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

Gespeichert in:

Autor*in:	Ciria C. Hernandez [verfasserIn] Ningning Hu [verfasserIn] Wangzhen Shen [verfasserIn] Robert L. Macdonald [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	loss-of-function mutations gain-of-function mutations GABA stability and flexibility of GABA channel gating

Übergeordnetes Werk:	In: Biomolecules - MDPI AG, 2013, 13(2023), 12, p 1790
Übergeordnetes Werk:	volume:13 ; year:2023 ; number:12, p 1790

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/biom13121790

Katalog-ID:	DOAJ09890406X

Internformat


LEADER	01000naa a22002652 4500
001	DOAJ09890406X
003	DE-627
005	20240414004443.0
007	cr uuu---uuuuu
008	240414s2023 xx \|\|\|\|\|o 00\| \|\|eng c
024	7		\|a 10.3390/biom13121790 \|2 doi
035			\|a (DE-627)DOAJ09890406X
035			\|a (DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f
040			\|a DE-627 \|b ger \|c DE-627 \|e rakwb
041			\|a eng
050		0	\|a QR1-502
100	0		\|a Ciria C. Hernandez \|e verfasserin \|4 aut
245	1	0	\|a Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects
264		1	\|c 2023
336			\|a Text \|b txt \|2 rdacontent
337			\|a Computermedien \|b c \|2 rdamedia
338			\|a Online-Ressource \|b cr \|2 rdacarrier
520			\|a 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.
650		4	\|a <i<GABRB</i<
650		4	\|a loss-of-function mutations
650		4	\|a gain-of-function mutations
650		4	\|a GABA<sub<A</sub< receptors
650		4	\|a stability and flexibility of GABA<sub<A</sub< receptors
650		4	\|a channel gating
653		0	\|a Microbiology
700	0		\|a Ningning Hu \|e verfasserin \|4 aut
700	0		\|a Wangzhen Shen \|e verfasserin \|4 aut
700	0		\|a Robert L. Macdonald \|e verfasserin \|4 aut
773	0	8	\|i In \|t Biomolecules \|d MDPI AG, 2013 \|g 13(2023), 12, p 1790 \|w (DE-627)735688915 \|w (DE-600)2701262-1 \|x 2218273X \|7 nnns
773	1	8	\|g volume:13 \|g year:2023 \|g number:12, p 1790
856	4	0	\|u https://doi.org/10.3390/biom13121790 \|z kostenfrei
856	4	0	\|u https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f \|z kostenfrei
856	4	0	\|u https://www.mdpi.com/2218-273X/13/12/1790 \|z kostenfrei
856	4	2	\|u https://doaj.org/toc/2218-273X \|y Journal toc \|z kostenfrei
912			\|a GBV_USEFLAG_A
912			\|a SYSFLAG_A
912			\|a GBV_DOAJ
912			\|a GBV_ILN_20
912			\|a GBV_ILN_22
912			\|a GBV_ILN_23
912			\|a GBV_ILN_24
912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_65
912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_95
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_151
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_206
912			\|a GBV_ILN_213
912			\|a GBV_ILN_230
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_602
912			\|a GBV_ILN_2005
912			\|a GBV_ILN_2009
912			\|a GBV_ILN_2011
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2055
912			\|a GBV_ILN_2111
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4367
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 13 \|j 2023 \|e 12, p 1790

