Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss.

Hearing loss is considered one of the most common sensory neurological defects, with approximately 60% of cases attributed to genetic factors. Human pathogenic variants in the TBC1D24 gene are associated with various clinical phenotypes, including dominant nonsyndromic hearing loss DFNA65, characterized by progressive hearing loss after the development of language. This study provides an in-depth analysis of the causative gene and mutations in a family with hereditary deafness. We recruited a three-generation family with autosomal dominant nonsyndromic hearing loss (ADNSHL) and conducted detailed medical histories and relevant examinations. Next-generation sequencing (NGS) was used to identify genetic variants in the proband, which were then validated using Sanger sequencing. Multiple computational software tools were employed to predict the impact of the variant on the function and structure of the TBC1D24 protein. A series of bioinformatics tools were applied to determine the conservation characteristics of the sequence, establish a three-dimensional structural model, and investigate changes in molecular dynamics. A detailed genotype and phenotype analysis were carried out. The family exhibited autosomal dominant, progressive, postlingual, and nonsyndromic sensorineural hearing loss. A novel heterozygous variant, c.1459C>T (p.His487Tyr), in the TBC1D24 gene was identified and confirmed to be associated with the hearing loss phenotype in this family. Conservation analysis revealed high conservation of the amino acid affected by this variant across different species. The mutant protein showed alterations in thermodynamic stability, elasticity, and conformational dynamics. Molecular dynamics simulations indicated changes in RMSD, RMSF, Rg, and SASA of the mutant structure. We computed the onset age of non-syndromic hearing loss associated with mutations in the TBC1D24 gene and identified variations in the hearing progression time and annual threshold deterioration across different frequencies. The identification of a new variant associated with rare autosomal dominant nonsyndromic hereditary hearing loss in this family broadens the range of mutations in the TBC1D24 gene. This variant has the potential to influence the interaction between the TLDc domain and TBC domain, thereby affecting the protein's biological function.

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

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.

[Expression of inhibitor of apoptosis protein XIAP in laryngeal carcinoma and its clinicopathological significance].

OBJECTIVE: To investigate the expression of X-chromosome-linked inhibitors of apoptosis (XIAP) XIAP in laryngeal squamous carcinomas and the relationship between the expression of XIAP and clinical biological behaviors. METHOD: Paraffin-embedded tissue specimens used for this study were obtained from 50 patients with laryngeal squamous carcinomas. The patients had received neither chemotherapy nor radiation therapy before tumor resection. Using immunohistochemical staining for the paraffin sections (SP methods), we examine the expression of XIAP protein in laryngeal squamous carcinomas and normal laryngeal tissues, investigate the connection of the XIAP expression with the clinicopathological parameters. RESULT: The expression of XIAP protein was observed mainly in the cytoplasm and nucleus. The staining color was dark brown. The expression of XIAP is remarkably higher in laryngeal squamous carcinomas than that in normal laryngeal tissue specimens. The statistical analysis revealed that in laryngeal squamous carcinomas XIAP expression had no relationship with the elements such as age, sex, smoking history, tumor site and lymph node metastases. However, there is significant correlation between XIAP expression and tumor clinical stage, T stage and pathological stage (P < 0.05). CONCLUSION: XIAP is expressed higher in laryngeal squamous carcinomas than in normal laryngeal tissues. The level of XIAP expression is associated with tumor clinicopathological characteristics in laryngeal squamous carcinomas. While tumor growth and malignancy increased, the expression of XIAP was up-regulated in laryngeal squamous carcinomas. It may play a role of anti-apoptosis in the process of carcinogenesis and development in laryngeal squamous carcinomas.

[Expression of Survivin and its correlation with tumor angiogenesis in differentiated thyroid carcinomas].

OBJECTIVE: To identify the expression of Survivin and its relationship with tumor angiogenesis in differentiated thyroid carcinomas. METHOD: The expression of Survivin, VEGF and MVD were detected by immuno-histochemical staining (SP methods) in 47 differentiated thyroid carcinomas, 10 thyroid adenoma and 10 normal thyroid tissues and their content were measured by pathological image analysis system. RESULT: The expression of Survivin and VEGF in differentiated thyroid carcinomas was 46.8% and 61.7%, respectively. No expression of Survivin was detected in thyroid adenoma and normal thyroid tissues. The expression of Survivin was significantly correlated with the expression of VEGF and MVD in differentiated thyroid carcinomas. The expression of Survivin was significantly associated with clinical stages, tumor complete capsule and lymph node metastasis. CONCLUSION: The up-regulation of Survivin expression and its close relationship with angiogenesis may play an important role in carcinogenesis and development of differentiated thyroid carcinomas.