A novel variant in GAS2 is associated with autosomal dominant nonsyndromic hearing impairment in a Chinese family.
GAS2
Apoptosis
Autosomal dominant nonsyndromic hearing loss
Microtubule
Protein degradation
Journal
Human genomics
ISSN: 1479-7364
Titre abrégé: Hum Genomics
Pays: England
ID NLM: 101202210
Informations de publication
Date de publication:
02 Jul 2024
02 Jul 2024
Historique:
received:
24
04
2024
accepted:
27
05
2024
medline:
3
7
2024
pubmed:
3
7
2024
entrez:
3
7
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38956677
doi: 10.1186/s40246-024-00628-2
pii: 10.1186/s40246-024-00628-2
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
73Subventions
Organisme : Social development project of Jiangsu Provincial Key R&D Program
ID : BE2022764
Organisme : National Natural Science Foundation of China
ID : 82171425
Organisme : Scientific Research Foundation for the high-level talents by the Second Affiliated Hospital of Nantong University
ID : YJRCJJ001
Informations de copyright
© 2024. The Author(s).
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