Spliceosomopathies: Diseases and mechanisms

Abstract

The spliceosome is a complex of RNA and proteins that function together to identify intron-exon junctions in precursor messenger-RNAs, splice out the introns, and join the flanking exons. Mutations in any one of the genes encoding the proteins that make up the spliceosome may result in diseases known as spliceosomopathies. While the spliceosome is active in all cell types, with the majority of the proteins presumably expressed ubiquitously, spliceosomopathies tend to be tissue-specific as a result of germ line or somatic mutations, with phenotypes affecting primarily the retina in retinitis pigmentosa, hematopoietic lineages in myelodysplastic syndromes, or the craniofacial skeleton in mandibulofacial dysostosis. Here we describe the major spliceosomopathies, review the proposed mechanisms underlying retinitis pigmentosa and myelodysplastic syndromes, and discuss how this knowledge may inform our understanding of craniofacial spliceosomopathies.

Keywords: mandibulofacial dysostosis; myelodysplastic syndromes; retinitis pigmentosa; spliceosome.

FIGURE 1

Spliceosomopathies are largely tissue-specific. The tissues affected by these pathologies and their association with mutations in genes encoding components of the spliceosome are indicated

FIGURE 2

Schematic representation of the major steps of precursor messenger-RNA splicing and the involvement of the proteins that have been linked to spliceosomopathies. Proteins are grouped based on their activity and association with a specific complex of the spliceosome. The link to a specific disease is color-coded based on Figure 1. Proteins mutated in retinitis pigmentosa (green) are primarily associated with U4/U6 complex. Proteins mutated in myelodysplastic syndromes (blue) are primarily associated with U2 complex. Proteins mutated in craniofacial spliceosomopathies (orange) are distributed across all complexes. Exons are represented as yellow boxes. EJC, exon-junction complex