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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| مؤلفون آخرون: | , , , , , , , , , |
| منشور في: |
2022
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| _version_ | 1864513519293038592 |
|---|---|
| author | Moza Alkowari (18288922) |
| author2 | Meritxell Espino-Guarch (15430868) Sahar Daas (18288925) Doua Abdelrahman (17280667) Waseem Hasan (17280670) Navaneethakrishnan Krishnamoorthy (391608) Abbirami Sathappan (12862993) Patrick Sheehan (1980892) Nicholas Panhuys (18288928) Xavier Estivill (23803) The Qatar Genome Program Research Consortium (14778616) |
| author2_role | author author author author author author author author author author |
| author_facet | Moza Alkowari (18288922) Meritxell Espino-Guarch (15430868) Sahar Daas (18288925) Doua Abdelrahman (17280667) Waseem Hasan (17280670) Navaneethakrishnan Krishnamoorthy (391608) Abbirami Sathappan (12862993) Patrick Sheehan (1980892) Nicholas Panhuys (18288928) Xavier Estivill (23803) The Qatar Genome Program Research Consortium (14778616) |
| author_role | author |
| dc.creator.none.fl_str_mv | Moza Alkowari (18288922) Meritxell Espino-Guarch (15430868) Sahar Daas (18288925) Doua Abdelrahman (17280667) Waseem Hasan (17280670) Navaneethakrishnan Krishnamoorthy (391608) Abbirami Sathappan (12862993) Patrick Sheehan (1980892) Nicholas Panhuys (18288928) Xavier Estivill (23803) The Qatar Genome Program Research Consortium (14778616) |
| dc.date.none.fl_str_mv | 2022-03-21T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/ijms23063369 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Functional_Characterization_of_the_MYO6_Variant_p_E60Q_in_Non-Syndromic_Hearing_Loss_Patients/25524031 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Chemical sciences Inorganic chemistry Organic chemistry Physical chemistry Theoretical and computational chemistry sensorineural hearing loss MYO6 whole-genome sequencing zebrafish hair cells |
| dc.title.none.fl_str_mv | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <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> |
| eu_rights_str_mv | openAccess |
| id | Manara2_607bf54bd8b2fbe217d58cde16bbce12 |
| identifier_str_mv | 10.3390/ijms23063369 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25524031 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss PatientsMoza Alkowari (18288922)Meritxell Espino-Guarch (15430868)Sahar Daas (18288925)Doua Abdelrahman (17280667)Waseem Hasan (17280670)Navaneethakrishnan Krishnamoorthy (391608)Abbirami Sathappan (12862993)Patrick Sheehan (1980892)Nicholas Panhuys (18288928)Xavier Estivill (23803)The Qatar Genome Program Research Consortium (14778616)Chemical sciencesInorganic chemistryOrganic chemistryPhysical chemistryTheoretical and computational chemistrysensorineural hearing lossMYO6whole-genome sequencingzebrafishhair cells<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>2022-03-21T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/ijms23063369https://figshare.com/articles/journal_contribution/Functional_Characterization_of_the_MYO6_Variant_p_E60Q_in_Non-Syndromic_Hearing_Loss_Patients/25524031CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/255240312022-03-21T03:00:00Z |
| spellingShingle | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients Moza Alkowari (18288922) Chemical sciences Inorganic chemistry Organic chemistry Physical chemistry Theoretical and computational chemistry sensorineural hearing loss MYO6 whole-genome sequencing zebrafish hair cells |
| status_str | publishedVersion |
| title | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients |
| title_full | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients |
| title_fullStr | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients |
| title_full_unstemmed | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients |
| title_short | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients |
| title_sort | Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients |
| topic | Chemical sciences Inorganic chemistry Organic chemistry Physical chemistry Theoretical and computational chemistry sensorineural hearing loss MYO6 whole-genome sequencing zebrafish hair cells |