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Nonsyndromic Hearing Loss and Deafness, Mitochondrial

Includes: MT-RNR1-Related Hearing Loss and Deafness (Aminoglycoside Ototoxicity), MT-TS1-Related Hearing Loss and Deafness
, MD, MBA
Associate Professor, Department of Human and Molecular Genetics
Virginia Commonwealth University Health System
Richmond, Virginia

Initial Posting: ; Last Update: April 21, 2011.

Summary

Disease characteristics. Nonsyndromic mitochondrial hearing loss and deafness is characterized by moderate-to-profound hearing loss and a mutation in either MT-RNR1 or MT-TS1. Mutations in MT-RNR1 can be associated with predisposition to aminoglycoside ototoxicity and/or late-onset sensorineural hearing loss. Mutations in MT-TS1 are usually associated with childhood onset of sensorineural hearing loss. Hearing loss associated with aminoglycoside ototoxicity is bilateral and severe to profound, occurring within a few days to weeks after administration of any amount (even a single dose) of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin. Although hearing loss associated with mutations in MT-TS1 is considered nonsyndromic, the m.7445A>G substitution is also associated with palmoplantar keratoderma (scaling, hyperkeratosis, and honeycomb appearance of the skin of the palms, soles, and heels) in some families.

Diagnosis/testing. MT-RNR1 (encoding mitochondrial 12S ribosomal RNA) and MT-TS1 (encoding mitochondrial transfer RNA serine 1) are the two genes in which mutations are currently known to cause nonsyndromic mitochondrial hearing loss and deafness.

Management. Treatment of manifestations: Appropriate rehabilitation (hearing aids, speech therapy, culturally appropriate language training, cochlear implantation, educational programs for the hearing impaired).

Prevention of primary manifestations: Avoidance of aminoglycosides.

Surveillance: Annual audiometric assessment to evaluate stability/progression of hearing loss.

Agents/circumstances to avoid: Aminoglycosides and noise exposure, especially in those with normal hearing who have the m.1555A>G mutation in MT-RNR1.

Evaluation of relatives at risk: Testing maternal relatives for the m.1555A>G mutation to identify those who should avoid use of aminoglycosides.

Genetic counseling. Nonsyndromic mitochondrial hearing loss and deafness is caused by mutations in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance. The father of a proband does not have the deafness-causing mtDNA mutation. The mother of a proband (usually) has the mtDNA mutation and may or may not have hearing loss. All offspring of females with a mtDNA mutation are at risk of inheriting the mutation. Offspring of males with a mtDNA mutation are not at risk of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mtDNA mutation in the family is known. Because of mitotic segregation, the mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues. Furthermore, the presence of the mtDNA mutation does not predict the age of onset or severity of hearing loss.

Diagnosis

Clinical Diagnosis

Nonsyndromic mitochondrial hearing loss and deafness is diagnosed with certainty in an individual with the following:

  • Moderate to profound hearing loss
  • Hearing loss graded by level of severity:
    • Mild (26-40 dB)
    • Moderate (41-55 dB)
    • Moderately severe (56-70 dB)
    • Severe (71-90 dB)
    • Profound (90 dB)
  • Hearing is assessed by a variety of methods; see Hereditary Hearing Loss and Deafness Overview.
  • No other systemic findings on history or physical examination
  • A mutation in either MT-RNR1, encoding mitochondrial 12S ribosomal RNA (12S rRNA) or MT-TS1, encoding mitochondrial transfer RNA serine 1 [tRNA-Ser(UCN)]
  • Mutations in MT-RNR1 can be associated with predisposition to aminoglycoside ototoxicity and/or late-onset sensorineural hearing loss.
  • Mutations in MT-TS1 are usually associated with childhood-onset sensorineural hearing loss.