Indexfelder

author_variant	c c h cch n h nh w s ws r l m rlm
matchkey_str	article:2218273X:2023----::plpiecpaoahiaritutrlainshrcmogt
hierarchy_sort_str	2023
callnumber-subject-code	QR
publishDate	2023
allfields	10.3390/biom13121790 doi (DE-627)DOAJ09890406X (DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f DE-627 ger DE-627 rakwb eng QR1-502 Ciria C. Hernandez verfasserin aut Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. <i<GABRB</i< loss-of-function mutations gain-of-function mutations GABA<sub<A</sub< receptors stability and flexibility of GABA<sub<A</sub< receptors channel gating Microbiology Ningning Hu verfasserin aut Wangzhen Shen verfasserin aut Robert L. Macdonald verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 12, p 1790 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:12, p 1790 https://doi.org/10.3390/biom13121790 kostenfrei https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f kostenfrei https://www.mdpi.com/2218-273X/13/12/1790 kostenfrei https://doaj.org/toc/2218-273X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 12, p 1790
spelling	10.3390/biom13121790 doi (DE-627)DOAJ09890406X (DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f DE-627 ger DE-627 rakwb eng QR1-502 Ciria C. Hernandez verfasserin aut Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. <i<GABRB</i< loss-of-function mutations gain-of-function mutations GABA<sub<A</sub< receptors stability and flexibility of GABA<sub<A</sub< receptors channel gating Microbiology Ningning Hu verfasserin aut Wangzhen Shen verfasserin aut Robert L. Macdonald verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 12, p 1790 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:12, p 1790 https://doi.org/10.3390/biom13121790 kostenfrei https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f kostenfrei https://www.mdpi.com/2218-273X/13/12/1790 kostenfrei https://doaj.org/toc/2218-273X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 12, p 1790
allfields_unstemmed	10.3390/biom13121790 doi (DE-627)DOAJ09890406X (DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f DE-627 ger DE-627 rakwb eng QR1-502 Ciria C. Hernandez verfasserin aut Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. <i<GABRB</i< loss-of-function mutations gain-of-function mutations GABA<sub<A</sub< receptors stability and flexibility of GABA<sub<A</sub< receptors channel gating Microbiology Ningning Hu verfasserin aut Wangzhen Shen verfasserin aut Robert L. Macdonald verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 12, p 1790 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:12, p 1790 https://doi.org/10.3390/biom13121790 kostenfrei https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f kostenfrei https://www.mdpi.com/2218-273X/13/12/1790 kostenfrei https://doaj.org/toc/2218-273X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 12, p 1790
allfieldsGer	10.3390/biom13121790 doi (DE-627)DOAJ09890406X (DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f DE-627 ger DE-627 rakwb eng QR1-502 Ciria C. Hernandez verfasserin aut Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. <i<GABRB</i< loss-of-function mutations gain-of-function mutations GABA<sub<A</sub< receptors stability and flexibility of GABA<sub<A</sub< receptors channel gating Microbiology Ningning Hu verfasserin aut Wangzhen Shen verfasserin aut Robert L. Macdonald verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 12, p 1790 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:12, p 1790 https://doi.org/10.3390/biom13121790 kostenfrei https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f kostenfrei https://www.mdpi.com/2218-273X/13/12/1790 kostenfrei https://doaj.org/toc/2218-273X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 12, p 1790
allfieldsSound	10.3390/biom13121790 doi (DE-627)DOAJ09890406X (DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f DE-627 ger DE-627 rakwb eng QR1-502 Ciria C. Hernandez verfasserin aut Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. <i<GABRB</i< loss-of-function mutations gain-of-function mutations GABA<sub<A</sub< receptors stability and flexibility of GABA<sub<A</sub< receptors channel gating Microbiology Ningning Hu verfasserin aut Wangzhen Shen verfasserin aut Robert L. Macdonald verfasserin aut In Biomolecules MDPI AG, 2013 13(2023), 12, p 1790 (DE-627)735688915 (DE-600)2701262-1 2218273X nnns volume:13 year:2023 number:12, p 1790 https://doi.org/10.3390/biom13121790 kostenfrei https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f kostenfrei https://www.mdpi.com/2218-273X/13/12/1790 kostenfrei https://doaj.org/toc/2218-273X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023 12, p 1790
language	English
source	In Biomolecules 13(2023), 12, p 1790 volume:13 year:2023 number:12, p 1790
sourceStr	In Biomolecules 13(2023), 12, p 1790 volume:13 year:2023 number:12, p 1790
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	<i<GABRB</i< loss-of-function mutations gain-of-function mutations GABA<sub<A</sub< receptors stability and flexibility of GABA<sub<A</sub< receptors channel gating Microbiology
isfreeaccess_bool	true
container_title	Biomolecules
authorswithroles_txt_mv	Ciria C. Hernandez @@aut@@ Ningning Hu @@aut@@ Wangzhen Shen @@aut@@ Robert L. Macdonald @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	735688915
id	DOAJ09890406X
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">DOAJ09890406X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240414004443.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240414s2023 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/biom13121790</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ09890406X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QR1-502</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Ciria C. Hernandez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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.</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. Macdonald</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Biomolecules</subfield><subfield code="d">MDPI AG, 2013</subfield><subfield code="g">13(2023), 12, p 1790</subfield><subfield code="w">(DE-627)735688915</subfield><subfield code="w">(DE-600)2701262-1</subfield><subfield code="x">2218273X</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:13</subfield><subfield code="g">year:2023</subfield><subfield code="g">number:12, p 1790</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3390/biom13121790</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://www.mdpi.com/2218-273X/13/12/1790</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/2218-273X</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">13</subfield><subfield code="j">2023</subfield><subfield code="e">12, p 1790</subfield></datafield></record></collection>
