Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients
<p dir="ltr">Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prev...
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2022
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| Summary: | <p dir="ltr">Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.178G>C, p.E60Q mutation in the <i>MYO6</i> gene, which was detected previously in a Qatari HHL family, using cellular and animal models. In vitro analysis was conducted in HeLa cells transiently transfected with plasmids carrying <i>MYO6</i><sup><em>W</em></sup><sup>T</sup> or <i>MYO6</i><sup><em>p.E60Q</em></sup>, and a zebrafish model was generated to characterize the in vivo phenotype. Cells transfected with <i>MYO6</i><sup><em>WT</em></sup> showed higher expression of MYO6 in the plasma membrane and increased ATPase activity. Modeling the human <i>MYO6</i> variants in zebrafish resulted in severe otic defects. At 72 h post-injection, <i>MYO6</i><sup><em>p.E60Q</em></sup> embryos demonstrated alterations in the sizes of the saccule and utricle. Additionally, zebrafish with <i>MYO6</i><sup><em>p.E60Q</em></sup> displayed super-coiled and bent hair bundles in otic hair cells when compared to control and <i>MYO6</i><sup><em>WT</em></sup> embryos. In conclusion, our cellular and animal models add support to the in silico prediction that the p.E60Q missense variant is pathogenic and damaging to the protein. Since the c.178G>C <i>MYO6</i> variant has a 0.5% allele frequency in the Qatari population, about 400 times higher than in other populations, it could contribute to explaining the high prevalence of hearing impairment in Qatar.</p><p dir="ltr"><br></p><h2>Other Information</h2><p dir="ltr">Published in: International Journal of Molecular Sciences<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/ijms23063369" target="_blank">https://dx.doi.org/10.3390/ijms23063369</a></p> |
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