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Two sides of the same medal: Noncoding mutations reveal new pathological mechanisms and insights into the regulation of gene expression

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Abstract Noncoding sequences constitute the major part of the human genome and also of pre‐mRNAs. Single nucleotide variants in these regions are often overlooked, but may be responsible for much of the variation of phenotypes observed. Mutations in the noncoding part of pre‐mRNAs often reveal new and meaningful insights into the regulation of cellular gene expression. Thus, the mechanistic analysis of the pathological mechanism of such mutations will both foster a deeper understanding of the disease and the underlying cellular pathways. Even synonymous mutations can cause diseases, since the primary mRNA sequence not only encodes amino acids, but also encrypts information on RNA‐binding proteins and secondary structure. In fact, the RNA sequence directs assembly of a specific mRNP complex, which in turn dictates the fate of the mRNA or regulates its biogenesis. The accumulation of genomic sequence information is increasing at a rapid pace. However, much of the diversity uncovered may not explain the phenotype of a certain syndrome or disease. For this reason, we also emphasize the value of mechanistic studies on pathological mechanisms being complementary to genome‐wide studies and bioinformatic approaches. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Disease
Cellular gene expression. (a) A cell nucleus with the nuclear membrane in black is depicted. A gene (DNA, blue line) is transcribed by RNA polymerase II (green). The emerging RNA is processed and exported through the nuclear pore. In the cytoplasm ribosomes (light blue) attach to the mRNA and translate the encoded information as shown by the growing polypeptide chain (yellow). (b) The structure of a gene is shown with the promoter in green, untranslated regions in orange, the coding sequence (CDS) in red and introns in gray. Splicing removes the introns yielding a continuous CDS
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Regulation of lactase expression. Upper panel: The promoter for lactase gene (LCT; green) depends on enhancer sequences (thick dark blue vertical lines) in the upstream intron 13 (gray) of the MCM6 gene. After childhood, the cytosine at pos. −13,910 becomes methylated and enhancer activity is lost (dashed arrow). Lower panel: a C>T mutation at pos. −13,910 prevents methylation and maintains enhancer activity and thus lactase expression persists into adulthood
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Model for miRNA‐mediated translational repression and RNA decay. An mRNA (black line) with cap (open circle) and poly (A) tail is recognized by a miRNA. The discontinuous binding is illustrated. The miRNA is incorporated into the RNA‐induced silencing complex (RISC; yellow) and its interactions (arrows) with the ribosome (light blue) and RNA decay factors (red) induces translational repression and enhanced RNA decay
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Splice site mutations and inhibition of cleavage and polyadenylation by U1 snRNP. (a) The scheme presents the possible outcomes of splice site mutations. The upper panel depicts the creation of new intronic splice sites that lead to the inclusion of intron fragments. In the middle panel a 5′SS mutation results in intron inclusion or activation of an alternative splice site (a. 5′SS). The bottom panel illustrates that mutations of the BPS, 3′SS or 5′SS can induce exon skipping. Exons are painted in red, introns in gray. (b) Scheme representing the possible outcome of the intron 3 5′SS mutation in the IL2RG gene. The mutation reduces the complementarity with the U1 snRNA and leads a strong decrease of the MaxEnt score. Consequently splicing of intron 3 is impaired, which results in intron retention in most of the transcripts. Due to an in‐frame stop codon, the translated protein is predicted to be truncated and presumably NMD is induced. Usage of an alternative 5′SS (a. 5′SS) leads to the insertion of a 60 nt intronic fragment in some transcripts, which are predicted to produce a IL2Rγ protein containing a 20 amino acid insertion in the extracellular domain. (c) If a 5′SS occurs close to the authentic polyadenylation signal (AAUAAA), U1 snRNP (secondary structure with associated proteins in blue) is able to inhibit the activity of cleavage factor I or II complexes (orange and yellow). This may prevent binding of cleavage and polyadenylation specificity factor (CPSF, green). The additional RNA elements are the CFIm binding site UGUA, the cleavage site (CA) and the downstream element (G/U) bound by cleavage stimulatory factor (CstF, light blue)
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The mRNP code. (a) The left panel depicts the genetic code with three nucleotides encoding one amino acid; in this example, leucine, and aspartic acid. The right panel illustrates that the same 6mer sequence can also be recognized by an RNA‐binding protein (RBP, green). (b) Depending on the primary sequence an mRNA assembles a unique mRNP complex as depicted by the colored RBPs and also complexes of proteins such as the cap‐binding complex (CBC, red) or the exon‐junction complex (EJC, dark blue). The poly (A) tail of mRNAs is bound by the poly (A)‐binding protein (PABP, orange)
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RNA in Disease and Development > RNA in Disease
RNA Processing > 3′ End Processing
RNA Processing > Splicing Regulation/Alternative Splicing

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