A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family

Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unkno...
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Gespeichert in:

Autor*in:	Zhang, Luping [verfasserIn] Zheng, Danya [verfasserIn] Xu, Lian [verfasserIn] Wang, Han [verfasserIn] Zhang, Shuqiang [verfasserIn] Shi, Jianhua [verfasserIn] Jin, Nana [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	Autosomal dominant nonsyndromic hearing loss Protein degradation Microtubule Apoptosis

Anmerkung:	© The Author(s) 2024

Übergeordnetes Werk:	Enthalten in: Human genomics - BioMed Central, 2003, 18(2024), 1 vom: 02. Juli
Übergeordnetes Werk:	volume:18 ; year:2024 ; number:1 ; day:02 ; month:07

Links:	Volltext

DOI / URN:	10.1186/s40246-024-00628-2

Katalog-ID:	SPR056440863

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520			\|a Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss.
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allfields	10.1186/s40246-024-00628-2 doi (DE-627)SPR056440863 (SPR)s40246-024-00628-2-e DE-627 ger DE-627 rakwb eng 610 570 VZ Zhang, Luping verfasserin (orcid)0000-0003-1745-081X aut A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss. Autosomal dominant nonsyndromic hearing loss (dpeaa)DE-He213 Protein degradation (dpeaa)DE-He213 Microtubule (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zheng, Danya verfasserin aut Xu, Lian verfasserin aut Wang, Han verfasserin aut Zhang, Shuqiang verfasserin aut Shi, Jianhua verfasserin aut Jin, Nana verfasserin aut Enthalten in Human genomics BioMed Central, 2003 18(2024), 1 vom: 02. Juli (DE-627)388549408 (DE-600)2147618-4 1479-7364 nnns volume:18 year:2024 number:1 day:02 month:07 https://dx.doi.org/10.1186/s40246-024-00628-2 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 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_2003 GBV_ILN_2014 GBV_ILN_2153 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 18 2024 1 02 07
spelling	10.1186/s40246-024-00628-2 doi (DE-627)SPR056440863 (SPR)s40246-024-00628-2-e DE-627 ger DE-627 rakwb eng 610 570 VZ Zhang, Luping verfasserin (orcid)0000-0003-1745-081X aut A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss. Autosomal dominant nonsyndromic hearing loss (dpeaa)DE-He213 Protein degradation (dpeaa)DE-He213 Microtubule (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zheng, Danya verfasserin aut Xu, Lian verfasserin aut Wang, Han verfasserin aut Zhang, Shuqiang verfasserin aut Shi, Jianhua verfasserin aut Jin, Nana verfasserin aut Enthalten in Human genomics BioMed Central, 2003 18(2024), 1 vom: 02. Juli (DE-627)388549408 (DE-600)2147618-4 1479-7364 nnns volume:18 year:2024 number:1 day:02 month:07 https://dx.doi.org/10.1186/s40246-024-00628-2 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 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_2003 GBV_ILN_2014 GBV_ILN_2153 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 18 2024 1 02 07
allfields_unstemmed	10.1186/s40246-024-00628-2 doi (DE-627)SPR056440863 (SPR)s40246-024-00628-2-e DE-627 ger DE-627 rakwb eng 610 570 VZ Zhang, Luping verfasserin (orcid)0000-0003-1745-081X aut A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss. Autosomal dominant nonsyndromic hearing loss (dpeaa)DE-He213 Protein degradation (dpeaa)DE-He213 Microtubule (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zheng, Danya verfasserin aut Xu, Lian verfasserin aut Wang, Han verfasserin aut Zhang, Shuqiang verfasserin aut Shi, Jianhua verfasserin aut Jin, Nana verfasserin aut Enthalten in Human genomics BioMed Central, 2003 18(2024), 1 vom: 02. Juli (DE-627)388549408 (DE-600)2147618-4 1479-7364 nnns volume:18 year:2024 number:1 day:02 month:07 https://dx.doi.org/10.1186/s40246-024-00628-2 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 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_2003 GBV_ILN_2014 GBV_ILN_2153 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 18 2024 1 02 07
