Abstract
microRNAs (miRNAs) are a class of small RNAs (19-25 nucleotides in length) processed from double-stranded hairpin precursors. They negatively regulate gene expression in animals, by binding, with imperfect base pairing, to target sites in messenger RNAs (usually in 3' untranslated regions) thereby either reducing translational efficiency or determining transcript degradation. Considering that each miRNA can regulate, on average, the expression of approximately several hundred target genes, the miRNA apparatus can participate in the control of the gene expression of a large quota of mammalian transcriptomes and proteomes. As a consequence, miRNAs are expected to regulate various developmental and physiological processes, such as the development and function of many tissue and organs. Due to the strong impact of miRNAs on the biological processes, it is expected that mutations affecting miRNA function have a pathogenic role in human genetic diseases, similar to protein-coding genes. In this review, we provide an overview of the evidence available to date which support the pathogenic role of miRNAs in human genetic diseases. We will first describe the main types of mutation mechanisms affecting miRNA function that can result in human genetic disorders, namely: (1) mutations affecting miRNA sequences; (2) mutations in the recognition sites for miRNAs harboured in target mRNAs; and (3) mutations in genes that participate in the general processes of miRNA processing and function. Finally, we will also describe the results of recent studies, mostly based on animal models, indicating the phenotypic consequences of miRNA alterations on the function of several tissues and organs. These studies suggest that the spectrum of genetic diseases possibly caused by mutations in miRNAs is wide and is only starting to be unravelled.
Highlights
MicroRNAs are a class of single-stranded RNAs, 19-25 nucleotides in length, generated from hairpin-shaped transcripts
It processes the pri-miRNAs into a smaller, stem-loop miRNA precursor of ~70 nucleotides [7]. pre-miRNAs are exported, in turn, across the nuclear membrane and into the cytoplasm by the Exportin-5 complex [8,9,10]. These pre-miRNAs are further cleaved by Dicer producing a 19- to 25-nucleotide RNA duplex. These duplexes are incorporated into a ribonucleoprotein complex (RNP) called RNAinduced silencing complex (RISC)-like complex [11,12], referred to as the miRNA-induced silencing complex
A crucial role in the recognition of the target messenger RNA (mRNA) by the miRNA is played by the so-called seed region, which is composed of six to seven nt, which shows a perfect complementarity between a miRNA and its target. miRNA can be localized in the intergenic (40%) or the intragenic (60%) regions [19]
Summary
Http://www.pathogeneticsjournal.com/content/2/1/7 pathogenesis of other forms of deafness. The second example is represented by two different point mutations in the 3'-UTR of the REEP1 gene which have been associated with an autosomal dominant form of hereditary spastic paraplegia (SPG31) [48,49] These mutations, which alter the sequence of a predicted http://www.pathogeneticsjournal.com/content/2/1/7 target site for miR-140, were found to segregate with the disease phenotype and were not detected in a large set of human controls. Damiani et al described a partial ablation of Dicer in the developing mouse retina by using a Cre line under the Chx promoter, a gene mostly expressed in retinal progenitors and specific adult retinal interneuronal cells These mice apparently showed no visible impact on early postnatal retinal structure and function. The fact that in some organs (that is, the heart, the eye and the immune system) the dysfunction of single miRNAs may underlie phenotypes, strongly resembling those observed in human disease, suggests that miRNAs should be considered potential candidates in the pathogenesis of human genetic disorders, even monogenetic forms, likewise protein-coding genes
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