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. 2020 Apr 27;10(1):7056.
doi: 10.1038/s41598-020-63690-5.

Novel ACTG1 mutations in patients identified by massively parallel DNA sequencing cause progressive hearing loss

Affiliations

Novel ACTG1 mutations in patients identified by massively parallel DNA sequencing cause progressive hearing loss

Hiroki Miyajima et al. Sci Rep. .

Abstract

Human ACTG1 mutations are associated with high-frequency hearing loss, and patients with mutations in this gene are good candidates for electric acoustic stimulation. To better understand the genetic etiology of hearing loss cases, massively parallel DNA sequencing was performed on 7,048 unrelated Japanese hearing loss probands. Among 1,336 autosomal dominant hearing loss patients, we identified 15 probands (1.1%) with 13 potentially pathogenic ACTG1 variants. Six variants were novel and seven were previously reported. We collected and analyzed the detailed clinical features of these patients. The average progression rate of hearing deterioration in pure-tone average for four frequencies was 1.7 dB/year from 0 to 50 years age, and all individuals over 60 years of age had severe hearing loss. To better understand the underlying disease-causing mechanism, intracellular localization of wild-type and mutant gamma-actins were examined using the NIH/3T3 fibroblast cell line. ACTG1 mutants p.I34M p.M82I, p.K118M and p.I165V formed small aggregates while p.R37H, p.G48R, p.E241K and p.H275Y mutant gamma-actins were distributed in a similar manner to the WT. From these results, we believe that some part of the pathogenesis of ACTG1 mutations may be driven by the inability of defective gamma-actin to be polymerized into F-actin.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Pedigree and audiograms for each family with an ACTG1 variant. Arrows show the probands in each family. Genetic findings for each individual are shown in the pedigree.
Figure 2
Figure 2
Rate of hearing loss deterioration for lower, middle and higher frequencies. The average progression rates of hearing deterioration in PTA for four frequencies (500, 1000, 2000, 4000 Hz) (A), lower frequencies (125,250,500 Hz) (B), and higher frequencies (2000,4000,8000 Hz) (C). Each solid line indicates the hearing thresholds of the same individual. Thin lines show the average progression rate of hearing deterioration.
Figure 3
Figure 3
An age-related typical audiogram (ARTA) demonstrating the progression of hearing loss for ACTG1.
Figure 4
Figure 4
Mutant γ-actin proteins failed to be incorporated into the F-actin network (1). (A-F) Confocal images of NIH/3T3 cells transfected with either wild-type or mutant halo-tagged γ-actin (red) analyzed by immunocytochemistry. F-actin localization was detected by phalloidin staining (green) and nuclear staining by DAPI (blue). (A) Untransfected cells show low background expression. (B) WT γ-actin exhibits smooth incorporation into the F-actin. (C) The previously published ACTG1:c.354 G > C:p.K118N failed to be incorporated into the F-actin, instead forming aggregates. (D, E, F) Mutations identified in this study, ACTG1:c.102 C > G:p.I34M, c.246 G > A:p.M82I, c.493 C > G:p.I165V, failed to incorporate into F-actin as marked by phalloidin staining, instead forming aggregates.

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