Pathological mechanisms of connexin26-related hearing loss: Potassium recycling, ATP-calcium signaling, or energy supply?

Chen, Penghui; Wu, Wenjin; Zhang, Jifang; Chen, Junmin; Li, Yue; Sun, Liang; Hou, Shule; Yang, Jun

doi:10.3389/fnmol.2022.976388

Cited by 11 publications

(10 citation statements)

References 85 publications

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“…The human Cx26 gene is highly conserved and ablation of Cx26 in mice is embryonic lethal, indicating the essential functional roles of Cx26 in maintaining hemostasis of the human body [ 15 ]. Currently, there are several hypotheses for the pathogenic mechanism of Cx26-related hearing loss caused by defective hemichannel or gap junction channel function: potassium recycling disruption, adenosine-triphosphate-calcium signaling propagation disruption, and energy supply dysfunction [ 16 , 17 , 18 ].…”

Section: Structure and Function Of The Gjb2 Genementioning

confidence: 99%

Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants

Mao

Wang²,

et al. 2023

Biology

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The GJB2 gene is the most common gene responsible for hearing loss (HL) worldwide, and missense variants are the most abundant type. GJB2 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 GJB2 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 GJB2 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.

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Section: Structure and Function Of The Gjb2 Genementioning

confidence: 99%

Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants

Mao

Wang²,

et al. 2023

Biology

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“…Specific type of mutations can cause abnormalities at any particular step in the life cycle of connexins [ 27 ], result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. Several mechanisms may be involved in transport disorders leading to connexin dysfunction and hearing loss, that is, impaired cochlear potassium recirculation [ 27 , 131 ], endothelial barrier breakage [ 132 ], defective gap junction facilitation of metabolite transport [ 133 ], disrupted adenosine-triphosphate-calcium signaling propagation [ 134 , 135 ] and dysfunctional energy supply [ 136 ].…”

Section: Discussionmentioning

confidence: 99%

Cytomembrane Trafficking Pathways of Connexin 26, 30, and 43

Zong

Liu

et al. 2023

IJMS

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The connexin gene family is the most prevalent gene that contributes to hearing loss. Connexins 26 and 30, encoded by GJB2 and GJB6, respectively, are the most abundantly expressed connexins in the inner ear. Connexin 43, which is encoded by GJA1, appears to be widely expressed in various organs, including the heart, skin, the brain, and the inner ear. The mutations that arise in GJB2, GJB6, and GJA1 can all result in comprehensive or non-comprehensive genetic deafness in newborns. As it is predicted that connexins include at least 20 isoforms in humans, the biosynthesis, structural composition, and degradation of connexins must be precisely regulated so that the gap junctions can properly operate. Certain mutations result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. In this review, we provide a discussion of the transport models for connexin 43, connexins 30 and 26, mutations affecting trafficking pathways of these connexins, the existing controversies in the trafficking pathways of connexins, and the molecules involved in connexin trafficking and their functions. This review can contribute to a new way of understanding the etiological principles of connexin mutations and finding therapeutic strategies for hereditary deafness.

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“…Specific type of mutations can cause abnormalities at any particular step in the life cycle of connexins [27], result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. Several mechanisms may be involved in transport disorders leading to connexin dysfunction and hearing loss, that is, impaired cochlear potassium recirculation [27,131], endothelial barrier breakage [132], defective gap junction facilitation of metabolite transport [133], disrupted adenosine-triphosphatecalcium signaling propagation [134,135] and dysfunctional energy supply [136].…”

Section: Discussionmentioning

confidence: 99%

Cytomembrane Trafficking Pathways of Connexin 26, 30 and 43: Recent Updates

Zong¹,

Liu²,

Tu³

et al. 2023

Preprint

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The connexin gene family is the most prevalent gene that contributes to hearing loss. Connexins 26 and 30, encoded by GJB2 and GJB6 respectively, are the most abundant expressed connexins in the inner ear. Connexin 43 which is encoded by GJA1 appears to be widely expressed in various organs, including the heart, skin, brain, and inner ear. The mutations that arise in GJB2, GJB6 and GJA1 can all result in comprehensive or non-comprehensive genetic deafness in newborns. As it is predicted that connexins include at least 20 isoforms in humans, the biosynthesis, structural composition, and degradation of connexins must be precisely regulated so that the gap junctions can operate properly. Certain mutations result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. In this review, we provide a discussion of the transport models for connexin 43, connexins 30 and 26, mutations affecting trafficking pathways of connexin 26, the existing controversies in trafficking pathways of connexins, and the molecules involved in connexin trafficking and their functions. This review can contribute to a new way of understanding the etiological principles of connexin mutations and finding therapeutic strategies for hereditary deafness.

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Pathological mechanisms of connexin26-related hearing loss: Potassium recycling, ATP-calcium signaling, or energy supply?

Cited by 11 publications

References 85 publications

Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants

Molecular Mechanisms and Clinical Phenotypes of GJB2 Missense Variants

Cytomembrane Trafficking Pathways of Connexin 26, 30, and 43

Cytomembrane Trafficking Pathways of Connexin 26, 30 and 43: Recent Updates

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