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

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.