PMC9645625_01
Pure-tone audiometry for affected individuals.. Audiograms were obtained with air conduction with the frequency range of 0.125 kHz to 8 kHz. Symbols "o" and "x" denotes air conduction pure-tone thresholds at different right and left ear frequencies.
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The hearing curves of the affected individuals showed that the low-frequency hearing was less impaired and got progressively worse with age, while the high-frequency hearing was more impaired at the beginning (Fig 2).
Audiological characteristics of GSDME-related hearing loss.. (A) ARTA for patients with pathogenic variants. (B) ATD: Rate of hearing loss deterioration in PTA.
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Table 2). Therefore, we combined the three datasets and calculated the pooled ATD, which ranged from 0.63 to 1.24 dB per year (Fig 3B). ATD growing as the frequency increased. ARTA (Fig 3A) confirms the down-sloping audiometric configuration, which starts as mild at low and mid frequencies and moderates at high frequencies.
Chromatogram of the genomic structure of GSDME and the location of this mutation (c. 991-15_991-13del).. Skipping of exon 8 can truncate the C-terminal domain of mutant GSDME, uncovering the apoptosis-inducing region, leading to apoptosis. On the other hand, caspase-3 can cleave wild-type GSDME to generate an active N-terminal that also forms pores in the plasma membrane and permeabilizes it.
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ADNSHL, the mutation in the GSDME gene was found in the proband. A 3-bp deletion (c.991-15_991-13delTTC, NM_004403) was identified in intron 7 (Fig 4). Sequencing analysis of the patient's RT-PCR product revealed a deletion of the exon 8 sequence (exon skipping) in his mutant transcript, resulting in a direct linkage between exon 7 and exon 9 sequences (Fig 4).
Significant KEGG enrichment plot from GSEA analysis.. A: The top three upregulated pathways; B: The top three downregulated pathways.
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WT group, our GSEA results (Fig 5) indicated that GSDME knockout upregulated acute myeloid leukemia, colorectal cancer, JAK/STAT signaling pathway, and hedgehog signaling pathway. We also found a significant downregulation in 11 signaling pathways involved in the peroxisome, valine leucine and isoleucine degradation, porphyrin and chlorophyll metabolism, pyruvate metabolism, selenoamino acid metabolism, base excision repair, propanoate metabolism, glycine serine and threonine metabolism, DNA replication, lysine degradation, and pyrimidine metabolism.