Servgen, Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
Functional Genomics and Bioinformatics Laboratory, Fiocruz, Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
J Mol Neurosci. 2019 Feb;67(2):295-304. doi: 10.1007/s12031-018-1235-7. Epub 2019 Jan 3.
MicroRNAs are endogenous non-protein-coding RNA molecules that regulate post-transcriptional gene expression. The majority of human miRNAs are brain-expressed and chromosome X is enriched in miRNA genes. We analyzed the genomic regions of 12 brain-expressed pre-miRNAs located on chromosome X coding for 18 mature miRNAs, aiming to investigate the involvement of miRNA sequence variants on X-linked intellectual disability (XLID). Genomic DNA samples from 135 unrelated Brazilian males with intellectual disability, suggestive of X-linked inheritance, were amplified through polymerase chain reaction and sequenced by Sanger sequencing. Although no sequence variations have been identified, suggesting an intense selective pressure, further computational analysis evidenced that eight mature miRNAs (miR-221-3p/222-3p, miR-223-3p, miR-361-5p, miR-362-5p, miR-504-5p.1, miR-505-3p.1, and miR-505-3p.2) act as critical regulators of X-linked and autosomal ID genes in a fully connected network. Enrichment approaches identify transcription regulation, nervous system development, and regulation of cell proliferation as the main common biological processes among the target ID genes. Besides, a clustered chromosomal coverage of the imputed miRNAs target genes and related regulators was found on X chromosome. Considering the role of miRNAs as fine-tuning regulators of gene expression, a systematic analysis of miRNAs' expression could uncover part of the genetic landscape subjacent to ID, being urgently necessary in patients with this condition, particularly XLID.
微小 RNA 是内源性非蛋白编码 RNA 分子，可调节转录后基因表达。大多数人类 miRNA 是在脑中表达的，X 染色体富含 miRNA 基因。我们分析了位于 X 染色体上的 12 个脑表达 pre-miRNA 的基因组区域，这些 pre-miRNA 编码 18 个成熟 miRNA，旨在研究 miRNA 序列变异与 X 连锁智力障碍 (XLID) 的关系。从 135 名具有智力障碍且提示 X 连锁遗传的巴西男性无关个体中提取基因组 DNA 样本，通过聚合酶链反应扩增并进行 Sanger 测序。尽管没有发现序列变异，提示存在强烈的选择压力，但进一步的计算分析表明，八个成熟 miRNA（miR-221-3p/222-3p、miR-223-3p、miR-361-5p、miR-362-5p、miR-504-5p.1、miR-505-3p.1 和 miR-505-3p.2）在一个全连接网络中作为 X 连锁和常染色体 ID 基因的关键调控因子。富集方法确定了转录调控、神经系统发育和细胞增殖调节是目标 ID 基因之间的主要共同生物学过程。此外，在 X 染色体上发现了推测的 miRNAs 靶基因和相关调节剂的聚类染色体覆盖。考虑到 miRNAs 作为基因表达精细调节因子的作用，对 miRNAs 表达的系统分析可以揭示 ID 相关遗传景观的一部分，对于这种情况下的患者，特别是 XLID 患者，这是非常必要的。
