Molecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants
The <i>GJB2</i> gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. <i>GJB2</i> pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin di...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Online Access: | https://www.mdpi.com/2079-7737/12/4/505 |
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| author | Lu Mao Yueqiang Wang Lei An Beiping Zeng Yanyan Wang Dmitrij Frishman Mengli Liu Yanyu Chen Wenxue Tang Hongen Xu |
| author_facet | Lu Mao Yueqiang Wang Lei An Beiping Zeng Yanyan Wang Dmitrij Frishman Mengli Liu Yanyu Chen Wenxue Tang Hongen Xu |
| author_sort | Lu Mao |
| collection | DOAJ |
| description | The <i>GJB2</i> gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. <i>GJB2</i> pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin diseases. However, the mechanism by which these different missense variants cause the different phenotypes is unknown. Over 2/3 of the <i>GJB2</i> missense variants have yet to be functionally studied and are currently classified as variants of uncertain significance (VUS). Based on these functionally determined missense variants, we reviewed the clinical phenotypes and investigated the molecular mechanisms that affected hemichannel and gap junction functions, including connexin biosynthesis, trafficking, oligomerization into connexons, permeability, and interactions between other coexpressed connexins. We predict that all possible <i>GJB2</i> missense variants will be described in the future by deep mutational scanning technology and optimizing computational models. Therefore, the mechanisms by which different missense variants cause different phenotypes will be fully elucidated. |
| first_indexed | 2024-03-11T05:14:06Z |
| format | Article |
| id | doaj.art-81cc672b2155480080d62cc8fd3f4a5c |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-11T05:14:06Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-81cc672b2155480080d62cc8fd3f4a5c2023-11-17T18:23:13ZengMDPI AGBiology2079-77372023-03-0112450510.3390/biology12040505Molecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense VariantsLu Mao0Yueqiang Wang1Lei An2Beiping Zeng3Yanyan Wang4Dmitrij Frishman5Mengli Liu6Yanyu Chen7Wenxue Tang8Hongen Xu9Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou 450052, ChinaBasecare Medical Device Co., Ltd., Suzhou 215000, ChinaTranslational Medicine Center, Huaihe Hospital of Henan University, Kaifeng 475000, ChinaPrecision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou 450052, ChinaThe Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, ChinaWissenschaftszentrum Weihenstephan, Technische Universitaet Muenchen, Am Staudengarten 2, 85354 Freising, GermanyPrecision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou 450052, ChinaPrecision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou 450052, ChinaThe Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, ChinaPrecision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou 450052, ChinaThe <i>GJB2</i> gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. <i>GJB2</i> pathogenic missense variants cause nonsyndromic HL (autosomal recessive and dominant) and syndromic HL combined with skin diseases. However, the mechanism by which these different missense variants cause the different phenotypes is unknown. Over 2/3 of the <i>GJB2</i> missense variants have yet to be functionally studied and are currently classified as variants of uncertain significance (VUS). Based on these functionally determined missense variants, we reviewed the clinical phenotypes and investigated the molecular mechanisms that affected hemichannel and gap junction functions, including connexin biosynthesis, trafficking, oligomerization into connexons, permeability, and interactions between other coexpressed connexins. We predict that all possible <i>GJB2</i> missense variants will be described in the future by deep mutational scanning technology and optimizing computational models. Therefore, the mechanisms by which different missense variants cause different phenotypes will be fully elucidated.https://www.mdpi.com/2079-7737/12/4/505hereditary hearing loss<i>GJB2</i>missense variantsmolecular mechanismsdeep mutational scanning |
| spellingShingle | Lu Mao Yueqiang Wang Lei An Beiping Zeng Yanyan Wang Dmitrij Frishman Mengli Liu Yanyu Chen Wenxue Tang Hongen Xu Molecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants Biology hereditary hearing loss <i>GJB2</i> missense variants molecular mechanisms deep mutational scanning |
| title | Molecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants |
| title_full | Molecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants |
| title_fullStr | Molecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants |
| title_full_unstemmed | Molecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants |
| title_short | Molecular Mechanisms and Clinical Phenotypes of <i>GJB2</i> Missense Variants |
| title_sort | molecular mechanisms and clinical phenotypes of i gjb2 i missense variants |
| topic | hereditary hearing loss <i>GJB2</i> missense variants molecular mechanisms deep mutational scanning |
| url | https://www.mdpi.com/2079-7737/12/4/505 |
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