Dataset Information

A novel pore-region mutation, c.887G?>?A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2.

ABSTRACT: Hereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. The KCNQ4 channel belongs to a family of potassium ion channels that play crucial roles in physiology and disease. Mutations in KCNQ4 underlie deafness non-syndromic autosomal dominant 2, a subtype of autosomal dominant, progressive, high-frequency hearing loss.A six-generation Chinese family from Hebei Province with autosomal dominantly inherited, sensorineural, postlingual, progressive hearing loss was enrolled in this study. Mutation screening of 129 genes associated with hearing loss was performed in five family members by next-generation sequencing (NGS). We also carried out variant analysis on DNA from 531 Chinese individuals with normal hearing as controls.This family exhibits postlingual, progressive, symmetrical, bilateral, non-syndromic sensorineural hearing loss. NGS, bioinformatic analysis, and Sanger sequencing confirmed the co-segregation of a novel mutation [c.887G?>?A (p.G296D)] in KCNQ4 with the disease phenotype in this family. This mutation leads to a glycine-to-aspartic acid substitution at position 296 in the pore region of the KCNQ4 channel. This mutation affects a highly conserved glutamic acid. NGS is a highly efficient tool for identifying gene mutations causing heritable disease.Progressive hearing loss is common in individuals with KCNQ4 mutations. NGS together with Sanger sequencing confirmed that the five affected members of this Chinese family inherited a missense mutation, c.887G?>?A (p.G296D), in exon 6 of KCNQ4. Our results increase the number of identified KCNQ4 mutations.

SUBMITTER: Huang B

PROVIDER: S-EPMC5366164 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2.

Huang Bangqing B Liu Yanping Y Gao Xue X Xu Jincao J Dai Pu P Zhu Qingwen Q Yuan Yongyi Y

BMC medical genetics 20170324 1

<h4>Background</h4>Hereditary non-syndromic hearing loss is the most common inherited sensory defect in humans. The KCNQ4 channel belongs to a family of potassium ion channels that play crucial roles in physiology and disease. Mutations in KCNQ4 underlie deafness non-syndromic autosomal dominant 2, a subtype of autosomal dominant, progressive, high-frequency hearing loss.<h4>Methods</h4>A six-generation Chinese family from Hebei Province with autosomal dominantly inherited, sensorineural, postli ...[more]

PMID: 28340560

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Project description: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.

Dataset Information

A novel pore-region mutation, c.887G?>?A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2.

Publications

A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2.

Similar Datasets

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