Nonsyndromic mitochondrial hearing loss is suspected in individuals with moderate-to-profound hearing loss when one of the following is present:

  • A family history of hearing loss suggestive of maternal inheritance (i.e., no transmission by a male)
  • Onset of hearing loss following administration of an aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin [Bates 2003]

Molecular Genetic Testing

Genes. MT-RNR1 and MT-TS1 are the two genes in which mutations are currently known to cause mitochondrial nonsyndromic hearing loss and deafness.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Mitochondrial Nonsyndromic Hearing Loss and Deafness

Gene SymbolProportion of Mitochondrial Nonsyndromic Hearing Loss and Deafness Attributed to Mutations in This Gene Test MethodMutations Detected
MT-RNR1~71%Targeted mutation analysis 1m.1555A>G
m.961_962delTinsC(n) 2
Sequence analysisTargeted mutations above and additional MT-RNR1 sequence variants 3
MT-TS1 ~29%Targeted mutation analysis 1m.7443A>G
m.74444G>A
m.7445A>G
Sequence analysisTargeted mutations above and additional MT-TS1 sequence variants 3

Individuals with mitochondrial nonsyndromic hearing loss and deafness accounted for 2% of 1200 deaf probands [Pandya, unpublished].

1. The panel of mutations tested may vary among testing laboratories.

2. For m.961_962delTinsC(n), the (n) indicates that a variable number of C nucleotides can be inserted.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • If hearing loss has followed aminoglycoside exposure, test for MT-RNR1 mutations, beginning with targeted mutation analysis for the m.1555A>G allele.
  • In a familial case involving matrilineal inheritance with no aminoglycoside exposure, test for mutations in both MT-RNR1 and MT-TS1. One can start with targeted mutation analysis; if no mutation is identified consider sequence analysis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Presymptomatic diagnosis to identify relatives at risk for aminoglycoside ototoxicity requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

MT-RNR1-Related Hearing Loss

Aminoglycoside ototoxicity. A single base-pair substitution from A to G at nucleotide 1555 that is homoplasmic (present in all mitochondria of a cell and/or tissue) predisposes an individual to hearing loss caused by aminoglycoside exposure. Two additional changes in this gene, m.961_962delTinsC(n) and a homoplasmic C-to-T transition at position 1494 (m.1494C>T), have also been associated wih aminoglycoside ototoxicy in certain populations [Guan 2011].

Hearing loss occurs within a few days to weeks after administration of any amount (including a single dose) of aminoglycoside antibiotic such as gentamycin, tobramycin, amikacin, kanamycin, or streptomycin [Bates 2003].

Hearing loss is bilateral and severe to profound. Once it appears, hearing loss is irreversible but not progressive. Hearing loss associated with the m.1555A>G mutation results from hair cell dysfunction and hence is cochlear in nature [Bravo et al 2006].

Vestibular symptoms are uncommon.

Note: Aminoglycoside ototoxicity secondary to presence of a predisposing mtDNA mutation appears to be related to administration of aminoglycosides (independent of dose) in contrast to "dose-related" aminoglycoside ototoxicity that is related to the dose and/or plasma concentration of aminoglycosides in individuals who do not have a predisposing mtDNA mutation.

Sensorineural hearing loss independent of aminoglycoside exposure. The median age of onset of sensorineural hearing loss in individuals who have a mutation in MT-RNR1 but are not exposed to aminoglycosides is around age 20 years [Estivill et al 1998]. For an individual with the m.1555A>G substitution who is not exposed to aminoglycosides, the probability of developing hearing loss is about 40% by age 30 years [Estivill et al 1998]. Thus, other as-yet unknown genes (possibly the mitochondrial haplotype or a major modifying nuclear gene) and/or environmental factors influence penetrance and age of onset of hearing loss in these individuals [Bykhovskaya et al 2001, Johnson et al 2001]. A small percent of individuals with the m.1555A>G mutation who did not develop hearing loss had subclinical findings of a lower amplitude of response to DPOAE (distortion-product otoacoustic emission), indicating a deficit in cochlear physiology [Bravo et al 2006].

Other. Although hearing loss associated with mutations in MT-RNR1 is considered nonsyndromic, a constellation of digital, spinal, and pigmentary disturbances has been reported in a family with the m.1555A>G substitution. Pigmentary findings in family members included development of gray hair with a salt-and-pepper distribution in teenagers and hypopigmented skin patches ranging in size from 2 to 10 cms on the wrist, knee, and groin [Nye et al 2000]. The correlation between the mitochondrial substitution and the presence of pigmentary changes remains unclear.

