RNA processing and human disease

Abstract

Gene expression involves multiple regulated steps leading from gene to active protein. Many of these steps involve some aspect of RNA processing. Diseases caused by mutations that directly affect RNA processing are relatively rare compared with mutations that disrupt protein function. The vast majority of diseases of RNA processing result from loss of function of a single gene due to mutations in cis-acting elements required for pre-messenger RNA (mRNA) splicing. However, a few diseases are caused by alterations in the trans-acting factors required for RNA processing and in the vast majority of cases it is the pre-mRNA splicing machinery that is affected. Clearly, alterations that disrupt splicing of pre-mRNAs from large numbers of genes would be lethal at the cellular level. A common theme among these diseases is that only subsets of genes are affected. This is consistent with an emerging view that different subsets of exons require different sets of cis-acting elements and trans-acting factors.

Molecular mechanisms regulating the tumor-targeting potential of splice-activated gene expression

“…Other functionally important genes whose protein products are differentially spliced in normal and malignant cells include prostate-specific membrane antigen, 30 the hyaluronan-binding protein RHAMM, 31 the estrogen receptor-alpha, 32 phosphatidic acid phosphatase, 33 Pmel17 (an important regulator of melanosome precursor morphogenesis), 34 the tumor metastasis suppressor KAI1, 35 and cyclin D1. 36 Although such aberrantly spliced proteins are thought to be produced mainly as a result of mutations occurring in the cis-acting sequence elements that control RNA processing, 37 changes in the expression, function and/or distribution of required trans-acting factors have also been noted in malignant cells. 38 Taken together, these data emphasize the potential of alternative splicing as a means of targeting the expression of therapeutic genes to tumor cells in vivo.…”

Serological identification and expression analysis of gastric cancer-associated genes

“…CD44, BRCA1, WT-1) have been implicated in tumorigenesis and correlate with tumour progression (Cooper and Dougherty, 1995;Liu et al, 2001). De-regulation of splice site selection may serve as an additional mechanism for the generation of protein diversity contributing to the selection of more aggressive tumour cells (Cooper and Mattox, 1997;Philips and Cooper, 2000). We identified several previously unknown splice variants of two genes -TACC1 represented by clone Ga55, and uncharacterised gene HSPC232 represented by clone Ga50.…”

Regulation of Alternative Splicing of Human Tau Exon 10 by Phosphorylation of Splicing Factors

“…With a better understanding of the molecular mechanisms regulating alternative splicing it is becoming clearer that defects in pre-mRNA splicing have been underestimated as a factor in human disease Philips and Cooper, 2000;Stoss et al, 2000). A number of studies show that missplicing events causing disease can be changed in cell culture systems (Friedman et al, 1999;Hofmann et al, 2000;Karras et al, 2000;Schmajuk et al, 1999;Wilton et al, 1999), suggesting that changing splice site selection, e.g., through low-molecular-weight substances affecting phosphorylation, could be a new therapeutic principle.…”

“…The loose consensus sequences, found in exonic elements that can work as either enhancers or silencers, are probably necessary to allow the proper protein coding (Elliot, 2000). Their importance is underlined by several diseases caused by mutations in exonic enhancers (Cooper and Mattox, 1997;Daoud et al, 2000;Philips and Cooper, 2000;Stoss et al, 2000).…”