Abstract
The U12-dependent (minor) spliceosome excises a rare group of introns that are characterized by a highly conserved 5′ splice site and branch point sequence. Several new congenital or somatic diseases have recently been associated with mutations in components of the minor spliceosome. A common theme in these diseases is the detection of elevated levels of transcripts containing U12-type introns, of which a subset is associated with other splicing defects. Here we review the present understanding of minor spliceosome diseases, particularly those associated with the specific components of the minor spliceosome. We also present a model for interpreting the molecular-level consequences of the different diseases.
Highlights
Pre-mRNA splicing is an essential step in the gene expression pathway of all eukaryotes
Three of them affect the components of the U11/U12 disnRNP, namely the U11/U12-65K protein (RNPC3; [27]), U12 small nuclear RNA (snRNA) (RNU12; [28]) and Urp protein (ZRSR2; [29]); while two diseases are attributed to mutations in the U4atac snRNA (RNU4ATAC; [30,31,32])
Apart from mutations in the core minor spliceosome components, we describe the few reported human diseases caused by mutations at the splice sites of U12-type introns, though we note that this appears to be underexplored territory given the small number of cases reported so far
Summary
Pre-mRNA splicing is an essential step in the gene expression pathway of all eukaryotes. U12-type introns are enriched in genes that represent a rather restricted set of functional classes and pathways They are present in genes related to ‘information processing functions’, such as DNA replication and repair, transcription, RNA processing, and translation, but can be found in genes related to cytoskeletal organization, vesicular transport, and voltage-gated ion channel activity, as suggested originally by Burge et al, [12] and verified later [13,14]. U11/U12 di-snRNP protein component, Urp/ZRSR2 takes up the role of 3 ss recognition with minor introns [19] Following this initial recognition, both splicing pathways proceed with association of a tri-snRNP, either U4atac/U6atac.U5 or U4/U6.U5 (Fig. 1B; [20,21]). Those have been discussed in detail elsewhere [24]
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