MT-TS1-Related Hearing Loss

Sensorineural hearing loss. The different MT-TS1 mutations associated with sensorineural hearing loss are heteroplasmic (i.e., both wild-type and mutant mtDNA are present in a cell and/or tissue). (See Mitochondrial Disorders Overview.)

Onset of sensorineural hearing loss is during childhood [Sevior et al 1998, Pandya et al 1999, Hutchin et al 2001]. The severity of hearing loss is highly variable, ranging from mild to severe. Progression in the severity of hearing loss is characteristic.

Other. Although hearing loss associated with mutations in MT-TS1 is considered nonsyndromic, the m.7445A>G substitution is associated in some families with palmoplantar keratoderma in addition to hearing loss. The skin changes can appear as early as age four to five years and consist of scaling, hyperkeratosis, and honeycomb appearance of the skin of the palms, soles, and heels [Sevior et al 1998]. Callus formation occurs on the heels and toes. Hyperkeratosis of palms with erythema is reported in a few individuals; marked variability in the severity and extent of involvement is characteristic. Individuals who have both the m.7444G>A and m.1555A>G mutations [Pandya et al 2004] or the m.7443A>G mutation alone do not have skin findings.

Genotype-Phenotype Correlations

See Clinical Description.

Penetrance

MT-RNR1

  • The m.1555A>G mutation occurs as a homoplasmic change; hence the penetrance of hearing loss is 100% in those with the mutation who receive aminoglycoside antibiotics (i.e., all individuals with this mutation will become deaf with any amount of aminoglycoside in a single dose).
  • In individuals who have the mutation but are not exposed to aminoglycoside antibiotics, the penetrance for hearing loss is approximately 80% by age 65 years.

Note: It has been suggested that penetrance for hearing loss is lower in some families from China [Young et al 2005].

MT-TS1. The mutations are heteroplasmic; therefore, the severity of hearing loss and age of onset vary depending on the mutational load in an individual.

Prevalence

MT-RNR1. Hearing loss caused by the m.1555A>G substitution in MT-RNR1 has been observed worldwide, e.g., in the Arab-Israeli, Japanese, Mongolian, Zairean, Spanish, Chinese, Turkish, Balinese, Moroccon, Greek, and Polish populations [Jaber et al 1992, Hutchin et al 1993, Matthijs et al 1996, El-Schahawi et al 1997, Pandya et al 1997, Usami et al 1997, Malik et al 2003, Tekin et al 2003, Yuan et al 2005, Mkaouar-Rebai et al 2006, Wang et al 2006, Kokotas et al 2009, Nahili et al 2010, Rydzanicz et al 2010].

The prevalence of the m.1555A>G mutation varies by population:

  • Between 20% and 30% in deaf individuals from Spain and Asia
  • 15% of all individuals with hearing loss and a history of aminoglycoside administration [Fischel-Ghodsian et al 1997]
  • Three of 955 (0.3%) deaf probands ascertained throughout the US [Arnos et al 2003]
  • 6%of postlingual hearing loss in deaf probands from the UK and southern Italy [Jacobs et al 2005]
  • 17% in deaf probands from Spain [Bravo et al 2006]

The prevalence of the m.961_962delTinsC(n) mutations in deaf probands has not yet been determined; screening of anonymized blood spots from newborns in the state of Texas revealed a prevalence of approximately 1% [Tang et al 2002].

MT-TS1. The prevalence of mutations, especially in the 3' end of the precursor, is 0.8%-1.1% in deaf probands studied from the United States and from Mongolia [Arnos et al 2003]. A Japanese family with the m.7511T>C mutation has been reported [Li et al 2005].

Differential Diagnosis

Other genetic causes of nonsyndromic hearing loss and deafness need to be considered (see Hereditary Hearing Loss and Deafness Overview).

Aminoglycoside drug toxicity. The hearing loss seen after use of aminoglycosides in individuals without the MT-RNR1 mutations m.961_962delTinsC(n) or m.1555A>G results from drug toxicity and is related to the dose administered and the metabolism of the drug (i.e., the peak and trough serum concentrations).

