Splicing and Disease

Abstract

KeyConcepts . An increasing number of diseases are now recognized to be caused by the selection of wrong splice sites. . The selection of wrong splice sites can be caused by mutation in the DNA, or by changes in trans-acting factors. . Aberrant splicing is best studied in monogenetic diseases, but is increasingly found in complex diseases. IntroductionIn order to ensure accurate gene expression, the pre-mRNA splicing process has the task of removing intervening sequences (or introns) from eukaryotic precursor messenger RNA (pre-mRNA) [1]. Since the pioneering studies on hemoglobin genes during the earliest days of splicing research [2-4], it has been well known that, in humans, any changes which impair this process may cause diseases. However, during the past 15 years or so, an increased knowledge of the pre-mRNA splicing process itself -coupled with major advances in diagnostic screening techniques -has greatly expanded that initial awareness [5]. Today, it is clear that splicing mutations can occur in virtually any human intron-containing gene, and that the resulting splicing alterations may cause disease. The pathological penetrance of these mutations may be variable, depending on the individual genetic background. Until now, the most widely studied examples have considered only classical genetic diseases linked to alterations in a single-gene splicing regulation. However, it is becoming increasingly clear that splicing alterations play equally important roles in the origin and progression of complex diseases, such as tumor formation or neurological defects. The aim of this chapter is to provide some basic pointers on splicing alterations and disease, and to focus especially on overviewing the consequences of genomic variations. The complexity of the splicing process is aimed at maintaining correct exon/intron recognition, and is one of the essential factors that influence the shape of human genes [6]. In keeping with this, many recent reports have consistently highlighted the observation that even apparently neutral changes in the sequence composition of exons may alter splicing, thus revealing evolutionary mechanisms aimed at maintaining correct splicing regulatory pathways [7][8][9].Both, constitutive and alternative splicing (AS) pathways are carried out by a large ribonucleoprotein complex referred to as the spliceosome [1,10]. The assembly of this highly sophisticated cellular machinery [11,12] in every exon-intron or intron-exon junction is controlled by conserved (but rather degenerate) sequence elements that include 5 0 splice sites (5 0 SS) and 3 0 splice sites (3 0 SS) and, upstream of the 3 0 SS, the polypyrimidine tract and the branchpoint sequence (BPS) (Figure 10.1) (Chapter 5 L€ uhrmann). Because of their degeneracy, however, these consensus splicing signals contain approximately half of the information necessary for accurate splice-site selection [13]. The remaining information is provided by auxiliary signals in introns Alternative pre-mRNA Splicing: Theory and Protocols, First Edition. Edite...