Elsevier

Gene

Volume 393, Issues 1–2, 15 May 2007, Pages 11-19
Gene

Very low penetrance of hearing loss in seven Han Chinese pedigrees carrying the deafness-associated 12S rRNA A1555G mutation

https://doi.org/10.1016/j.gene.2007.01.001Get rights and content

Abstract

Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report here the clinical, genetic and molecular characterizations of seven Han Chinese pedigrees with aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the variable phenotype of hearing impairment including severity, age-at-onset and audiometric configuration in these subjects. The penetrance of hearing loss in these pedigrees ranged from 3% to 29%, with an average of 13.6%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees varied from 0% to 17%, with an average of 5.3%. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA A1555G mutation, in addition to distinct sets of mtDNA polymorphism belonging to East Asian haplogroups B4, D4, D5 and F1, respectively. This suggested that the A1555G mutation occurred sporadically and multiplied through evolution of the mtDNA in China. Despite the presence of several evolutionary conservative variants in protein-encoding genes, there was the absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in these seven Chinese families. These suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the A1555G mutation in those Chinese families with very low penetrance of hearing loss. However, aminoglycosides appear to be a major modifier factor for the phenotypic manifestation of the A1555G mutation in these Chinese families.

Introduction

Mitochondrial 12S rRNA has been shown to be the hot spot for mutations associated with both aminoglycoside-induced and nonsyndromic hearing loss (Fischel-Ghodsian, 2005, Guan, 2005). Of these, the C1494T mutation in the highly conserved A-site of the 12S rRNA has been associated with both aminoglycoside-induced and nonsyndromic hearing loss in two Chinese families (Zhao et al., 2004, Zhao et al., 2005a), while the A1555G mutation in the highly conserved A-site of the 12S rRNA has been associated with both aminoglycoside-induced and nonsyndromic hearing loss in many families worldwide (Prezant et al., 1993, Matthijs et al., 1996, Pandya et al., 1997, Usami et al., 1997, Estivill et al., 1998, del Castillo et al., 2003, Li et al., 2004a, Li et al., 2004b, Li et al., 2005b, Young et al., 2005, Yuan et al., 2005, Zhao et al., 2005b, Jacobs et al., 2005). Matrilineal relatives within and among families carrying the A1555G mutation exhibited a wide range of penetrance, severity and age-of-onset in hearing loss (Estivill et al., 1998, del Castillo et al., 2003, Li et al., 2004b, Young et al., 2005, Yuan et al., 2005, Zhao et al., 2005b). Varying degrees of penetrance and expressivity of hearing loss as well as mild biochemical defects associated with this mutation indicated that the A1555G mutation itself is not sufficient to produce a deafness phenotype (Prezant et al., 1993, Estivill et al., 1998, Guan et al., 1996, Guan et al., 2000, Guan et al., 2001, Li et al., 2004b, Young et al., 2005). Therefore, other modifier factors, such as aminoglycosides, nuclear modifier genes and mitochondrial haplotypes, modulate the phenotypic manifestation of the A1555G mutation (Bykhovskaya et al., 1998, Fischel-Ghodsian, 2005, Guan et al., 1996, Guan et al., 2000, Guan et al., 2001, Guan et al., 2006, Young et al., 2006).

To further investigate the molecular mechanism of maternally transmitted hearing loss, we have initiated a systematic and extended mutational screening of the 12S rRNA in several cohorts of hearing-impaired subjects (Li et al., 2004a, Li et al., 2005b, Dai et al., 2006, Young et al., 2005, Young et al., 2006, Zhao et al., 2005b). In the previous investigation, we showed the highly variable penetrance and expressivity of hearing loss in 29 Han Chinese families carrying the A1555G mutation (Li et al., 2004b, Li et al., 2005b, Young et al., 2005, Young et al., 2006, Zhao et al., 2005b, Dai et al., 2006, Yuan et al., 2005). Sequence analysis of complete mitochondrial genomes as well as clinical and genetic valuations in ten Chinese pedigrees suggested that five mitochondrial tRNA variants: tRNAGlu A14693G, tRNAThr T15908C, tRNAArg T10454C, tRNASer(UCN) G7444A and tRNACys G5821A, may influence the phenotypic manifestation of the A1555G mutation (Yuan et al., 2005, Young et al., 2006, Zhao et al., 2005b). In the present study, we performed the clinical, molecular and genetic characterizations of another seven Han Chinese pedigrees carrying the A1555G mutation. Strikingly, these pedigrees displayed very low penetrances of hearing loss. To assess the contribution that mtDNA variants make toward the phenotypic expression of the A1555G mutation, we performed PCR-amplification of fragments spanning an entire mitochondrial genome and subsequent DNA sequence analysis in the matrilineal relatives of those families.

Section snippets

Subjects and audiological examinations

As the part of a genetic screening program for hearing impairment, seven Han Chinese families, as shown in Fig. 1, were ascertained through the Otology Clinic of the First Affiliated Hospital, Wenzhou Medical College. A comprehensive history and physical examination were performed to identify any syndromic findings, the history of the use of aminoglycosides and genetic factors related to the hearing impairment in members of this pedigree. An age-appropriate audiological examination was

Mutational screening of 12S rRNA gene in Chinese subjects with hearing loss

To further elucidate the molecular basis of hearing loss, we have performed a mutational analysis of the mitochondrial 12S rRNA gene in a cohort of Han Chinese subjects, who were diagnosed as aminoglycoside ototoxicity by the Otology Clinic at the Wenzhou Medical College. Firstly, DNA fragments spanning the 12S rRNA were PCR amplified from each affected subject. Each fragment was digested by restriction enzyme BsmAI and subsequent electrophoresis analysis. Of those, seven subjects harbored the

Discussion

In the present study, we have performed the clinical, genetic and molecular characterizations of seven Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing impairment. Hearing impairment as a sole clinical phenotype was only present in the maternal lineage of those pedigrees. Mutational analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical homoplasmic A1555G mutation. Strikingly, those

Acknowledgements

This work was supported by Public Health Service grants RO1DC05230 from the National Institute on Deafness and Other Communication Disorders, and RO1NS44015 from the National Institute of Neurological Disorders and Stroke and grants from National Basic Research Priorities Program of China 2004CCA02200, Ministry of Public Heath of Zhejiang Province 2006A100 and Ministry of Science and Technology of Zhejiang Province 2007G50G2090026 to M.X.G.

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    The first five authors had equally contributed to this work.

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