Maternally inherited diabetes mellitus and deafness (MIDD). A single base-pair substitution of A to G at position 3243 (m.3243A>G) in MTTL1 (NC_012920.1), which encodes tRNA leucine, is associated with MIDD [Suzuki et al 2003, Wang et al 2006]. MIDD accounts for 0.5%-2.8% of diabetes mellitus. The onset of diabetes mellitus occurs in the third decade or later in non-obese individuals. The disease can be acute or slowly progressive with or without insulin dependence, and is characterized by absence of anti-GAD (glutamic acid decarboxylase) antibodies and by rapidly progressive advanced microvascular complications. The deafness is progressive and sensorineural [Suzuki et al 2003].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of hearing loss in an individual diagnosed with nonsyndromic mitochondrial hearing loss and deafness, the following evaluations are recommended:

Treatment of Manifestations

Treatment includes the following:

  • Appropriate rehabilitation, e.g., hearing aids, speech therapy, culturally appropriate language training, and evaluation for eligibility for cochlear implantation [Sinnathuray et al 2003]
  • Enrollment in educational programs appropriate for the hearing impaired
  • For mild keratoderma, use of lotions and emollients; for severe keratoderma, dermatologic evaluation

Prevention of Primary Manifestations

MT-RNR1-related aminoglycoside-induced ototoxicity. Physicians can inquire about a family history of aminoglycoside-induced hearing loss prior to the administration of aminoglycosides, either systemically or locally (e.g., into the cochlea as treatment for Meniere disease). In individuals with a positive family history, alternatives to aminoglycoside treatment should be considered when possible.

In the US, aminoglycoside use is most common in the neonatal intensive care unit; however, the therapeutic imperative of treatment with antibiotics in a neonatal intensive care unit setting does not always lend itself to pre-treatment screening by molecular genetic testing.

  • Bitner-Glindzicz et al [2009] report a population frequency of 0.19% for the A to G change in a European cohort of seven- to nine-year old children who had the mutation but did not have hearing loss because they were not exposed to aminoglycosides, and make an argument for screening on demand to avoid a preventable cause of hearing loss
  • In a recent commentary by Boles & Friedlich [2010], the authors suggest a prospective study into the feasibility of screening for these mitochondrial mutations, especially in busy neonatal units in an effort to identify this preventable form of hearing loss.

Surveillance

The following assessments are indicated:

  • Annual audiometric assessment to evaluate stability or progression of hearing loss
  • Annual examination by a physician to assess for related clinical findings (e.g., palmoplantar keratosis)

Agents/Circumstances to Avoid

Aminoglycosides and noise exposure should be avoided, particularly in individuals with normal hearing who have the m.1555A>G mutation in MT-RNR1.

Evaluation of Relatives at Risk

Retrospective studies in the US have shown that about 10% of individuals with hearing loss attributed to aminoglycoside administration have the m.1555A>G mutation in MT-RNR1 [Fischel-Ghodsian et al 1997]. Thus, detection of the m.1555A>G mutation in an individual with hearing loss secondary to aminoglycoside exposure can be of value in identifying maternal relatives who are at risk for aminoglycoside ototoxicity and would thus benefit from avoiding the use of aminoglycosides.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Nonsyndromic mitochondrial hearing loss and deafness is caused by mutations in mitochondrial DNA (mtDNA) and is transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

  • The father of a proband does not have the deafness-causing mtDNA mutation.
  • The mother of a proband (usually) has the mtDNA mutation and may or may not have hearing loss.
  • Alternatively, the proband may have a de novo (somatic) mtDNA mutation.

Sibs of a proband

  • The risk to the sibs depends on the genetic load of the mitochondrial mutation in the mother (e.g., homoplasmic versus heteroplasmic mutation).
  • If the mother has the mtDNA mutation, all sibs will inherit the mutation; however, the risk of hearing loss depends on (a) the mutational load and (b) exposure to aminoglycosides.

Offspring of a proband

  • All offspring of females with a mtDNA mutation are at risk of inheriting the mutation.
  • Offspring of males with a mtDNA mutation are not at risk of inheriting the mutation.