callnumber-first	Q - Science
author	Ciria C. Hernandez
spellingShingle	Ciria C. Hernandez misc QR1-502 misc <i<GABRB</i< misc loss-of-function mutations misc gain-of-function mutations misc GABA<sub<A</sub< receptors misc stability and flexibility of GABA<sub<A</sub< receptors misc channel gating misc Microbiology Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects
authorStr	Ciria C. Hernandez
ppnlink_with_tag_str_mv	@@773@@(DE-627)735688915
format	electronic Article
delete_txt_mv	keep
author_role	aut aut aut aut
collection	DOAJ
remote_str	true
callnumber-label	QR1-502
illustrated	Not Illustrated
issn	2218273X
topic_title	QR1-502 Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects <i<GABRB</i< loss-of-function mutations gain-of-function mutations GABA<sub<A</sub< receptors stability and flexibility of GABA<sub<A</sub< receptors channel gating
topic	misc QR1-502 misc <i<GABRB</i< misc loss-of-function mutations misc gain-of-function mutations misc GABA<sub<A</sub< receptors misc stability and flexibility of GABA<sub<A</sub< receptors misc channel gating misc Microbiology
topic_unstemmed	misc QR1-502 misc <i<GABRB</i< misc loss-of-function mutations misc gain-of-function mutations misc GABA<sub<A</sub< receptors misc stability and flexibility of GABA<sub<A</sub< receptors misc channel gating misc Microbiology
topic_browse	misc QR1-502 misc <i<GABRB</i< misc loss-of-function mutations misc gain-of-function mutations misc GABA<sub<A</sub< receptors misc stability and flexibility of GABA<sub<A</sub< receptors misc channel gating misc Microbiology
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
format_main_str_mv	Text Zeitschrift/Artikel
carriertype_str_mv	cr
hierarchy_parent_title	Biomolecules
hierarchy_parent_id	735688915
hierarchy_top_title	Biomolecules
isfreeaccess_txt	true
familylinks_str_mv	(DE-627)735688915 (DE-600)2701262-1
title	Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects
ctrlnum	(DE-627)DOAJ09890406X (DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f
title_full	Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects
author_sort	Ciria C. Hernandez
journal	Biomolecules
journalStr	Biomolecules
callnumber-first-code	Q
lang_code	eng
isOA_bool	true
recordtype	marc
publishDateSort	2023
contenttype_str_mv	txt
author_browse	Ciria C. Hernandez Ningning Hu Wangzhen Shen Robert L. Macdonald
container_volume	13
class	QR1-502
format_se	Elektronische Aufsätze
author-letter	Ciria C. Hernandez
doi_str_mv	10.3390/biom13121790
author2-role	verfasserin
title_sort	epileptic encephalopathy <i<gabrb</i< structural variants share common gating and trafficking defects
callnumber	QR1-502
title_auth	Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects
abstract	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.
abstract_unstemmed	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.
collection_details	GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700
container_issue	12, p 1790
title_short	Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects
url	https://doi.org/10.3390/biom13121790 https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f https://www.mdpi.com/2218-273X/13/12/1790 https://doaj.org/toc/2218-273X
remote_bool	true
author2	Ningning Hu Wangzhen Shen Robert L. Macdonald
author2Str	Ningning Hu Wangzhen Shen Robert L. Macdonald
ppnlink	735688915
callnumber-subject	QR - Microbiology
mediatype_str_mv	c
isOA_txt	true
hochschulschrift_bool	false
doi_str	10.3390/biom13121790
callnumber-a	QR1-502
up_date	2024-07-03T19:53:51.070Z
_version_	1803588920748802048
fullrecord_marcxml	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">DOAJ09890406X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240414004443.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240414s2023 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.3390/biom13121790</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ09890406X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ9a0837e3da4f4e31a92284985a43ac8f</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QR1-502</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Ciria C. Hernandez</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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.</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. Macdonald</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">In</subfield><subfield code="t">Biomolecules</subfield><subfield code="d">MDPI AG, 2013</subfield><subfield code="g">13(2023), 12, p 1790</subfield><subfield code="w">(DE-627)735688915</subfield><subfield code="w">(DE-600)2701262-1</subfield><subfield code="x">2218273X</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:13</subfield><subfield code="g">year:2023</subfield><subfield code="g">number:12, p 1790</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.3390/biom13121790</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doaj.org/article/9a0837e3da4f4e31a92284985a43ac8f</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://www.mdpi.com/2218-273X/13/12/1790</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="856" ind1="4" ind2="2"><subfield code="u">https://doaj.org/toc/2218-273X</subfield><subfield code="y">Journal toc</subfield><subfield code="z">kostenfrei</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_DOAJ</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_206</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2009</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2011</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2055</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2111</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4012</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4112</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4126</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4249</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4305</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4306</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4313</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4322</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4324</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4325</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4338</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4367</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4700</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">13</subfield><subfield code="j">2023</subfield><subfield code="e">12, p 1790</subfield></datafield></record></collection>
score	7.400567

Nicht das Richtige dabei?

Schreiben Sie uns!

Epileptic Encephalopathy <i<GABRB</i< Structural Variants Share Common Gating and Trafficking Defects

Nicht das Richtige dabei?

Zugang & Verfügbarkeit

Vorhandene Bände

Nicht das Richtige dabei?