Abstract
Mutations in mitochondrial DNA (mtDNA) are one of the most important causes of hearing loss. Of these, the homoplasmic A1555G and C1494T mutations at the highly conserved decoding site of the 12S rRNA gene are well documented as being associated with either aminoglycoside-induced or nonsyndromic hearing loss in many families worldwide. Moreover, five mutations associated with nonsyndromic hearing loss have been identified in the tRNASer(UCN) gene: A7445G, 7472insC, T7505C, T7510C, and T7511C. Other mtDNA mutations associated with deafness are mainly located in tRNA and protein-coding genes. Failures in mitochondrial tRNA metabolism or protein synthesis were observed from cybrid cells harboring these primary mutations, thereby causing the mitochondrial dysfunctions responsible for deafness. This review article provides a detailed summary of mtDNA mutations that have been reported in deafness and further discusses the molecular mechanisms of these mtDNA mutations in deafness expression.
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Introduction
Hearing loss is one of the most common sensory disorders, affecting approximately 120 million patients all over the world. About 30% of them have syndromic hearing loss, and the remaining 70% have nonsyndromic hearing loss. In addition, a large number of elderly people worldwide suffer from age-related (late-onset) hearing loss (Lalwani and Gürtler 2008; Brown et al. 2008; Gratton and Vázquez 2003). Hearing loss can be caused by genetic and environmental factors; genetic factors account for at least half of all cases of profound congenital deafness, and single gene mutations can also lead to hearing loss (Nance 2003). It has been estimated that more than 50% of pediatric cases have a genetic etiology with autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFN), or mitochondrial mode of inheritance (Jacobs et al. 2005; Guan 2011). Although most hereditary hearing loss is caused by a deficiency in nuclear genes, it has become clear that mitochondrial genes also play important roles in deafness expression. Mitochondrial DNA mutations have been found to be associated with both maternally inherited syndromic and nonsyndromic hearing loss worldwide (Fischel-Ghodsian 1999; Guan 2011). This review summarizes the basic knowledge of mitochondrial genetics and the most common mtDNA mutations associated with deafness. We also briefly discuss the molecular mechanisms by which mtDNA mutations lead to human hearing loss.
The Mitochondrial Genome and Mitochondrial Genetics
Mitochondria are ubiquitous organelles in eukaryotic cells. Their primary role is to generate energy (i.e., ATP) through oxidative phosphorylation (Attardi and Schatz 1988). They have their own DNA, known as mtDNA, encoding certain essential components of mitochondrial respiratory chain and protein synthesis apparatus. Human mtDNA is a double-stranded, circular molecule (Fig. 1) encoding 13 protein subunits of 4 biochemical complexes and 24 structural RNAs (2 ribosomal RNAs and 22 transfer RNAs) that are responsible for intramitochondrial translation of protein-coding units (Anderson et al. 1981).
The human mitochondrial genome. Inner circles show the two rRNA genes (12S rRNA and 16S rRNA). White bars show the reading frames and 22 tRNAs
Mitochondrial DNA is inherited maternally and does not recombine; mutations thus accumulate sequentially through maternal lineages. Each mitochondrion contains 2–10 DNA molecules, and each cell contains multiple mitochondria. Since mtDNA is in the proximity of reactive oxygen species generation sites and mitochondria have relatively less sophisticated DNA protection and repair systems, it is therefore vulnerable to high mutation rates (DiMauro and Schon 2001). If all the mtDNAs in a cell are identical, the cell status is referred to as “homoplasmy”; if not, it is called “heteroplasmy.” Neutral polymorphisms are usually homoplasmic, whereas pathogenic mutations are usually heteroplasmic in nature (Table 1), and mtDNA mutations associated with deafness are generally homoplasmic or almost homoplasmic (>85%) (Fischel-Ghodsian 1999; Fischel-Ghodsian et al. 2004).