Other family members. The risk to other family members depends on the genetic status of the proband's mother. If the mother of the proband has a mtDNA mutation, her sibs and mother are also at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and possible prevention.

Many culturally deaf individuals view medical advances in hearing loss as a threat to the existence of their culture; it is important to acknowledge this point of view. A skilled sign language interpreter should be present during counseling sessions. The counseling session provides an opportunity to educate the individual regarding the etiology and natural history of the hearing loss and to discuss appropriate resources for services and information; such counseling is generally well received. Issues of prevention, cochlear implants, reproduction, and family planning should be dealt with in a culturally sensitive manner [Arnos & Oelrich 2002]. (See also Hereditary Hearing Loss and Deafness Overview).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the specific MT-RNR1 or MT-TS1 mutation in the mother has been identified, prenatal diagnosis for MT-RNR1-related sensorineural and MT-TS1-related hearing loss is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).. Accurate interpretation of a positive prenatal test result is difficult for the following reasons:

  • Because of mitotic segregation, the mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other fetal or adult tissues.
  • The presence of the mtDNA mutation does not predict the age of onset or severity of hearing loss.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for hearing loss are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    #2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Nonsyndromic Hearing Loss and Deafness, Mitochondrial: Genes and Databases

Gene SymbolChromosomal LocusProtein Name
MT-TS1MitochondriaNot applicable
MT-RNR1MitochondriaNot applicable

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Nonsyndromic Hearing Loss and Deafness, Mitochondrial (View All in OMIM)

500008DEAFNESS, NONSYNDROMIC SENSORINEURAL, MITOCHONDRIAL
561000RIBOSOMAL RNA, MITOCHONDRIAL, 12S; MTRNR1
580000DEAFNESS, AMINOGLYCOSIDE-INDUCED
590080TRANSFER RNA, MITOCHONDRIAL, SERINE, 1; MTTS1

MT-RNR1

Normal allelic variants. See Mitochondrial Disorders Overview.

Pathologic allelic variants. The m.1555A>G mutation lies in a highly conserved region of the MT-RNR1 product, mitochondrial 12S rRNA, which is involved in the binding of aminoglycosides in bacteria. Although linkage analysis has implicated a locus on chromosome 8 as a nuclear modifier [Bykhovskaya et al 2000], at least in some families, no candidate gene has been identified [Carelli et al 2003]. More recently, Ballana et al [2006] have suggested that the reduced penetrance observed in individuals with the m.1555A>G mutation results from an alteration in the secondary structure of RNA caused by additional sequence changes in MT-RNR1.

Table 2. Selected MT-RNR1 Pathologic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequence
m.961_962delTinsC(n)
(961delT+Cn)
NAAC_000021​.2
m.1555A>GNA

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable.

1. Variant designation that does not conform to current naming conventions

Normal gene product. See Mitochondrial Disorders Overview.

Abnormal gene product: Mutations in this region alter the susceptibility of ribosomes to aminoglycosides by making the rRNA more similar to a bacterial rRNA, leading to increased binding of aminoglycosides to the mitochondrial rRNA, which results in destruction of the sensory hair cells in the inner ear that are involved with auditory function [Bates 2003]. Hamasaki & Rando [1997] demonstrated specific binding of aminoglycosides to the m.1555A>G transition in a 12S rRNA construct. However, the mechanism of action for hearing loss in the absence of exposure to aminoglycosides is unclear. See also Mitochondrial Disorders Overview.

MT-TS1

Normal allelic variants. The base pairs at 7443, 7444, and 7445 are in the precursor for tRNA-Ser(UCN), with bp 7445 being adjacent to the 3' endonuclease cleavage site. See Mitochondrial Disorders Overview.

Pathologic allelic variants. See Table 3 and Mitochondrial Disorders Overview.

Table 3. Selected MT-TS1 Pathologic Allelic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequence
m.7443A>GNAAC_000021​.2
m.7444G>A NA
m.7445A>GNA
m.7445A>CNA
m.7510T>CNA
m.7511T>CNA

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

Normal gene product. see Mitochondrial Disorders Overview.

