DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?

Booth, Kevin T.; Azaiez, Héla; Smith, Richard J.H.

doi:10.3390/ijms21113951

Cited by 10 publications

(4 citation statements)

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“…this study, a GSDME mutation (c.991-15_991-13delTTC) was detected in the family and reported in several East Asian families [9][10][11]18,19]. These findings suggest that GSDME mutations may be ethnically specific and that the c.991-15_991-13del mutation may be a more recurrent causative factor in autosomal dominant hearing loss in East Asians.…”

Section: Plos Onesupporting

confidence: 59%

“…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%

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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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Section: Plos Onesupporting

confidence: 59%

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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“…All DFNA5 mutations reported to date are splice-site variants leading to the skipping of exon 8 (Table 1; Van Laer et al, 1998;Yu et al, 2003;Bischoff et al, 2004;Cheng et al, 2007;Park et al, 2010;Chai et al, 2014;Nishio et al, 2014;Li-Yang et al, 2015;Nadol et al, 2015;Booth et al, 2018;Wang et al, 2018;Booth et al, 2020). The common phenotype in families with a DFNA5 mutation is bilateral, symmetrical, late-onset hearing loss, starting at high frequencies and ultimately progressing to involve all frequencies, with the severity ranging from moderate to profound.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Novel Heterozygous DFNA5 Splicing Variant Responsible for Autosomal Dominant Non-syndromic Hearing Loss in a Chinese Family

Chen

Jia

et al. 2020

Front. Genet.

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Autosomal dominant non-syndromic hearing loss (ADNSHL) has a broad phenotypic spectrum which includes bilateral, symmetrical, and high-frequency sensorineural hearing loss, that eventually progresses into hearing loss at all frequencies. Several genetic variations have been identified as causal factors underlying deafness, autosomal dominant 5 (DFNA5) gene-related hearing loss. Here, we report a novel mutation (c.991-1G > C) in DFNA5, which co-segregated with late-onset ADNSHL in a Chinese family and was identified via exome sequencing and Sanger sequencing of DNA from peripheral blood of the family members. Further sequencing of cDNA derived from peripheral blood mRNA revealed that the c.991-1G >C mutation led to the skipping of exon 8, which is a known pathogenic mechanism for DFNA5-related hearing loss.

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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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DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?

Cited by 10 publications

References 29 publications

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

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

Case Report: Novel Heterozygous DFNA5 Splicing Variant Responsible for Autosomal Dominant Non-syndromic Hearing Loss in a Chinese Family

Alternative splicing in shaping the molecular landscape of the cochlea

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