Mitochondrial 12S rRNA Mutations and Ototoxic Hearing Loss
Aminoglycosides (such as gentamicin, kanamycin, and streptomycin) were first discovered in the 1940s and used for the treatment of tuberculosis and bacterial infections (Schacht 1993). The ototoxic and nephrotoxic effects of aminoglycosides, however, still do not receive enough attention in developing countries. Patients treated with aminoglycosides may exhibit a high frequency of sensorineural hearing loss that is permanent and bilateral. In familial cases of ototoxic hearing loss, aminoglycoside hypersensitivity is often maternally transmitted, suggesting that mutations in mtDNA are the molecular basis for this susceptibility (Fischel-Ghodsian 1999). Since the first report that the 12S rRNA A1555G mutation played an active role in aminoglycoside-induced and nonsyndromic hearing loss (Prezant et al. 1993), many efforts have been carried out to identify other potential mtDNA pathogenic mutations associated with aminoglycoside ototoxicity (Fischel-Ghodsian et al. 2004). In fact, the A1555G mutation is located at the aminoacyl-tRNA acceptor site (A-site) of the small ribosomal subunit, which is highly conserved from bacteria to mammals (Ruiz-Pesini and Wallace 2006). This mutation has been found in many families with maternally inherited, nonsyndromic hearing loss and also in patients with hearing loss after the use of aminoglycosides. In an Arab–Israeli family carrying the A1555G mutation, under a constant nuclear background, average reductions of 35 and 37% in the rate of mitochondrial protein synthesis were observed in cybrid cell lines derived from asymptomatic or symptomatic individuals in this family (Guan et al. 2001).
The 12S rRNA C1494T mutation has been found to be associated with aminoglycoside-induced and nonsyndromic hearing loss in some Chinese and Spanish families (Zhao et al. 2004, 2005a; Rodriguez-Ballesteros et al. 2006; Wang et al. 2006; Chen et al. 2007). It is interesting to note that in the human mitochondrial 12S rRNA, C1494 forms a noncanonical RNA base pair with the adenine encoded by the 12S rRNA position 1555, both of them located in the A-site of the 12S rRNA (Ogle and Ramakrishnan 2005). The region of the 16S rRNA in Escherichia coli, corresponding to that of the human mitochondrial 12S rRNA A-site (Fig. 2), is the target for the aminoglycoside antibioitic (Recht et al. 1996; Fourmy et al. 1996) and is crucial for subunit association either by RNA–protein or RNA–RNA interaction (Zwieb et al. 1986). Moreover, the sensitivity to aminoglycosides involves their direct binding to a C–G base pair at positions 1409–1491 of the penultimate helix in the small ribosomal subunit rRNA (Purohit and Stern 1994). This transition makes the secondary structure of rRNA more closely resemble the corresponding region of Escherichia coli 16S rRNA. Similarly, the new G–C pair in 12S rRNA is expected to create a binding site for aminoglycoside, which facilitates the binding of these drugs (Hamasaki and Rando 1987) and causes the mistranslation or premature termination of protein synthesis (Chamber and Sande 1996; Davies and Davis 1968). As a result, the exposure to aminoglycosides can induce or aggravate hearing loss in individuals carrying one of these mutations.
Comparison of secondary structure of decoding-site rRNA in the small ribosomal subunit: A-site of bacterial 16S rRNA (left) and human 12S rRNA (right). The corresponding regions of human mitochondrial A1555G and C1494U are indicated, creating a novel 1494C-G1555 or 1494U-A1555 base-pairing
The association of the 12S rRNA T1095C mutation (conservation index 93%) with deafness is controversial. This mutation has been found in several genetically unrelated families with nonsyndromic hearing loss (Tessa et al. 2002; Zhao et al. 2005b; Wang et al. 2005). The T1095C mutation was first identified in a family with hearing loss and neuropathic symptoms (Thyagarajan et al. 2000). Phylogenetic analysis of this mutation reveals it to be a genetic polymorphism, unlikely to be of pathogenic significance (Yao et al. 2006).
The 961insC mutation is a deletion of a single T with an insertion of a varying number of Cs in the 12S rRNA gene. In a recent study of 1,642 Han Chinese pediatric subjects with hearing loss, this mutation accounted for 1.8% in this genetic population (Lu et al. 2010a). Although it is postulated that alteration of the tertiary structure of 12S rRNA caused by 961insC may affect the binding of aminoglycoside (Guan 2005), its functional role needs to be further addressed experimentally.
Mitochondrial tRNASer(UCN): Hot Spot for Pathogenic Mutations with Deafness
Mutations in the gene encoding tRNASer(UCN) have been implicated with the development of sensorineural hearing loss. They include A→G (T or C) at position 7445 (Fischel-Ghodsian et al. 1995; Reid et al. 1994), the insertion of a new cytidine at position 7472 (Verhoeven et al. 1999; Jacobs et al. 2005), T→C transition at positions 7505 (Tang et al. 2010), 7510 (Hutchin et al. 2000; del Castillo et al. 2002; Labay et al. 2008), and 7511 (Sue et al. 1999; Li et al. 2005a). These mutations often occur in homoplasmy or in high levels of heteroplasmy, indicating a high threshold for pathogenicity. It is believed that mutations in this gene can cause a failure in tRNA metabolism, thereby altering mitochondrial translation and respiration (Guan et al. 1998; Li et al. 2004).
