Mitochondrial ribosomal RNA mutation associated with both antibiotic–induced and non–syndromic deafness

Abstract

Maternally transmitted non-syndromic deafness was described recently both in pedigrees with susceptibility to aminoglycoside ototoxicity and in a large Arab-Israeli pedigree. Because of the known action of aminoglycosides on bacterial ribosomes, we analysed the sequence of the mitochondrial rRNA genes of three unrelated patients with familial aminoglycoside-induced deafness. We also sequenced the complete mitochondrial genome of the Arab-Israeli pedigree. All four families shared a nucleotide 1555 A to G substitution in the 12S rRNA gene, a site implicated in aminoglycoside activity. Our study offers the first description of a mitochondrial rRNA mutation leading to disease, the first cases of non-syndromic deafness caused by a mitochondrial DNA mutation and the first molecular genetic study of antibiotic-induced ototoxicity.

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

“…29 In Japan, the mutation was detected in 3% of all patients with SNHL. 30 As patients with the m.1555A4G mutation are susceptible to aminoglycoside ototoxicity, [7][8][9] screening for this mutation is therefore beneficial for people who are going to be administered aminoglycoside. Furthermore, this mutation has also been demonstrated in patients with non-syndromic HL without defined past medication histories of aminoglycoside, and even in patients without any apparent maternal inheritance.…”

“…Furthermore, this mutation has also been demonstrated in patients with non-syndromic HL without defined past medication histories of aminoglycoside, and even in patients without any apparent maternal inheritance. [9][10][11][12] In contrast, the m.3243A4G mutation causes several major clinical phenotypes of mitochondrial disease such as myopathy, encephalopathy, lactic acidosis, stroke-like episodes, maternally inherited diabetes and deafness, chronic progressive external ophthalmoplegia and mitochondrial diabetes. [31][32][33] However, epidemiological evidence of the prevalence of the patients with the m.3243A4G mutation in the population still has limitations.…”

“…[3][4][5][6] A representative homoplasmic mutation at m.1555A4G in the MT-RNR1 (12S ribosomal RNA) gene causes non-syndromic (isolated) hearing loss (HL) associated with a susceptibility to aminoglycoside antibiotics. [7][8][9] Moreover, it is not uncommon to find the m.1555A4G mutation in HL patients without defined past medication histories of aminoglycoside. [9][10][11][12] Other pathogenic mtDNA mutations have also been identified in syndromic HL with various clinical phenotypes, such as mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes, Kearns-Sayre syndrome, myoclonic epilepsy and ragged-red fibers 13 or maternally inherited diabetes and deafness.…”

“…[7][8][9] Moreover, it is not uncommon to find the m.1555A4G mutation in HL patients without defined past medication histories of aminoglycoside. [9][10][11][12] Other pathogenic mtDNA mutations have also been identified in syndromic HL with various clinical phenotypes, such as mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes, Kearns-Sayre syndrome, myoclonic epilepsy and ragged-red fibers 13 or maternally inherited diabetes and deafness. 14 Furthermore, the m.3243A4G heteroplasmic mutation in MT-TL1 (tRNA Leu(UUR) ) gene is found in patients with nonsyndromic HL.…”

Non-syndromic hearing impairment in a multi-ethnic population of Northeastern Brazil

“…The A1555G mutation in mitochondrial gene MTRNR1 has been identified in hereditary NSHI and in aminoglycoside-induced HI in families from several countries [29][30][31][32][33]. The A1555G mutation also has been reported in cases of NSHI in Brazil [8,9,34].…”