1 gene and the precursor of tRNA{sup Ser(UCN)} gene is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families and 164 Chinese controls. Their mitochondrial genomes belong to the Eastern Asian haplogroups C5a and D4a, respectively. In fact, the occurrence of the G7444A mutation in these several genetically unrelated subjects affected by hearing impairment strongly indicates that this mutation is involved in the pathogenesis of hearing impairment. However, there was the absence of other functionally significant mtDNA mutations in two Chinese pedigrees carrying the G7444A mutation. Therefore, nuclear modifier gene(s) or aminoglycoside(s) may play a role in the phenotypic expression of the deafness-associated G7444A mutation in these Chinesemore » pedigrees.« less

Authors:
; ; ;  [1];  [2]; ;  [3];  [2];  [2];  [3];  [4];  [5];  [6]
  1. Department of Otolaryngology and Zhejiang Provincial Key Laboratory of Medical Genetics, First Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang (China)
  2. Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 (United States)
  3. Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang (China)
  4. Center for Hearing and Deafness Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 (United States)|[Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 (United States)
  5. Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang (China). E-mail: jx@mail.wz.zj.cn
  6. Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 (United States)|[Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang (China)|[Center for Hearing and Deafness Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229 (United States)|[Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229 (United States). E-mail: min-xin.guan@chmcc.org
Publication Date:
OSTI Identifier:
20798895
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 342; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2006.02.027; PII: S0006-291X(06)00317-2; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARBON MONOXIDE; DNA; EVALUATION; GENES; MUTATIONS; PATHOGENESIS; STRUCTURAL CHEMICAL ANALYSIS