allfieldsGer	10.1186/s40246-024-00628-2 doi (DE-627)SPR056440863 (SPR)s40246-024-00628-2-e DE-627 ger DE-627 rakwb eng 610 570 VZ Zhang, Luping verfasserin (orcid)0000-0003-1745-081X aut A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss. Autosomal dominant nonsyndromic hearing loss (dpeaa)DE-He213 Protein degradation (dpeaa)DE-He213 Microtubule (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zheng, Danya verfasserin aut Xu, Lian verfasserin aut Wang, Han verfasserin aut Zhang, Shuqiang verfasserin aut Shi, Jianhua verfasserin aut Jin, Nana verfasserin aut Enthalten in Human genomics BioMed Central, 2003 18(2024), 1 vom: 02. Juli (DE-627)388549408 (DE-600)2147618-4 1479-7364 nnns volume:18 year:2024 number:1 day:02 month:07 https://dx.doi.org/10.1186/s40246-024-00628-2 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 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_2003 GBV_ILN_2014 GBV_ILN_2153 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 18 2024 1 02 07
allfieldsSound	10.1186/s40246-024-00628-2 doi (DE-627)SPR056440863 (SPR)s40246-024-00628-2-e DE-627 ger DE-627 rakwb eng 610 570 VZ Zhang, Luping verfasserin (orcid)0000-0003-1745-081X aut A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss. Autosomal dominant nonsyndromic hearing loss (dpeaa)DE-He213 Protein degradation (dpeaa)DE-He213 Microtubule (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213 Zheng, Danya verfasserin aut Xu, Lian verfasserin aut Wang, Han verfasserin aut Zhang, Shuqiang verfasserin aut Shi, Jianhua verfasserin aut Jin, Nana verfasserin aut Enthalten in Human genomics BioMed Central, 2003 18(2024), 1 vom: 02. Juli (DE-627)388549408 (DE-600)2147618-4 1479-7364 nnns volume:18 year:2024 number:1 day:02 month:07 https://dx.doi.org/10.1186/s40246-024-00628-2 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 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_2003 GBV_ILN_2014 GBV_ILN_2153 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 18 2024 1 02 07
language	English
source	Enthalten in Human genomics 18(2024), 1 vom: 02. Juli volume:18 year:2024 number:1 day:02 month:07
sourceStr	Enthalten in Human genomics 18(2024), 1 vom: 02. Juli volume:18 year:2024 number:1 day:02 month:07
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institution	findex.gbv.de
topic_facet	Autosomal dominant nonsyndromic hearing loss Protein degradation Microtubule Apoptosis
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container_title	Human genomics
authorswithroles_txt_mv	Zhang, Luping @@aut@@ Zheng, Danya @@aut@@ Xu, Lian @@aut@@ Wang, Han @@aut@@ Zhang, Shuqiang @@aut@@ Shi, Jianhua @@aut@@ Jin, Nana @@aut@@
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author	Zhang, Luping
spellingShingle	Zhang, Luping ddc 610 misc Autosomal dominant nonsyndromic hearing loss misc Protein degradation misc Microtubule misc Apoptosis A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family
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topic_title	610 570 VZ A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family Autosomal dominant nonsyndromic hearing loss (dpeaa)DE-He213 Protein degradation (dpeaa)DE-He213 Microtubule (dpeaa)DE-He213 Apoptosis (dpeaa)DE-He213
topic	ddc 610 misc Autosomal dominant nonsyndromic hearing loss misc Protein degradation misc Microtubule misc Apoptosis
topic_unstemmed	ddc 610 misc Autosomal dominant nonsyndromic hearing loss misc Protein degradation misc Microtubule misc Apoptosis
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title	A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family
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title_full	A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family
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title_sort	a novel variant in gas2 is associated with autosomal dominant nonsyndromic hearing impairment in a chinese family
title_auth	A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family
abstract	Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss. © The Author(s) 2024
abstractGer	Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss. © The Author(s) 2024
abstract_unstemmed	Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss. © The Author(s) 2024
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title_short	A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family
url	https://dx.doi.org/10.1186/s40246-024-00628-2
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author2	Zheng, Danya Xu, Lian Wang, Han Zhang, Shuqiang Shi, Jianhua Jin, Nana
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up_date	2024-07-10T07:09:50.053Z
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Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. 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A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family

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