MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics

Abstract

MicroRNAs are evolutionarily conserved small non-coding RNAs known to inhibit the translation of proteins by binding to the target transcript in the 3' untranslated region. Functional polymorphisms in 3' UTRs of several genes have been reported to be associated with diseases by affecting gene expression. The mechanism by which these polymorphisms affect gene expression and induce variability in a cell is not well understood. It has been suggested that these polymorphisms may interfere with regulatory elements that bind to untranslated region of a gene. Recently, a novel class of functional polymorphisms termed miRSNPs/polymorphisms was reported. 1,2 defined as a polymorphism present at or near a microRNA binding sites of functional genes that can affect gene expression by interfering with a miRNA function. The work elucidated the mechanism of a functional miRSNP 829C→ T present in 3' UTR of dihydrofolate reductase, an important drug target. The SNP interferes with the miR24 microRNA function and leads to DHFR over expression and methotrexate resistance. In this article we highlight the importance of these miRSNPs or miR-polymorphisms in gene regulation and the mechanism by which these miRSNPs can induce variability in the SNP expressing mutant cell by using drug resistance as an example.

PDGFRa mutations in humans with isolated cleft palate

“…[19][20][21] Variants near binding sites were previously proved to be pathogenic. The c.*829C4T, a naturally occurring SNP, near the miR-24 binding site in the 3 0 UTR of human dihydrofolate reductase (DHFR) affects DHFR expression by interfering with miR-24 function, resulting in DHFR overexpression and methotrexate resistance.…”

Single-nucleotide polymorphisms among microRNA: big effects on cancer

“…SNPs are the most frequently identified variants in DNA sequences. miRNA-related SNPs could potentially affect the maturation of miRNAs, the silencing machinery, the structure or the expression level of mature miRNA, and the base pairing at the target site; they may also have functional role in miRNA-mediated gene regulation, thereby affecting cancer risk[80],[81] (Figure 1). That this is indeed the case as has been demonstrated by a germline DNA variant (C/T) in the primary sequence of the miRNA cluster encoding miR-16-1 and miR-15a (7 bp in the 3′ direction after the precursor).…”

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

“…Despite their efficiency and potential for leading to useful clinical medicine and public health applications, however, genome-wide association studies have been used in only two drug clinical trials so far, each nonetheless providing relevant insights for future research (Russo et al, 2011, Maitland et al, 2007. A new and promising field of research is pharmacogenomics of miRNA (Lagos-Quintana et al, 2001;Lau et al, 2001;Lee & Ambros, 2001), defined as the study of microRNAs and polymorphisms affecting miRNA function with the aim to predict drug behaviour and improve drug efficiency (Mishra et al, 2008;Mishra & Bertino, 2009). MiRNAs, small, single-stranded, 21-23 nucleotide-long, independent functional units of noncoding RNA, are drug targets that regulate expression of several important proteins in the cell and are differentially expressed in malignant versus normal cells, thus providing MiRNA pharmacogenomics with strong clinical implications (Mishra et al, 2007;Calin et al, 2002;Hon & Zhang, 2007;Iorio et al, 2005).…”