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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 - PubMed

  • ️Sat Jan 01 2005

Comparative Study

. 2005 Oct 1;138A(2):133-40.

doi: 10.1002/ajmg.a.30952.

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Comparative Study

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

Huijun Yuan et al. Am J Med Genet A. 2005.

Abstract

We report here on the characterization of a three-generation Chinese family with aminoglycoside-induced 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.

(c) 2005 Wiley-Liss, Inc.

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Figures

Figure 1
Figure 1. A three-generation Chinese pedigree with aminoglycoside-induced and nonsyndromic hearing impairment

Hearing impaired individuals are indicated by filled symbols. Arrow denotes proband. Asterisks denote individuals who had a history of exposure to aminoglycosides.

Figure 2
Figure 2. Air conduction audiogram of some members in the Chinese family

Symbols: X-left, O-right ear.

Figure 3
Figure 3. Qualification of the A1555G mutation of matrilineal relatives in this Chinese family

PCR products around A1555G region of mtDNA were digested with BsmAI and analyzed by electrophoresis in a 1.5% agarose gel stained with ethidium bromide. A2 is a Chinese control subject [Zhao et al., 2004a].

Figure 4
Figure 4. Identification and qualification of G7444A mutation

(A) Partial sequence chromatograms of COI/tRNASer(UCN) genes from affected individual III-3 and a married-in-control III-1. An arrow indicates the location of the base changes at position 7444; (B) Quantification of G7444A mutation of matrilineal relatives and control subjects derived from the Chinese family. PCR products around G7444A region of mitochondrial genome were digested with XbaI and analyzed by electrophoresis in a 1.5% agarose gel stained with ethidium bromide.

Figure 5
Figure 5. Location of deafness-associated mutations in the tRNASer(UCN) and adjacent COI

Arrows indicate the position of the T7510C, T7511C and 7472insC mutations in the tRNASer(UCN) and the A7445G and G7444A mutation in the precursor of this tRNA and adjacent sequence of COI from wild-type (WT) and mutant (MT). The processing site for the 3-end of tRNASer(UCN) precursor, determined by and 3’-endonuclease [Guan et al., 1998], was indicated by arrow.

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