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Abstract：
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：DNA甲基化可能在单基因感音神经性听力损失和复合体中起调节作用，听力损失的多基因表型形式，包括年龄相关的听力障碍或梅尼埃病。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的表型中的功能作用的证据。
结果：搜索策略共产生661篇文章。经过质量评估，选择了25条记录(12项人类DNA甲基化研究，5个实验动物研究和8个报告DNMT1基因突变的研究)。尽管一些甲基化研究报道了与复杂听力损失表型相关的不同基因启动子中CpG甲基化的显着差异（ARHI，耳硬化症,MD),只有一项研究包括一个复制队列,该队列支持在ARHI中TCF25和POLE基因中CpG甲基化的调节作用.相反，几项研究独立证实了DNMT1基因外显子21内的致病性突变，其编码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遗传的小脑共济失调定义的罕见疾病密切相关。耳聋和嗜睡症（ADCA-DN）。值得注意的是，DNMT1和DNMT3A基因的罕见变异也被报道在噪声诱导的听力损失中。
结论：支持DNA甲基化在听力损失中的功能作用的证据仅限于ARHI等复杂疾病中的少数基因。DNMT1基因突变与ADCA-DN,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。
结果：搜索策略共产生661篇文章。经过质量评估，选择了25条记录(12项人类DNA甲基化研究，5个实验动物研究和8个报告DNMT1基因突变的研究)。尽管一些甲基化研究报道了与复杂听力损失表型相关的不同基因启动子中CpG甲基化的显着差异（ARHI，耳硬化症,MD),只有一项研究包括一个复制队列,该队列支持在ARHI中TCF25和POLE基因中CpG甲基化的调节作用.相反，几项研究独立证实了DNMT1基因外显子21内的致病性突变，其编码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遗传的小脑共济失调定义的罕见疾病密切相关。耳聋和嗜睡症（ADCA-DN）。值得注意的是，DNMT1和DNMT3A基因的罕见变异也被报道在噪声诱导的听力损失中。
结论：支持DNA甲基化在听力损失中的功能作用的证据仅限于ARHI等复杂疾病中的少数基因。DNMT1基因突变与ADCA-DN,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。
