Roles of RNAs in disease pathophysiology

The normal cellular function depends on the accurate expression of numerous protein coding RNAs (mRNAs) and non-coding RNAs (ncRNAs). Mutations that disrupt the production or activity of either the RNA or protein components can be deleterious to cells and cause diseases.

The most well-studied sequences in the human transcriptome are those of protein-coding mRNAs, although these mRNAs only account for 1-4 % of the whole transcriptome. Traditionally, it is considered that the disease-causing mutations generally interfere with the production or activity of particular proteins and thereby lead to human genetic disorders. These disease-causing mutations could be identified by analyzing the sequences or expression levels of the corresponding protein-coding mRNAs. To date, there are plenty examples of genetic disorders caused by mutations on protein-coding regions, including familial hypercholesterolemia, sickle cell anaemia and cystic fibrosis.

Considering the vast repertoire of ncRNAs and their crucial functional importance, mutations in non-protein-coding regions theoretically have the potential to generate deleterious RNAs with the similar effects of some mutant proteins. At present, the nature and extent of the involvement of ncRNAs in pathogenesis are only beginning to be understand and appreciated. The roles of ncRNAs in human diseases have most thoroughly been investigated with respect to miRNAs, particularly in cancer. It has been shown that defects in miRNAs and their processing machinery are a common feature of diseases.

In addition, other ncRNAs, such as PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs) and the heterogeneous group of long non-coding RNAs (lncRNAs), are emerging as key players of cellular homeostasis. Dysregulation of these ncRNAs is being found to contribute to the development of many different human disorders, such as various malignancies, neurological, cardiovascular, autoimmune, developmental and other diseases. Recent insights into new disease-causing mutations in RNAs is yielding a range of therapeutic targets, and the continuing elucidation of RNA biochemistry and biology is believed to provide novel tools for developing therapeutics in the near feature.