Synaptojanin2 Mutation Causes Progressive High-frequency Hearing Loss in Mice

Abstract

Progressive hearing loss is very common in the human population but we know little about the underlying molecular mechanisms. Synaptojanin2 (Synj2) has been reported to be involved, as a mouse mutation led to a progressive increase in auditory thresholds with age. Synaptojanin2 is a phosphatidylinositol (PI) phosphatase that removes the five-position phosphates from phosphoinositides, such as PIP 2 and PIP 3 , and is a key enzyme in clathrin-mediated endocytosis. To investigate the mechanisms underlying progressive hearing loss, we have studied a different mutation of mouse Synj2 to look for any evidence of involvement of vesicle trafficking particularly affecting the synapses of sensory hair cells. Auditory brainstem responses (ABR) developed normally at first but started to decline between 3 and 4 weeks of age in Synj2 tm1b mutants. At 6 weeks old, some evidence of outer hair cell (OHC) stereocilia fusion and degeneration was observed, but this was only seen in the extreme basal turn so cannot explain the raised ABR thresholds that correspond to more apical regions of the cochlear duct. We found no evidence of any defect in inner hair cell (IHC) exocytosis or endocytosis using single hair cell recordings, nor any sign of hair cell synaptic abnormalities. Endocochlear potentials (EP) were normal. The mechanism underlying progressive hearing loss in these mutants remains elusive, but our findings of raised distortion product otoacoustic emission (DPOAE) thresholds and signs of OHC degeneration both suggest an OHC origin for the hearing loss. Synaptojanin2 is not required for normal development of hearing but it is important for its maintenance.

Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

“…In SYNJ2 , we identified an association with a missense (Thr656Met) 18 variant that lies in the catalytic domain of this inositol polyphosphate 5-phosphatase 42 . Mice harboring homozygous mutations in Synj2 that are predicted to reduce protein levels or the 5-phosphatase catalytic activity show progressive high-frequency hearing loss and a degeneration of hair cells that is most profound in the outer hair cells 43,44 .…”

“…Consistent with the hypothesis from our genetic findings that loss of KLHDC7B function increases risk for hearing loss, initial characterization of Klhdc7B null mice by IMPC showed that homozygous carriers have hearing loss 26 . Mouse models Fscn2 and Synj2 also develop hearing loss 41,43,44 . Based on our association results, it would also be interesting to test heterozygous null Klhdc7b, Fscn2 , and Synj2 animals for increased susceptibility to hearing loss with age or environmental insults such as noise-exposure.…”

“…COCH Cys542Phe and MYO6 His246Arg), we do not observe any common variants of large effect. We further estimated phenotypic variance explained by the genetic data, or heritability h 2 Tot , using LD score regression (LDSC) partitioning into functional categories and stratifying by minor allele frequency 44,45 . We estimated a total heritability (h 2 Tot ) of 0.089, with contributions from common variation (h 2 CV , MAF > 0.05) and low-frequency variation (h 2 LFV , 0.001 < MAF £ 0.05) of 0.074 and 0.015, respectively (Supplementary Figure 3, Supplementary Table 11).…”

A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens

“…Mozart mice also exhibit stereociliar fusion, loss of hair cell bundles, and subsequent hair cell degeneration [44]. A second study on mice with a different Synj2 mutation in the phosphatase catalytic domain was able to confirm the observation of progressive hearing loss in Synj2-deficient mice [114].…”

“…IHC = inner hair cell, OHCs = outer hair cells, Pv = Parvalbumin, cut. = cuticula, TJ = tight junction, SC = stereocilia, Ph = phalangeal cell, r = stereociliar rootlet inner hair cells [44] as well as the spiral ganglion [114] (Fig. 5C).…”