To elucidate the pathophysiological and genetic mechanisms of hearing loss associated with the homoplasmic mitochondrial A1555G mutation in the absence of aminoglycoside exposure, we conducted audiological and genetic analyses on 67 maternally related members of a large Japanese family carrying this mutation. A consistent pattern was evident in the audiograms, with features of sensory presbycusis, cochlear origin at all levels of hearing loss, and a high degree of vulnerability of outer hair cells. That the degree of hearing loss was similar in affected subjects within the same sibling group but differed between sibling groups suggests the involvement of nuclear modifier genes. Total mitochondrial DNA sequences were completely identical among subjects with various levels of hearing loss, and lacked additional pathogenic mutations. For the diagnosis of sensorineural hearing loss, the mitochondrial A1555G mutation should be considered when these features are present even in the absence of aminoglycoside exposure.
PrezantTRAgapianJVBohlmanMC. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet1993; 4: 289–94.
3.
HamasakiKRandoRR. Specific binding of aminoglycosides to a human rRNA construct based on a DNA polymorphism which causes aminoglycoside-induced deafness. Biochemistry1997; 36: 12323–8.
4.
MatthijsGClaesSLongo-MbenzaBCassimanJ-J. Non-syndromic deafness associated with a mutation and a polymorphism in the mitochondrial 12S ribosomal RNA gene in a large Zairean pedigree. Eur J Hum Genet1996; 4: 46–51.
5.
UsamiSAbeSKasaiM. Genetic and clinical features of sensorineural hearing loss associated with the 1555 mitochondrial mutation. Laryngoscope1997; 107: 483–90.
6.
el-SchahawiMLopez de MunainASarrazinAM. Two large Spanish pedigrees with nonsyndromic sensorineural deafness and the mtDNA mutation at nt 1555 in the 12S rRNA gene: Evidence of heteroplasmy. Neurology1997; 48: 453–6.
7.
CasanoRAMSBykhovskayaYJohnsonDF. Hearing loss due to the mitochondrial A1555G mutation in Italian families. Am J Med Genet1998; 79: 388–91.
8.
EstivillXGoveaNBarceloA. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am J Hum Genet1998; 62: 27–35.
9.
BravermanIJaberLLeviH. Audiovestibular findings in patients with deafness caused by a mitochondrial susceptibility mutation and precipitated by an inherited nuclear mutation or aminoglycosides. Arch Otolaryngol Head Neck Surg1996; 122: 1001–4.
10.
MatsunagaTKumanomidoHShiromaM. Delineation of the phenotypic expression in a large Japanese family with A1555G mitochondrial mutation. In: Abstracts of the Twenty-Sixth Midwinter Research Meeting of the Association for Research in Otolaryngology, Daytona Beach, Fla, 2003: 487.
11.
GelfandSA. Essentials of audiology. 2nd ed.New York, NY: Thieme, 2001: 139–71, 257–90.
12.
AkanumaJMurakiKKomakiHNonakaIGotoY. Two pathogenic point mutations exist in the authentic mitochondrial genome, not in the nuclear pseudogene. J Hum Genet2000; 45: 337–41.
ISO. Acoustics: Statistical Distribution of Hearing Thresholds as a Function of Age. ISO 7029. Geneva, Switzerland: International Organization for Standardization, 2000: 1–9.
15.
JergerJ. Diagnostic audiometry. In: JergerJ, ed. Modern developments in audiology. 2nd ed.New York, NY: Academic Press, 1973: 75–115.
16.
SiningerYSAbdalaC. Physiologic assessment of hearing. In: LalwaniAKGrundfastKM, eds. Pediatric otology and neurotology. Philadelphia, Pa: Lippincott-Raven, 1998: 127–54.
17.
CoatsACMartinJL. Human auditory nerve action potentials and brain stem evoked responses: Effects of audiogram shape and lesion location. Arch Otolaryngol1977; 103: 605–22.
18.
SeltersWABrackmannDE. Acoustic tumor detection with brain stem electric response audiometry. Arch Otolaryngol1977; 103: 181–7.
19.
NussbaumRLMcInnesRRWillardHF. Thompson and Thompson genetics in medicine. 6th ed.Philadelphia, Pa: WB Saunders, 2001: 244–9.
20.
SajjadiHPaparellaMMCanalisRF. Presbycusis. In: CanalisRFLambertPR, eds. The ear: comprehensive otology. Philadelphia Pa: Lippincott Williams & Wilkins, 2000: 545–57.
21.
BrierleyEJJohnsonMALightowlersRNJamesOFTurnbullDM. Role of mitochondrial DNA mutations in human aging: Implications for the central nervous system and muscle. Ann Neurol1998; 43: 217–23.
22.
TonoTUshisakoYKiyomizuK. Cochlear implantation in a patient with profound hearing loss with the A1555G mitochondrial mutation. Am J Otol1998; 19: 754–7.
23.
NortonSJ. Cochlear function and otoacoustic emissions. Semin Hear1992; 13: 1–14.
24.
PandyaAXiaX-JErdenetungalagR. Heterogeneous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. Am J Hum Genet1999; 65: 1803–6.
25.
GuanM-XFischel-GhodsianNAttardiG. Biochemical evidence for nuclear gene involvement in phenotype of nonsyndromic deafness associated with mitochondrial 12S rRNA mutation. Hum Mol Genet1996; 5: 963–71.
26.
BykhovskayaYShohatMEhrenmanK. Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation. Am J Med Genet1998; 77: 421–6.
