Cosegregation of the G7444A mutation in the mitochondrial COI/tRNA^Ser(UCN) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside‐induced and nonsyndromic hearing loss

Abstract

We report here on the characterization of a three-generation Chinese family with aminoglycosideinduced and nonsyndromic hearing impairment. Ten of 17 matrilineal relatives exhibited bilateral and sensorineural hearing impairment. Of these, nine matrilineal relatives, who had a history of exposure to aminoglycosides, exhibited variable severity and audiometric configuration of hearing loss. The dose and age at the time of drug administration seemed to be correlated with the severity of the hearing loss experienced by affected individuals. Sequence analysis of the complete mitochondrial genome in the pedigree showed the presence of homoplasmic A1555G mutation and 37 variants belonging to haplogroup D4a. Of those variants, the G7444A mutation is of special interest as the mutation at this position results in a read-through of the stop condon AGA of the COI message, thereby adding three amino acids (Lys-Gln-Lys) to the C-terminal of the polypeptide. Alternatively, the G7444A mutation is adjacent to the site of 3' end endonucleolytic processing of L-strand RNA precursor, spanning tRNA Ser(UCN) and ND6 mRNA. Thus, the G7444A mutation, similar to the deafness-associated A7445G mutation, may lead to a defect in the processing of the L-strand RNA precursor, thus influencing the phenotypic expression of the A1555G mutation. These data also imply that nuclear background plays a role in the aminoglycoside ototoxicity associated with the A1555G mutation in this Chinese pedigree.

Mitochondrial rRNA and tRNA and hearing function

“…This mutation was implicated to be associated with nonsyndromic SNHL [55] or to influence the phenotypic expression of hearing loss associated with the A1555G mutation [56]. The pathogenicity was supported by a recent observation of two Chinese families with aminoglycosideinduced and nonsyndromic SNHL, in which the homoplasmic G7444A mutation was present only in the maternal lineage but not in other members of these pedigrees and 164 Chinese controls [57].…”

“…In the mitochondrial tRNA Ser(UCN) gene, five nonsyndromic deafness-associated mutations, A7445G [42][43][44], 7472insC [45][46][47], T7510C [48,84], T7511C [49][50][51][52][53], and G7444A [55][56][57], have been found in families from various ethnic backgrounds. These mutations often occur in homoplasmy or in high levels of heteroplasmy, indicating a high threshold for pathogenicity.…”

“…The fifth nonsyndromic deafness-associated mutation in the mitochondrial COI/tRNA Ser(UCN) gene is the G7444A substitution, which was first identified to coexist with the A1555G mutation in six Mongolian subjects and a Chinese pedigree with aminoglycoside-induced SNHL [55,56]. This mutation was implicated to be associated with nonsyndromic SNHL [55] or to influence the phenotypic expression of hearing loss associated with the A1555G mutation [56].…”

Are GJB2 mutations an aggravating factor in the phenotypic expression of mitochondrial non-syndromic deafness?

“…Several families have been reported to have one mtDNA deafness-causing mutation and several other mtDNA variants described as polymorphisms, but only a few individuals were found with more than one mtDNA deafness-causing mutation. 16,19,22 THE GJB2 35delG AND A1555G mtDNA MUTATIONS IN A SPANISH FAMILY Ló pez-Bigas et al 17 studied the GJB2 35delG mutation in 154 deaf individuals with the A1555G mutation and also analyzed the entire coding region of GJB2 in 42 unrelated patients from their cohort. They detected only one family with the 35delG mutation in heterozygosity, including four patients also having the A1555G mutation and two patients with the A1555G alone.…”

A novel method of detecting mitochondrial m.1494C>T and m.1555A>G mutations in a single PCR reaction using base-quenched probe

“…It has been demonstrated that mutation m.1494C>T might associate with aminoglycoside-induced hearing loss in a large Chinese family [8,10,11]., while the mutation m.1555A>G may contribute to both aminoglycoside-induced and nonsyndromic hearing loss in families worldwide [12,13]. Both m.1555A>G and m.1494C>T mutations locate in a highly conserved region of 12SrRNA that is implicated in aminoglycoside binding in bacteria.…”