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Fig. 1 Wild-type aminoglycoside binding site in E. coli 16S rRNA (A) and human 12S rRNA (B) (numbers are in E. coli numbering system in A). Positions of the A1555G (C) and C1494T (D) mutations.

showed a lower growth rate, mitochondrial protein synthesis, total oxygen consumption, and respiratory chain complexes-dependent respiration compared with control cell lines.[6] The severity of mitochondrial dysfunction in the mutant cell lines was correlated with the presence or absence of hearing loss in persons carrying the mutation.[6] Exposure of the cells to high concentrations of aminoglycosides significantly decreased the rates of growth and translation.1-6,7-1 When the mitochondria with A1555G was transferred into human mtDNA-less cells, the transformant cells exhibited significantly lower growth rate, mitochondrial protein synthesis, and substrate-dependent respiration compared with control cells. These decreases were very similar in deaf and hearing members of the family with the mutation, suggesting that the nuclear gene(s) plays an important role(s) in deafness phenotype.[8]

Epidemiology

Because A1555G can be found in persons with completely normal hearing, AID, progressive and late-onset high-frequency hearing loss, and congenital- or prelingual-onset severe to profound deafness without aminoglycoside exposure, it is difficult to obtain its true frequency in a given population. Although A1555G was originally described and frequently found in patients coming from families in which other relatives also have AID, sporadic cases with or without AID,[9,10] patients coming from families with hearing loss showing maternal inheritance, or one of the forms of Mendelian inheritance without AID is reported.[11,12]

The proportion of cases with mutation among patients with AID has ranged from 3%[9] to 44%[13,14] in different populations with different ascertainment strategies (Table 1). If there is a family history of AID[14] or maternal inheritance in the pedigree,[11] the possibility of finding this mutation increases. A number of studies have demonstrated that A1555G is associated with different mitochondrial haplotypes,[11,25] although founder effects have also been identified in some families,[25] implying that this mutation has arisen several times in the past and is not limited to a certain ethnic group.

It is important, yet difficult, to find the frequency of A1555G in the hearing population. Based on their results of screening in matrilineal pedigrees, Lehtonen et al.[16] estimated that the minimum frequency of A1555G was 4.7/100,000 in northern Finland. Tang et al.[24] studied anonymized 1173 blood samples obtained for newborn screening in Texas and identified one positive result (9/10,000). Similarly, in a study from New Zealand,[26] A1555G was found in 1 of 206 unselected samples. However, it should be noted that the A1555G mutation was not found in approximately 1500 control samples studied as control in different populations.[1,11,17,21]

Phenotype Associated with the A1555G Mutation

Hearing loss usually manifests itself within 1-3 months following—sometimes even one dose of—aminoglycoside use.[27] The onset and severity of hearing loss are unrelated to age at the time of exposure. The hearing loss is sensorineural (originating from the cochlear lesion) and, in most cases, is symmetrical—almost always involving the high frequencies.1-27-1 The vestibular system appears not to be involved.

A significant portion of individuals with A1555G has normal hearing for their entire life in case they have not been exposed to aminoglycosides. In the absence of aminoglycoside exposure, the probability of an individual possessing the mtDNA A1555G mutation developing hearing loss has been estimated to be 40% by the age of 30 years, and 60% by the age of 60 years.[11]

Genetic Modifiers Implicated in A1555G-Related Deafness

The original Arab-Israeli family and additional families with A1555G without AID suggested the presence of a nuclear modifier gene. Extensive search using different linkage strategies yielded a region on chromosome 8, around the microsatellite marker D8S277.[28]

The common deafness gene GJB2 and mitochondrial A7444G mutations have been reported to act as modifiers for A1555G in some studies,[21,29] although further

Table 1 Summary of published studies on the frequency of A1555G in different populations (country names in alphabetical order)

Numbers of Numbers of Numbers of

A1555G-detected/ A1555G-detected/ A1555G-detected/ Characteristics of the

Country screened families AID AID screened population Control group Reference

China

1/36 (3%)

1/36

Sporadic cases with AID

[9]

China

15/34 (44%)

15/34

15/34

Familial cases with AID

[14]

Denmark

2/85 (2.4%)

Varying degrees of hearing loss

[15]

Finland

2/117 (1.7%)

2/117

Families with MID

[16]

Germany

1/139 (0.7%)

Severe to profound congenital deafness

0/160

[17]

Hungary

0/56

Sporadic cases with severe to profound deafness

0/224

[17]

Indonesia

4/75 (5.3%)

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