Fig. 1: The jordan mutation causes progressive hearing loss in a mouse model of DFNB3.
A Schematic showing the protein domains of the long (MYO15A-1) and short (MYO15A-2) isoforms encoded by the Myo15a gene. The jordan and shaker-2 deafness mutations are shown. B ABR phenotyping of the jordan pedigree at 3 months identified 10 mice with statistically-elevated hearing thresholds (red circles) for click and at 8, 16, and 32 kHz stimuli, compared to their normal hearing pedigree mates (n = 73 mice, black circles). Statistical outliers were detected using robust regression and outlier removal (red circles, ROUT, Q = 1%). Thresholds of affected mice that did not respond to the highest intensity stimulus (90 dB SPL) are recorded as 95 dB SPL. C Evolutionary conservation of the aspartate (D) residue of MYO15A altered to glycine (G) in jordan mice that causes hearing loss. Residue positions refer to mouse MYO15A-1 (NP_034992.2). D ABR recordings of Myo15ajd/sh2 (n = 7 mice) compound heterozygotes at P28 shows profound hearing loss, similar to Myo15ash2/sh2 (n = 4), with thresholds elevated compared with normal hearing Myo15a+/jd (n = 9) or Myo15a+/sh2 littermates (n = 4). Arrows indicate no response. E, F Longitudinal auditory phenotyping of jordan mice at 1- (E) and 3- (F) months of age. ABR recordings show that Myo15a jd/jd mice (red, n = 10 mice) exhibit a progressive, moderate-to-severe hearing loss affecting all frequencies, whereas age-matched Myo15a+/+ (black, n = 10) and Myo15a+/jd (grey, n = 15) littermate controls have normal thresholds (15–45 dB SPL). Myo15a+/+ vs Myo15ajd/jd comparison, ****, P < 0.0001, ANOVA with Tukey’s multiple comparisons test. Data are mean ± SD.