The homoplasmic A7445G mutation in the precursor of tRNASer(UCN) was first identified in New Zealand, Ukraine, Japanese, and Mongolian families with nonsyndromic deafness (Fischel-Ghodsian et al. 1995; Hutchin et al. 2000; Pandya et al. 1999). Structurally, this mutation is located at the stop codon (AGA) of the mRNA encoding CO1 on the H-strand. As the AGA normal codon is replaced by an AGG stop codon, however, the A7445G mutation has no effect on CO1 expression. Therefore, this mutation leaves the structure of the tRNASer(UCN) intact but affects the rate of processing of the tRNASer(UCN) precursor, which results in a reduction in tRNASer(UCN) level and also leads to a significant reduction in the amount of ND6 mRNA and protein synthesis (Guan et al. 1998; Reid et al. 1997; Li et al. 2005b). Alternatively, the A7445T or A7445C mutation is adjacent to the 3′ end site of endonucleolytic processing of the L-strand RNA precursor, spanning tRNASer(UCN) and ND6 mRNA, and may also affect the processing of the L-strand RNA precursor, causing mitochondrial dysfunction (Chen et al. 2008).
The 7472insC mutation in tRNASer(UCN) was originally described in a Sicilian family (Tiranti et al. 1995). In a large Dutch family, this mutation was found to be responsible for the nonsyndromic hearing loss in all family members; one individual in this family exhibited the syndrome of hearing loss, ataxia, and myoclonus. This mutation templates the insertion of an extra G into a run of six G residues, located within the T arm and extra arm of tRNASer(UCN) (Verhoeven et al. 1999; Tiranti et al. 1995). It impairs the 5′ and 3′ processing of tRNASer(UCN) (Toompuu et al. 2004) and decreases the steady-state level of this tRNA post-transcriptionally (Toompuu et al. 1999). Cybrid cells harboring the 7472insC mutation exhibit a significant decrease (70%) of tRNASer(UCN) abundance by affecting its synthesis rather than the stability of its structure, also causing a mild decline (25%) in steady-state aminoacylation of tRNASer(UCN) (Toompuu et al. 2004).
The homoplasmic T7505C mutation was reported from a Han Chinese pedigree with maternally inherited nonsyndromic hearing loss (Tang et al. 2010). This mutation is located at the second base-pairing (10A–20U) in the D stem of tRNA (Florentz et al. 2003). Functional analysis of cybrid cells showed that the T7505C mutation reduced the level of tRNASer(UCN) by 65%, thus impairing mitochondrial protein synthesis (Tang et al. 2010).
The T7510C and T7511C mutations occur at the acceptor arm of tRNA and disrupt the highly conserved secondary structure of tRNASer(UCN). The T7511C mutation has been identified in African (Sue et al. 1999; Friedman et al. 1999), French (Chapiro et al. 2002), and Japanese families (Ishikawa et al. 2002) with nonsyndromic hearing loss. In a large African family carrying the T7511C mutation, in conjunction with homoplasmic ND1 T3308C and tRNAAla T5655C mutations, 75–83% reductions in the level of tRNASer(UCN) were observed in cybrid cells carrying the T7511C mutation (Li et al. 2004). The T5655C mutation caused a 50% reduction in the tRNAAla level, which may result in a failure to aminoacylate properly and in post-transcriptional modification of this tRNA. A significant reduction in steady-state levels of both ND1 mRNA and the adjacent tRNALeu(UUR) observed in the cybrids carrying the T3308C mutation is likely due to an alteration in the processing of the H-strand polycistronic RNA precursors or the destabilization of ND1 mRNA (Rossmanith et al. 1995). Therefore, combined with the T3308C and T5655C mutations, the T7511C mutation accounts for a high penetrance of deafness in this African family (Li et al. 2004).
