Very low penetrance of hearing loss in seven Han Chinese pedigrees carrying the deafness-associated 12S rRNA A1555G mutation
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.
References (37)
- et al.
Sequence and gene organization of mouse mitochondrial DNA
Cell
(1981) Extremely low penetrance of deafness associated with the mitochondrial 12S rRNA mutation in 16 Chinese families: implication for early detection and prevention of deafness
Biochem. Biophys. Res. Commun.
(2006)Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycosides
Am. J. Hum. Genet.
(1998)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.
(2006)Maternally inherited nonsyndromic hearing loss is associated with the mitochondrial tRNASer(UCN) 7511C mutation in a Japanese family
Biochem. Biophys. Res. Commun.
(2005)The A1555G mutation in the 12S rRNA gene of human mtDNA: recurrent origins and founder events in families affected by sensorineural deafness
Am. J. Hum. Genet.
(1999)Extremely low penetrance of hearing loss in four Chinese families with the mitochondrial 12S rRNA A1555G mutation
Biochem. Biophys. Res. Commun.
(2005)Maternally inherited aminoglycoside-induced and non-syndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family
Am. J. Hum. Genet.
(2004)Clinical evaluation and mitochondrial genome sequence analysis of two Chinese families with aminoglycoside-induced and nonsyndromic hearing loss
Biochem. Biophys. Res. Commun.
(2005)Phylogenetic analysis of mitochondrial DNA in Japanese pedigrees of sensorineural hearing loss associated with the A1555G mutation
Eur. J. Hum. Genet.
(1998)
Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA
Nat. Genet.
MITOMAP: a human mitochondrial genome database—2004 update
Nucleic Acids Res.
Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation
Am. J. Med. Genet.
Heteroplasmy for the 1555A>G mutation in the mitochondrial 12S rRNA gene in six Spanish families with non-syndromic hearing loss
J. Med. Genet.
Genetic factors in aminoglycoside toxicity
Pharmacogenomics
The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome: cryptic signals revealed by comparative analysis between vertebrates
J. Mol. Evol.
Prevalence of mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity
Voltra Rev.
Biochemical evidence for nuclear gene involvement in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation
Hum. Mol. Genet.
Cited by (45)
Investigation of the mtDNA mutations in Syrian families with non-syndromic sensorineural hearing loss
2018, International Journal of Pediatric OtorhinolaryngologyCitation Excerpt :In human, the A1555G mutation is the most common mutation causing NSHL, with frequency varying between 0.0% and 7.7% in many populations of different ethnicity in the world. Although a much higher prevalence for this mutation has been reported among Spanish and Asian patients [23,24]. Also, The A3243G mutation in the tRNA Leu (UUR) gene represents one common cause of NSHL and diabetes [25] A number of cases are deaf at birth while some cases develop a slowly progressing hearing loss at puberty.
Mitochondrial DNA mutations associated with aminoglycoside induced ototoxicity
2017, Journal of OtologyCitation Excerpt :However, in the absence of aminoglycosides, subjects bearing the m.1555A>G mutation can exhibit considerable phenotypic variation (Prezant et al., 1993; Matthijs et al., 1996; Estivill et al., 1998; Li et al., 2004; Young et al., 2005; Tang et al., 2007; Chen et al., 2008; Al-Malky et al., 2014). Some Chinese pedigrees carrying the m.1555A>G mutation exhibit very low penetrance of hearing loss (Young et al., 2005; Dai et al., 2006; Tang et al., 2007; Chen et al., 2008), while a large Arab-Israeli pedigree carrying the m.1555A>G mutation showed high penetrance of hearing loss (Bykhovskaya et al., 1998). After analyzing the haplogroups of 69 Chinese pedigrees carrying the m.1555A>G mutation, Lu et al. found that all of these Chinese pedigrees belonged to ten different haplogroups, including A, B, C, D, F, G, M, N, R, and Y (Lu et al., 2010b).
Normal hearing in a child with the m.1555A>G mutation despite repeated exposure to aminoglycosides. Has the penetrance of this pharmacogenetic interaction been overestimated?
2014, International Journal of Pediatric OtorhinolaryngologyCitation Excerpt :The same mutation is also reported to cause non-syndromic sensorineural hearing loss without aminoglycoside exposure in a fraction of cases although the penetrance of this effect is lower and less well established. However, even in these families every matrilineal relative that reported exposure to aminoglycosides had evidence of hearing loss suggesting high penetrance in the presence of aminoglycosides, which are considered to be a major modifying factor in the phenotypic expression of deafness [4,5,11–13]. Here, we report the case of a child with the m.1555A>G mutation and confirmed history of exposure to aminoglycosides yet having completely normal hearing and absence of any evidence of ototoxicity.
Mitochondrial 12S rRNA mutations associated with aminoglycoside ototoxicity
2011, MitochondrionCitation Excerpt :The severity of hearing loss in these families ranged from profound congenital deafness, to severe and moderate progressive hearing loss of later onset, to completely normal hearing (Estivill et al., 1998; Li et al., 2004a; H. Zhao et al., 2004; Lu et al., 2010a). The patterns of audiograms in these hearing-impaired subjects were sloping pattern, flat pattern and U-shaped pattern (Usami et al., 1997; H. Zhao et al., 2004; Yuan et al., 2005; L. Zhao et al., 2005; Dai et al., 2006; Young et al., 2006; Tang et al., 2007; Lu et al., 2010b). The penetrances of hearing loss (affected matrilineal relatives/total matrilineal relatives) in 69 Chinese pedigrees carrying the 1555A>G mutation ranged from 0% to 47.8%, with an average of 17.6% (Lu et al., 2010a).
- 1
The first five authors had equally contributed to this work.