Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects
Variants in the <i<GABRB</i< gene, which encodes the β subunit of the GABA<sub<A</sub< receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental disorders such as Dravet syndrome and Angelman syndrome. These conditions are often assoc...
Ausführliche Beschreibung
Autor*in: |
Ciria C. Hernandez [verfasserIn] Ningning Hu [verfasserIn] Wangzhen Shen [verfasserIn] Robert L. Macdonald [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2023 |
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Übergeordnetes Werk: |
In: Biomolecules - MDPI AG, 2013, 13(2023), 12, p 1790 |
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Übergeordnetes Werk: |
volume:13 ; year:2023 ; number:12, p 1790 |
Links: |
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DOI / URN: |
10.3390/biom13121790 |
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Katalog-ID: |
DOAJ09890406X |
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Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects |
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Variants in the <i<GABRB</i< gene, which encodes the β subunit of the GABA<sub<A</sub< receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental disorders such as Dravet syndrome and Angelman syndrome. These conditions are often associated with early-onset seizures, developmental regression, and cognitive impairments. The severity and specific features of these encephalopathies can differ based on the nature of the genetic variant and its impact on GABA<sub<A</sub< receptor function. These variants can lead to dysfunction in GABA<sub<A</sub< receptor-mediated inhibition, resulting in an imbalance between neuronal excitation and inhibition that contributes to the development of seizures. Here, 13 <i<de novo</i< EE-associated <i<GABRB</i< variants, occurring as missense mutations, were analyzed to determine their impact on protein stability and flexibility, channel function, and receptor biogenesis. Our results showed that all mutations studied significantly impact the protein structure, altering protein stability, flexibility, and function to varying degrees. Variants mapped to the GABA-binding domain, coupling zone, and pore domain significantly impact the protein structure, modifying the β+/α− interface of the receptor and altering channel activation and receptor trafficking. Our study proposes that the extent of loss or gain of GABA<sub<A</sub< receptor function can be elucidated by identifying the specific structural domain impacted by mutation and assessing the variability in receptor structural dynamics. This paves the way for future studies to explore and uncover links between the incidence of a variant in the receptor topology and the severity of the related disease. |
abstractGer |
Variants in the <i<GABRB</i< gene, which encodes the β subunit of the GABA<sub<A</sub< receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental disorders such as Dravet syndrome and Angelman syndrome. These conditions are often associated with early-onset seizures, developmental regression, and cognitive impairments. The severity and specific features of these encephalopathies can differ based on the nature of the genetic variant and its impact on GABA<sub<A</sub< receptor function. These variants can lead to dysfunction in GABA<sub<A</sub< receptor-mediated inhibition, resulting in an imbalance between neuronal excitation and inhibition that contributes to the development of seizures. Here, 13 <i<de novo</i< EE-associated <i<GABRB</i< variants, occurring as missense mutations, were analyzed to determine their impact on protein stability and flexibility, channel function, and receptor biogenesis. Our results showed that all mutations studied significantly impact the protein structure, altering protein stability, flexibility, and function to varying degrees. Variants mapped to the GABA-binding domain, coupling zone, and pore domain significantly impact the protein structure, modifying the β+/α− interface of the receptor and altering channel activation and receptor trafficking. Our study proposes that the extent of loss or gain of GABA<sub<A</sub< receptor function can be elucidated by identifying the specific structural domain impacted by mutation and assessing the variability in receptor structural dynamics. This paves the way for future studies to explore and uncover links between the incidence of a variant in the receptor topology and the severity of the related disease. |
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Variants in the <i<GABRB</i< gene, which encodes the β subunit of the GABA<sub<A</sub< receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental disorders such as Dravet syndrome and Angelman syndrome. These conditions are often associated with early-onset seizures, developmental regression, and cognitive impairments. The severity and specific features of these encephalopathies can differ based on the nature of the genetic variant and its impact on GABA<sub<A</sub< receptor function. These variants can lead to dysfunction in GABA<sub<A</sub< receptor-mediated inhibition, resulting in an imbalance between neuronal excitation and inhibition that contributes to the development of seizures. Here, 13 <i<de novo</i< EE-associated <i<GABRB</i< variants, occurring as missense mutations, were analyzed to determine their impact on protein stability and flexibility, channel function, and receptor biogenesis. Our results showed that all mutations studied significantly impact the protein structure, altering protein stability, flexibility, and function to varying degrees. Variants mapped to the GABA-binding domain, coupling zone, and pore domain significantly impact the protein structure, modifying the β+/α− interface of the receptor and altering channel activation and receptor trafficking. Our study proposes that the extent of loss or gain of GABA<sub<A</sub< receptor function can be elucidated by identifying the specific structural domain impacted by mutation and assessing the variability in receptor structural dynamics. This paves the way for future studies to explore and uncover links between the incidence of a variant in the receptor topology and the severity of the related disease. |
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These conditions are often associated with early-onset seizures, developmental regression, and cognitive impairments. The severity and specific features of these encephalopathies can differ based on the nature of the genetic variant and its impact on GABA<sub<A</sub< receptor function. These variants can lead to dysfunction in GABA<sub<A</sub< receptor-mediated inhibition, resulting in an imbalance between neuronal excitation and inhibition that contributes to the development of seizures. Here, 13 <i<de novo</i< EE-associated <i<GABRB</i< variants, occurring as missense mutations, were analyzed to determine their impact on protein stability and flexibility, channel function, and receptor biogenesis. Our results showed that all mutations studied significantly impact the protein structure, altering protein stability, flexibility, and function to varying degrees. Variants mapped to the GABA-binding domain, coupling zone, and pore domain significantly impact the protein structure, modifying the β+/α− interface of the receptor and altering channel activation and receptor trafficking. Our study proposes that the extent of loss or gain of GABA<sub<A</sub< receptor function can be elucidated by identifying the specific structural domain impacted by mutation and assessing the variability in receptor structural dynamics. This paves the way for future studies to explore and uncover links between the incidence of a variant in the receptor topology and the severity of the related disease.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a"><i<GABRB</i<</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">loss-of-function mutations</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">gain-of-function mutations</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">GABA<sub<A</sub< receptors</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">stability and flexibility of GABA<sub<A</sub< receptors</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">channel gating</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Microbiology</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Ningning Hu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Wangzhen Shen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Robert L. 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