Other mtDNA Mutations Associated with Deafness
G1606A in the tRNAVal Gene
The heteroplasmic tRNAVal G1606A mutation was first identified in a 48-year-old man with bilateral hearing loss, vision loss, and mild muscle weakness (Tiranti et al. 1998). Later, Sacconi et al. (2002) described a 37-year-old woman with hearing loss, ataxia, retinitis pigmentosa, and hypothyroidism. This mutation was located on the acceptor arm of tRNAVal; genotype-phenotype analysis suggested that it may be related not only to changes in the DNA sequence but also to disruptions in the secondary and tertiary structure of tRNAVal (Schon et al. 1997). Moreover, analysis of single muscle fibers revealed a significantly greater level of mutant mtDNA in cytochrome c oxidase-negative fibers, suggesting that this mutation is involved in the pathogenesis of clinical diseases.
A3243G in the tRNALeu(UUR) Gene
The heteroplasmic A3243G mutation has been reported to be associated with maternally inherited diabetes and deafness syndrome (Maassen 2004; Ohkubo et al. 2001; van den Ouweland et al. 1992). The primary defect in this mutation is an inefficient aminoacylation of tRNALeu(UUR) (Chomyn et al. 2000; El Meziane et al. 1998). In addition, this mutation affects the processing of mitochondrial RNA precursors (Rossmanith and Karwan 1998). The deficiency of aminoacylation of tRNALeu(UUR) mainly contributes to a shortage of tRNALeu(UUR) (Li and Guan 2010), thereby causing a reduced rate of mitochondrial protein synthesis and respiration defects (King et al. 1992; Janssen et al. 2007).
A4295G in the tRNAIle Gene
McFarland et al. (2004) provided a program for assigning a pathogenicity score to mt-tRNA mutations. Their weighting scoring system was revised in 2011 (Yarham et al. 2011), and it predicted the A4295G mutation to be definitely pathogenic. The homoplasmic A4295G mutation reduces the efficiency with which tRNAIle can be processed by 3′-tRNase, decreases the level of functional tRNAIle (Levinger et al. 2003), and thereby leads to the defects in mitochondrial translation (Gutiérrez Cortés et al. 2012).
G8363A in the tRNALys Gene
The heteroplasmic G8363A mutation was first identified in two unrelated families carrying a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy (Santorelli et al. 1996). Moreover, Virgilio et al. (2009) reported a large Italian family with heterogeneous mitochondrial disease phenotypes associated with the G8363A mutation. This mutation abolishes a highly conserved base-pairing at the acceptor arm of tRNALys; the absence of a hydrogen-bonded base pair at the end of the acceptor stem is likely to impair the activity of peptidyl-tRNA hydrolase, which is critical for protein translation (Dutka et al. 1993). Defects in oxidative phosphorylation metabolism were observed in muscle biopsies from a patient with the G8363A mutation, suggesting a direct pathogenic role.
T12201C in the tRNAHis Gene
The heteroplasmic T12201C mutation was originally detected in a large Chinese family with high penetrance of hearing impairment (Yan et al. 2011). The T→C transition at position 12201 disrupts a very conservative base-pairing (5A–68U) in the acceptor arm of tRNAHis and causes a failure in tRNA metabolism. Functional characterization of a cell line derived from T12201C mutation reveals a 75% reduction in the tRNAHis steady-state level, thus impairing mitochondrial translation.
ND1 C3388A and CO2 G8078A: Novel Pathogenic Mutations with Deafness
Previously, Lévêque et al. (2007) identified several novel candidate mtDNA mutations, localized in a variety of mitochondrial genes, found in patients with deafness. Of these, the homoplasmic C3388A mutation, which affects the gene encoding the ND1 subunit, causes a significant decrease in complex I protein level. The G8078A mutation results in mild defects of the respiratory chain complex IV. These findings indicate that mutations in protein-coding genes can also be responsible for nonsyndromic hearing loss (Gutiérrez Cortés et al. 2012).
