Hunter Genetics, Waratah, NSW 2298, Australia.
School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW 2308, Australia.
Genes (Basel). 2024 Sep 25;15(10):1243. doi: 10.3390/genes15101243.
The role of microRNAs (miRNAs) in the pathogenesis of rare genetic disorders has been gradually discovered. MiRNAs, a class of small non-coding RNAs, regulate gene expression by silencing target messenger RNAs (mRNAs). Their biogenesis involves transcription into primary miRNA (pri-miRNA), processing by the DROSHA-DGCR8 (DiGeorge syndrome critical region 8) complex, exportation to the cytoplasm, and further processing by DICER to generate mature miRNAs. These mature miRNAs are incorporated into the RNA-induced silencing complex (RISC), where they modulate gene expression.
METHODS/RESULTS: The dysregulation of miRNAs is implicated in various Mendelian disorders and familial diseases, including DICER1 syndrome, neurodevelopmental disorders (NDDs), and conditions linked to mutations in miRNA-binding sites. We summarized a few mechanisms how miRNA processing and regulation abnormalities lead to rare genetic disorders. Examples of such genetic diseases include hearing loss associated with mutations, eye disorders linked to mutations, and skeletal dysplasia involving mutations.
Understanding these molecular mechanisms is crucial, as miRNA dysregulation is a key factor in the pathogenesis of these conditions, offering significant potential for the diagnosis and potential therapeutic intervention.
微小 RNA（miRNA）在罕见遗传疾病发病机制中的作用逐渐被发现。miRNA 是一类小的非编码 RNA，通过沉默靶信使 RNA（mRNA）来调节基因表达。它们的生物发生包括转录为初级 miRNA（pri-miRNA）、由 DROSHA-DGCR8（DiGeorge 综合征关键区域 8）复合物进行加工、输出到细胞质，并进一步由 DICER 加工生成成熟 miRNA。这些成熟 miRNA 被整合到 RNA 诱导的沉默复合物（RISC）中，在那里它们调节基因表达。
方法/结果：miRNA 的失调与各种孟德尔疾病和家族性疾病有关，包括 DICER1 综合征、神经发育障碍（NDD）和与 miRNA 结合位点突变相关的疾病。我们总结了一些 miRNA 加工和调节异常导致罕见遗传疾病的机制。例如，与 突变相关的听力损失、与 突变相关的眼部疾病以及涉及 突变的骨骼发育不良等遗传疾病。
了解这些分子机制至关重要，因为 miRNA 失调是这些疾病发病机制中的关键因素，为诊断和潜在的治疗干预提供了重要的潜力。