Citation Formats

Zhu Yi, Liao Zhisu, Li Zhiyuan, Chen Jianfu, Qian Yaping, Tang Xiaowen, Wang Jindan, Yang Li, Li Ronghua, Ji Jinzhang, Choo, Daniel I., Lu Jianxin, and Guan Minxin. Aminoglycoside-induced and non-syndromic hearing loss is associated with the G7444A mutation in the mitochondrial COI/tRNA{sup Ser(UCN)} genes in two Chinese families. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2006.02.027.
Zhu Yi, Liao Zhisu, Li Zhiyuan, Chen Jianfu, Qian Yaping, Tang Xiaowen, Wang Jindan, Yang Li, Li Ronghua, Ji Jinzhang, Choo, Daniel I., Lu Jianxin, & Guan Minxin. Aminoglycoside-induced and non-syndromic hearing loss is associated with the G7444A mutation in the mitochondrial COI/tRNA{sup Ser(UCN)} genes in two Chinese families. United States. doi:10.1016/j.bbrc.2006.02.027.
Zhu Yi, Liao Zhisu, Li Zhiyuan, Chen Jianfu, Qian Yaping, Tang Xiaowen, Wang Jindan, Yang Li, Li Ronghua, Ji Jinzhang, Choo, Daniel I., Lu Jianxin, and Guan Minxin. Fri . "Aminoglycoside-induced and non-syndromic hearing loss is associated with the G7444A mutation in the mitochondrial COI/tRNA{sup Ser(UCN)} genes in two Chinese families". United States. doi:10.1016/j.bbrc.2006.02.027.
@article{osti_20798895,
title = {Aminoglycoside-induced and non-syndromic hearing loss is associated with the G7444A mutation in the mitochondrial COI/tRNA{sup Ser(UCN)} genes in two Chinese families},
author = {Zhu Yi and Liao Zhisu and Li Zhiyuan and Chen Jianfu and Qian Yaping and Tang Xiaowen and Wang Jindan and Yang Li and Li Ronghua and Ji Jinzhang and Choo, Daniel I. and Lu Jianxin and Guan Minxin},
abstractNote = {We report here the clinical, genetic, and molecular characterization of two Chinese families with aminoglycoside induced and non-syndromic hearing impairment. Clinical and genetic evaluations revealed the variable severity and age-of-onset in hearing impairment in these families. Strikingly, there were extremely low penetrances of hearing impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical G7444A mutation associated with hearing loss. Indeed, the G7444A mutation in the CO1 gene and the precursor of tRNA{sup Ser(UCN)} gene is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families and 164 Chinese controls. Their mitochondrial genomes belong to the Eastern Asian haplogroups C5a and D4a, respectively. In fact, the occurrence of the G7444A mutation in these several genetically unrelated subjects affected by hearing impairment strongly indicates that this mutation is involved in the pathogenesis of hearing impairment. However, there was the absence of other functionally significant mtDNA mutations in two Chinese pedigrees carrying the G7444A mutation. Therefore, nuclear modifier gene(s) or aminoglycoside(s) may play a role in the phenotypic expression of the deafness-associated G7444A mutation in these Chinese pedigrees.},
doi = {10.1016/j.bbrc.2006.02.027},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 342,
place = {United States},
year = {Fri Apr 14 00:00:00 EDT 2006},
month = {Fri Apr 14 00:00:00 EDT 2006}
}
  • Mutations in mitochondrial DNA are one of the important causes of hearing loss. We report here the clinical, genetic, and molecular characterization of two Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the wide range of severity, age-at-onset, and audiometric configuration of hearing impairment in matrilineal relatives in these families. The penetrances of hearing loss in these pedigrees were 20% and 18%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees were 10% and 15%. Sequence analysis of the complete mitochondrialmore » genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA C1494T and CO1/tRNA{sup Ser(UCN)} G7444A mutations. Their distinct sets of mtDNA polymorphism belonged to Eastern Asian haplogroup C4a1, while other previously identified six Chinese mitochondrial genomes harboring the C1494T mutation belong to haplogroups D5a2, D, R, and F1, respectively. This suggested that the C1494T or G7444A mutation occurred sporadically and multiplied through evolution of the mitochondrial DNA (mtDNA). The absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in their mtDNA suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the 12S rRNA C1494T and CO1/tRNA{sup Ser(UCN)} G7444A mutations in those Chinese families. However, aminoglycosides and other nuclear modifier genes play a modifying role in the phenotypic manifestation of the C1494T mutation in these Chinese families.« less
  • We explored the mitochondrial 12S rRNA and the tRNA{sup Ser(UCN)} genes in 100 Tunisian families affected with NSHL and in 100 control individuals. We identified the mitochondrial A1555G mutation in one out of these 100 families and not in the 100 control individuals. Members of this family harbouring the A1555G mutation showed phenotypic heterogeneity which could be explained by an eventual nuclear-mitochondrial interaction. So, we have screened three nuclear genes: GJB2, GJB3, and GJB6 but we have not found correlation between the phenotypic heterogeneity and variants detected in these genes. We explored also the entire mitochondrial 12S rRNA and themore » tRNA{sup Ser(UCN)} genes. We detected five novel polymorphisms: T742C, T794A, A813G, C868T, and C954T, and 12 known polymorphisms in the mitochondrial 12S rRNA gene. None of the 100 families or the 100 controls were found to carry mutations in the tRNA{sup Ser(UCN)} gene. We report here First mutational screening of the mitochondrial 12S rRNA and the tRNA{sup Ser(UCN)} genes in the Tunisian population which describes the second family harbouring the A1555G mutation in Africa and reveals novel polymorphisms in the mitochondrial 12S rRNA gene.« less
  • We report here the clinical, genetic, and molecular characterization of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. Five of nine matrilineal relatives had aminoglycoside-induced hearing loss. These matrilineal relatives exhibited variable severity and audiometric configuration of hearing impairment, despite sharing some common features: being bilateral and having sensorineural hearing impairment. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified 16 variants and the homoplasmic 12S rRNA C1494T mutation, which was associated with hearing loss in the other large Chinese family. In fact, the occurrence of the C1494T mutation in these genetically unrelated pedigrees affected by hearingmore » impairment strongly indicated that this mutation is involved in the pathogenesis of aminoglycoside-induced and nonsyndromic hearing loss. However, incomplete penetrance of hearing loss indicated that the C1494T mutation itself is not sufficient to produce a clinical phenotype but requires the involvement of modifier factors for the phenotypic expression. Those mtDNA variants, showing no evolutional conservation, may not have a potential modifying role in the pathogenesis of the C1494T mutation. However, nuclear background seems to contribute to the phenotypic variability of matrilineal relatives in this family. Furthermore, aminoglycosides modulate the expressivity and penetrance of deafness associated with the C1494T mutation in this family.« less
  • A novel G8363A mutation in the mtDNA tRNA{sup Lys} gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% {plus_minus} 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome c oxidase-negative fibers than in cytochrome c oxidase-positive fibers. The mutation was notmore » found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity. 23 refs., 3 figs., 1 tab.« less
  • Autosomal dominant mutations in the transcription factor POU4F3 gene are associated with non-syndromic hearing loss in humans; however, there have been few reports of mutations in this gene worldwide. We performed a mutation analysis of the POU4F3 gene in 42 unrelated Koreans with autosomal dominant non-syndromic hearing loss, identifying a novel 14-bp deletion mutation in exon 2 (c.662del14) in one patient. Audiometric examination revealed severe bilateral sensorineural hearing loss in this patient. The novel mutation led to a truncated protein that lacked both functional POU domains. We further investigated the functional distinction between wild-type and mutant POU4F3 proteins using inmore » vitro assays. The wild-type protein was completely localized in the nucleus, while the truncation of protein seriously affected its nuclear localization. In addition, the mutant failed to activate reporter gene expression. This is the first report of a POU4F3 mutation in Asia, and moreover our data suggest that further investigation will need to delineate ethnicity-specific genetic background for autosomal dominant non-syndromic hearing loss within Asian populations.« less