Mitochondrial Secondary Variants
Variable phenotypes of hearing loss within and among the families carrying A1555G or A7445G mutations indicate the involvement of mitochondrial secondary variants (Lu et al. 2010b; Maász et al. 2008). In a recent mutational screening of 1,642 pediatric subjects with hearing loss from Zhejiang Province in China, 69 families exhibited the homoplasmic A1555G mutation; in particular, nine mitochondrial secondary variants (tRNAThr G15927A, T15908C, tRNASer(UCN) G7444A, ND5 T12338C, tRNAGlu A14693G, tRNAArg T10454C, tRNASer(AGY) C12224T, tRNACys T5802C, G5821A) were implicated in enhancing the penetrance and expressivity of hearing loss among those families (Lu et al. 2010b) (Table 1; Fig. 3). Of these, the G15927A variant is located at the fourth base in the anti-codon stem of tRNAThr (conventional position 42). The abolished base-pairing (28C-42G) of this tRNA alters tRNAThr metabolism (Florentz et al. 2003; Wang et al. 2008). Moreover, the G7444A variant results in a read-through of the stop codon AGA of the CO1 message, thereby adding three amino acids (Lys–Gln–Lys) to the C-terminal of the polypeptide (Pandya et al. 1999; Yuan et al. 2005). The ND5 T12338C variant results in the replacement of the first amino acid, translation-initiating methionine, with a threonine (Chen et al. 2008). Thus, the truncated ND5 mRNA is shortened by two amino acids. In addition, the T12338C variant is also located in two nucleotides adjacent to the 3′ end of tRNALeu(CUN). Consequently, the T12338C variant may lead to a reduction in the tRNALeu(CUN) level. Furthermore, the A14693G variant occurs at position 54 in the T arm of tRNAGlu, and the T10454C variant is located at position 55 in the T arm of tRNAArg. Nucleotides at position 54 and 55 of the T arm are often modified and thereby contribute to the structural formation and stabilization of functional tRNAs (Björk 1995). In addition, the T5802C, G5821A, and T15908C variants disrupt the highly conserved base-pairing of tRNACys and tRNAThr. The C12224T variant in tRNASer(AGY) occurs adjacent to the anti-codon of this tRNA. Thus, the alteration of the tertiary structure of the mitochondrial tRNA may result in a failure in this tRNA metabolism. Therefore, these secondary variants may worsen mitochondrial dysfunction caused by the A1555G mutation, increasing the penetrance and expressivity of hearing loss in these Chinese families.
Cloverleaf structure of mt-tRNA with standard nucleotide numbering
Deletions
Mitochondrial DNA deletions associated with deafness do not occur frequently in population genetics. Three deletions have been reported: the 10.4 kb deletion, the 7 kb deletion, and the common deletion of 4,977 bp. Ballinger et al. (1992) first reported a three-generation family with maternally inherited diabetes mellitus and deafness. Mutational analysis of the mitochondrial genome showed a large deletion of 10.4 kb, which removed the light strand origin (OL) of mtDNA replication and inhibited mitochondrial protein synthesis. The heteroplasmic deletion of 7 kb in mtDNA was identified in a 17-year-old patient with diabetes, deafness, cataract, and maculopathy (Souied et al. 1998), but the molecular pathogenesis of this deletion remains mysterious. The common deletion of 4,977 bp (Bai and Seidman 2001) may alter the mitochondrial copy number (Chen et al. 2011) and affect mitochondrial protein synthesis, and it is anticipated that individuals carrying these deletions would have an oxidative phosphorylation level lower than that of the normal genotype.
Molecular Mechanism of mtDNA Mutations with Deafness
Mitochondrial DNA mutations have structural and functional effects, including altering the RNA structure, reducing the steady-state level of tRNA or mRNA, and causing tRNA modification. Failures in mitochondrial tRNA metabolism or protein synthesis were observed from cybrid cells carrying these primary mutations, which subsequently reduced the ATP synthesis. Deficiencies in oxidative phosphorylation appear to be the main pathogenic factors (McKenzie et al. 2004); increased ROS may damage the hair cells and cochlear neurons. As a result, the mitochondrial permeability transition pore opens and activates apoptosis, leading to hearing loss.
Accumulating evidence shows that mtDNA mutations play important roles in both syndromic and nonsyndromic hearing loss. Mitochondrial dysfunctions caused by these mtDNA mutations or secondary mutations are the major molecular mechanisms responsible for deafness. These data will offer valuable information for early diagnosis, management, and treatment of maternally transmitted hearing loss.
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This work was supported by grants from Nanjing Medical University (No. 2010NJMU011) and the Ministry of Science and Technology of Zhejiang Province (No. 2008R40G2090027).
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Ding, Y., Leng, J., Fan, F. et al. The Role of Mitochondrial DNA Mutations in Hearing Loss. Biochem Genet 51, 588–602 (2013). https://doi.org/10.1007/s10528-013-9589-6
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DOI: https://doi.org/10.1007/s10528-013-9589-6