Meniere's Disease Neuroscience Research Program, Faculty of Medicine and Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Rm 611024, Level 11 Kolling Institute | 10 Westbourne St, St Leonards, Sydney, NSW, 2064, Australia.
Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, Ibs.Granada, Universidad de Granada, Granada, Spain.
Clin Epigenetics. 2024 Jul 5;16(1):88. doi: 10.1186/s13148-024-01697-9.
DNA methylation may have a regulatory role in monogenic sensorineural hearing loss and complex, polygenic phenotypic forms of hearing loss, including age-related hearing impairment or Meniere disease. The purpose of this systematic review is to critically assess the evidence supporting a functional role of DNA methylation in phenotypes associated with hearing loss.
The search strategy yielded a total of 661 articles. After quality assessment, 25 records were selected (12 human DNA methylation studies, 5 experimental animal studies and 8 studies reporting mutations in the DNMT1 gene). Although some methylation studies reported significant differences in CpG methylation in diverse gene promoters associated with complex hearing loss phenotypes (ARHI, otosclerosis, MD), only one study included a replication cohort that supported a regulatory role for CpG methylation in the genes TCF25 and POLE in ARHI. Conversely, several studies have independently confirmed pathogenic mutations within exon 21 of the DNMT1 gene, which encodes the DNA (cytosine-5)-methyltransferase 1 enzyme. This methylation enzyme is strongly associated with a rare disease defined by autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Of note, rare variants in DNMT1 and DNMT3A genes have also been reported in noise-induced hearing loss.
Evidence supporting a functional role for DNA methylation in hearing loss is limited to few genes in complex disorders such as ARHI. Mutations in the DNMT1 gene are associated with ADCA-DN, suggesting the CpG methylation in hearing loss genes deserves further attention in hearing research.
DNA 甲基化可能在单基因感觉神经性听力损失和复杂的多基因表型听力损失中具有调节作用，包括与年龄相关的听力损失或梅尼埃病。本系统评价的目的是批判性地评估支持 DNA 甲基化在与听力损失相关表型中具有功能作用的证据。
搜索策略共产生了 661 篇文章。经过质量评估，选择了 25 篇记录（12 项人类 DNA 甲基化研究、5 项实验动物研究和 8 项报告 DNMT1 基因突变的研究）。尽管一些甲基化研究报告了与复杂听力损失表型（ARHI、耳硬化症、MD）相关的不同基因启动子中 CpG 甲基化的显著差异，但只有一项研究包括了一个复制队列，该队列支持 CpG 甲基化在 ARHI 基因 TCF25 和 POLE 中的调节作用。相反，几项研究独立证实了 DNMT1 基因外显子 21 内的致病突变，该基因编码 DNA（胞嘧啶-5）-甲基转移酶 1 酶。这种甲基化酶与一种由常染色体显性小脑共济失调、耳聋和嗜睡（ADCA-DN）定义的罕见疾病强烈相关。值得注意的是，DNMT1 和 DNMT3A 基因中的罕见变异也已在噪声性听力损失中报道。
支持 DNA 甲基化在听力损失中具有功能作用的证据仅限于 ARHI 等复杂疾病中的少数基因。DNMT1 基因的突变与 ADCA-DN 相关，这表明听力损失基因中的 CpG 甲基化值得在听力研究中进一步关注。
