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Systematic analysis of mitochondrial genes associated with hearing loss in the Japanese population: dHPLC reveals a new candidate mutation - PubMed

  • ️Sat Jan 01 2011

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Systematic analysis of mitochondrial genes associated with hearing loss in the Japanese population: dHPLC reveals a new candidate mutation

Hideki Mutai et al. BMC Med Genet. 2011.

Abstract

Background: Variants of mitochondrial DNA (mtDNA) have been evaluated for their association with hearing loss. Although ethnic background affects the spectrum of mtDNA variants, systematic mutational analysis of mtDNA in Japanese patients with hearing loss has not been reported.

Methods: Using denaturing high-performance liquid chromatography combined with direct sequencing and cloning-sequencing, Japanese patients with prelingual (N = 54) or postlingual (N = 80) sensorineural hearing loss not having pathogenic mutations of m.1555A > G and m.3243A > G nor GJB2 were subjected to mutational analysis of mtDNA genes (12S rRNA, tRNALeu(UUR), tRNASer(UCN), tRNALys, tRNAHis, tRNASer(AGY), and tRNAGlu).

Results: We discovered 15 variants in 12S rRNA and one homoplasmic m.7501A > G variant in tRNASer(UCN); no variants were detected in the other genes. Two criteria, namely the low frequency in the controls and the high conservation among animals, selected the m.904C > T and the m.1105T > C variants in 12S rRNA as candidate pathogenic mutations. Alterations in the secondary structures of the two variant transcripts as well as that of m.7501A > G in tRNASer(UCN) were predicted.

Conclusions: The m.904C > T variant was found to be a new candidate mutation associated with hearing loss. The m.1105T > C variant is unlikely to be pathogenic. The pathogenicity of the homoplasmic m.7501T > A variant awaits further study.

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Figures

Figure 1
Figure 1

Pedigree of a family carrying the m.904C > T variant. (A) Pedigree of a family carrying the homoplasmic m.904C > T variant. Individuals with hearing loss are indicated by filled symbols. The arrow indicates the proband. (B) Audiogram of the proband of m.904C > T. Open circles with the line indicate the air conduction thresholds of the right ear; the X's with dotted line indicate the air conduction thresholds of the left ear; [, bone conduction thresholds of the right ear; ], bone conduction thresholds of the left ear. Arrows indicate the scale-out level of hearing loss. (C, D) Secondary structures of wild-type 12S rRNA (C) and 12S rRNA with the m.904C > T (D) predicted by Centroid Fold. To the right is shown an enlargement of the region of predicted secondary structures surrounding nucleotide positions including 904 and 1005 (bold arrows with red circles). Positions 862, 917, 1021, and 1030 are marked by dashed arrows with black circles for easy comparison of the structural changes. Each predicted base pair is indicated by a gradation of color (red to blue) corresponding to the base-pairing probability from 1 (red) to 0 (blue) according to Centroid Fold.

Figure 2
Figure 2

Pedigrees of families carrying the m.1005T > C variant. (A,B) Pedigree of a family carrying the homoplasmic m.1005T > C (A), and the audiogram of the proband (B). (C-F) Pedigree of a family carrying heteroplasmic m.1005T > C (C), and the chromatogram of dHPLC of the MT4 fragment of the proband (D). The arrows indicate split peaks of the fragment owing to the heteroplasmic m.1005T > C. Audiograms of the siblings (III:1, 2) are shown in (E-F).

Figure 3
Figure 3

Pedigrees of families carrying the m.1005T > C variant (continued). (A,B) Audiograms of the siblings (III: 3, 4) of a family carrying the heteroplasmic m.1005T > C (Figure 2C). (C) Predicted secondary structure of the 12S rRNA transcript with the m.1005T > C. To the right is shown an enlargement of the region of predicted secondary structures surrounding nucleotide position 1005.

Figure 4
Figure 4

Pedigrees of families carrying the m.7501T > A variant. (A-F) Pedigrees of three families carrying the homoplasmic m.7501T > A, and audiograms of the probands (A and B, C and D, E and F). (G,H) Predicted secondary structure of the tRNASer(UCN) transcript (G) and the tRNASer(UCN) with m.7501T > A (H). Because the gene is transcribed in the reverse direction, thymine at 7501 (G) and adenine (H) are indicated as a and u, respectively (bold arrows).

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