Identification of the First Single GSDME Exon 8 Structural Variants Associated with Autosomal Dominant Hearing Loss

Mansard, Luke; Vaché, Christel; Bianchi, Julie; Baudoin, Claude; Perthus, Isabelle; Isidor, Bertrand; Blanchet, C.; Baux, David; Kœnig, M.; Kalatzis, Vasiliki; Roux, Anne‐Françoise

doi:10.3390/diagnostics12010207

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…Every pathogenic GSDME mutation identified thus far has been found to cause exon 8 skipping. These variants include disruptions in the consensus splice acceptor site (Bischoff et al, 2004;Chai et al, 2014;Wang et al, 2018;Chen et al, 2020;Yuan et al, 2020;Mansard et al, 2022), the splice donor site (Cheng et al, 2007;Li-Yang et al, 2015), the intronic splicing regulatory elements (Van Laer et al, 1998;Yu et al, 2003;Park et al, 2010;Nishio et al, 2014;Nadol et al, 2015;Booth et al, 2018b;Booth et al, 2020), or exonic splicing regulatory elements (Booth et al, 2018b).…”

Section: Dfna5: a Gain-of-function Splice Alterationmentioning

confidence: 99%

Alternative splicing in shaping the molecular landscape of the cochlea

Kim

Koo²,

Bok³

2023

Front. Cell Dev. Biol.

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The cochlea is a complex organ comprising diverse cell types with highly specialized morphology and function. Until now, the molecular underpinnings of its specializations have mostly been studied from a transcriptional perspective, but accumulating evidence points to post-transcriptional regulation as a major source of molecular diversity. Alternative splicing is one of the most prevalent and well-characterized post-transcriptional regulatory mechanisms. Many molecules important for hearing, such as cadherin 23 or harmonin, undergo alternative splicing to produce functionally distinct isoforms. Some isoforms are expressed specifically in the cochlea, while some show differential expression across the various cochlear cell types and anatomical regions. Clinical phenotypes that arise from mutations affecting specific splice variants testify to the functional relevance of these isoforms. All these clues point to an essential role for alternative splicing in shaping the unique molecular landscape of the cochlea. Although the regulatory mechanisms controlling alternative splicing in the cochlea are poorly characterized, there are animal models with defective splicing regulators that demonstrate the importance of RNA-binding proteins in maintaining cochlear function and cell survival. Recent technological breakthroughs offer exciting prospects for overcoming some of the long-standing hurdles that have complicated the analysis of alternative splicing in the cochlea. Efforts toward this end will help clarify how the remarkable diversity of the cochlear transcriptome is both established and maintained.

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Section: Dfna5: a Gain-of-function Splice Alterationmentioning

confidence: 99%

Alternative splicing in shaping the molecular landscape of the cochlea

Kim

Koo²,

Bok³

2023

Front. Cell Dev. Biol.

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“…11 Since the Dutch study, only a limited number of families with GSDME variants associated with hereditary NSHL have been documented in current scientific literature. [12][13][14][15][16][17][18] Although the age of initial onset varies, ranging from 11 to 50 years, the hearing loss function in these families exhibits similar characteristics. These presentations include progressive hearing loss, with higher frequencies being affected first and the remaining frequencies later; nonsyndromic and sensorineural deafness.…”

Section: Introductionmentioning

confidence: 99%

“…Since the Dutch study, only a limited number of families with GSDME variants associated with hereditary NSHL have been documented in current scientific literature 12–18 . Although the age of initial onset varies, ranging from 11 to 50 years, the hearing loss function in these families exhibits similar characteristics.…”

Section: Introductionmentioning

confidence: 99%

Novel, pathogenic insertion variant of GSDME associates with autosomal dominant hearing loss in a large Chinese pedigree

Cheng,

Li,

Tan

et al. 2023

J Cellular Molecular Medi

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Nonsyndromic hearing loss (NSHL) is a genetically diverse, highly heterogeneous condition characterised by deafness, and Gasdermin E (GSDME) variants have been identified as directly inducing autosomal dominant NSHL. While many NSHL cases associated with GSDME involve the skipping of exon 8, there is another, less understood pathogenic insertion variant specifically found in Chinese pedigrees that causes deafness, known as autosomal dominant 5 (DFNA5) hearing loss. In this study, we recruited a large Chinese pedigree, conducted whole‐exome and Sanger sequencing to serve as a comprehensive clinical examination, and extracted genomic DNA samples for co‐segregation analysis of the members. Conservation and expression analyses for GSDME were also conducted. Our clinical examinations revealed an autosomal dominant phenotype of hearing loss in the family. Genetic analysis identified a novel insertion variant in GSDME exon 8 (GSDME: NM_004403.3: c.1113_1114insGGGGTGCAGCTTACAGGGTGGGTGT: p. P372fs*36). This variant is segregated with the deafness phenotype of this pedigree. The GSDME gene was highly conserved in the different species we analysed, and its mRNA expression was ubiquitously low in different human tissues. In conclusion, we have successfully identified a novel pathogenic insertion variant of GSDME in a Chinese pedigree that causes deafness, shedding light on the genetic basis of hearing loss within this specific family. Our findings expand the spectrum of known variants associated with GSDME‐related deafness and may further support both the underlying gain‐of‐function mechanism and functional associations of GSDME hearing loss variants.

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“…However, the biological function of GSDME and the upstream pathways need to be further investigated. To date, several mutations in GSDME have been reported to cause ADNSHL [7][8][9][10][11][12][13][14]. These reported mutations lead to the skipping of exon 8 at the mRNA level, resulting in a frameshift and producing a prematurely truncated GSDME protein.…”

Section: Introductionmentioning

confidence: 99%

Mutation analysis of the GSDME gene in a Chinese family with non-syndromic hearing loss

Lei

Zhu²,

Wang³

et al. 2022

PLoS ONE

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Background Hearing loss is considered one of the most common sensory nervous system defects, about 60% of which are caused by genetic factors. Mutations in the GSDME gene are responsible for post-lingual, progressive, autosomal dominant hearing loss. This study aimed to characterize the genetic mutations and clinical features of a Chinese GSDME family. Methods After clinical evaluations, high-throughput DNA sequencing was conducted using DNA samples from this family. Sanger sequencing was performed to verify the suspected variants. A detailed genotype and phenotype analysis were carried out. Gene set enrichment analysis (GSEA) was performed to identify the signaling pathway associated with GSDME expression. Results A known hotspot heterozygous splice-site variation (c.991-15_991_13delTTC) was identified and shown to segregate with the hearing loss phenotype in the family. This pathogenic splice-site variant results in skipping of exon 8. GSEA analysis identified changes in regulation of the cell cycle checkpoint, peroxisome, and amino acid metabolism signaling pathways. Conclusions We identified a reported mutation in the GSDME gene. Our findings support the 3 bp deletion (c.991-15_991-13del) was a hotspot variation, and it emerged as an essential contributor to autosomal dominant progressive hearing loss in East Asians. GSDME gene is closely associated with a range of signaling pathways. These characterized findings may provide new evidence for pathogenesis.

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Identification of the First Single GSDME Exon 8 Structural Variants Associated with Autosomal Dominant Hearing Loss

Cited by 7 publications

References 25 publications

Alternative splicing in shaping the molecular landscape of the cochlea

Alternative splicing in shaping the molecular landscape of the cochlea

Novel, pathogenic insertion variant of GSDME associates with autosomal dominant hearing loss in a large Chinese pedigree

Mutation analysis of the GSDME gene in a Chinese family with non-syndromic hearing loss

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