Abnormal gene product. The pathogenic mechanism for the m.7445A>G mutation in the 3' end of tRNA-Ser(UCN) precursor is suggested to be secondary to the decreased rate of tRNA-Ser(UCN) production and an overall reduction in mitochondrial protein synthesis [Guan et al 1998]. In vitro studies indicate an endonucleolytic processing defect (caused by the placement of a non-cleavable C at the processing junction) as the basis of nonsyndromic hearing loss for the m.7445A>G mitochondrial mutation [Levinger et al 2001]. Because the two adjoining mutations at positions 7444 and 7443 do not alter the cleavage and processing of the tRNA-Ser(UCN) in a similar fashion, they are unlikely to share this pathogenic mechanism. These three base pairs also encode the stop codon in MT-CO1 (mitochondrially encoded cytochrome c oxidase I gene) mRNA on the H strand, and each one converts this "stop" to a sense codon with elongation of the MT-CO1 reading frame by three amino acids, after which it encounters a stop codon.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements.

  1. American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. (pdf) Available online. 2002. Accessed 2-27-13.

Literature Cited

  1. Arnos KS, Oelrich MK. Genetic counseling for deafness. In: Keats BJB, Fay R, Popper A, eds. Genetics and Auditory Disorders. New York: Springer-Verlag; 2002:297-314.
  2. Arnos KS, Xia XJ, Norris G, Landa B. Relative frequencies of the mitochondrial A1555G and 961 del T mutations in the 12SrRNA gene in a large sample of deaf probands from the United States. Am J Hum Genet. 2003;73:S543.
  3. Ballana E, Morales E, Rabionet R, Montserrat B, Ventayol M, Bravo O, Gasparini P, Estivill X. Mitochondrial 12S rRNA gene mutations affect RNA secondary structure and lead to variable penetrance in hearing impairment. Biochem Biophys Res Commun. 2006;341:950–7. [PubMed: 16458854]
  4. Bates DE. Aminoglycoside ototoxicity. Drugs Today (Barc). 2003;39:277–85. [PubMed: 12743643]
  5. Bitner-Glindzicz M, Pembrey M, Duncan A, Heron J, Ring SM, Hall A, Rahman S. Prevalence of mitochondrial 1555A-->G mutation in European children. N Engl J Med. 2009;360:640–2. [PubMed: 19196684]
  6. Boles RG, Friedlich P. Should patients be screened for 12SrRNA mutations before treatment with aminoglycosides? Mitochondrion. 2010;10:391–2. [PubMed: 20302974]
  7. Bravo O, Ballana E, Estivill X. Cochlear alterations in deaf and unaffected subjects carrying the deafness-associated A1555G mutation in the mitochondrial 12S rRNA gene. Biochem Biophys Res Commun. 2006;344:511–6. [PubMed: 16631122]
  8. Bykhovskaya Y, Estivill X, Taylor K, Hang T, Hamon M, Casano RA, Yang H, Rotter JI, Shohat M, Fischel-Ghodsian N. Candidate locus for a nuclear modifier gene for maternally inherited deafness. Am J Hum Genet. 2000;66:1905–10. [PMC free article: PMC1378050] [PubMed: 10788333]
  9. Bykhovskaya Y, Yang H, Taylor K, Hang T, Tun RY, Estivill X, Casano RA, Majamaa K, Shohat M, Fischel-Ghodsian N. Modifier locus for mitochondrial DNA disease: linkage and linkage disequilibrium mapping of a nuclear modifier gene for maternally inherited deafness. Genet Med. 2001;3:177–80. [PubMed: 11388757]
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Suggested Reading

  1. Fischel-Ghodsian N. Mitochondrial deafness. Ear Hear. 2003;24:303–13. [PubMed: 12923421]
  2. Munnich A, Rotig A, Cormier-Daire V, Rustin P. Clinical presentation of respiratory chain deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 99. New York, NY: McGraw-Hill. Available online. 2002. Accessed 2-27-13.

Chapter Notes

Revision History

  • 21 April 2011 (me) Comprehensive update posted live
  • 24 July 2007 (me) Comprehensive update posted to live Web site
  • 22 October 2004 (me) Review posted to live Web site
  • 13 August 2003 (ap) Original submission
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