Mutations in spliceosomal proteins and retina degeneration

Šárka Růžičková, David Staněk
2016 RNA Biology  
A majority of human genes contain non-coding intervening sequencesintrons that must be precisely excised from the pre-mRNA molecule. This event requires the coordinated action of five major small nuclear ribonucleoprotein particles (snRNPs) along with additional non-snRNP splicing proteins. Introns must be removed with nucleotidal precision, since even a single nucleotide mistake would result in a reading frame shift and production of a non-functional protein. Numerous human inherited diseases
more » ... re caused by mutations that affect splicing, including mutations in proteins which are directly involved in splicing catalysis. One of the most common hereditary diseases associated with mutations in core splicing proteins is retinitis pigmentosa (RP). So far, mutations in more than 70 genes have been connected to RP. While the majority of mutated genes are expressed specifically in the retina, eight target genes encode for ubiquitous core snRNP proteins (Prpf3, Prpf4, Prpf6, Prpf8, Prpf31, and SNRNP200/Brr2) and splicing factors (RP9 and DHX38). Why mutations in spliceosomal proteins, which are essential in nearly every cell in the body, causes a disease that displays such a tissue-specific phenotype is currently a mystery. In this review, we recapitulate snRNP functions, summarize the missense mutations which are found in spliceosomal proteins as well as their impact on protein functions and discuss specific models which may explain why the retina is sensitive to these mutations. KEYWORDS Retinitis pigmentosa; snRNP; splicing Small nuclear ribonucleoprotein particles Spliceosomal snRNPs are complex particles consisting of small nuclear RNA (snRNA), a heptameric ring of Sm or Like-Sm (LSm) proteins and 1-13 proteins that are specific for each snRNP. Five major and four minor snRNPs have been described and named according to their snRNA composition. The major snRNPs are U1, U2, U4, U5 and U6 and the minor snRNPs are U11, U12, U4atac and U6atac. The U5 snRNP is common to both major and minor splicing pathways. The most accepted view of spliceosome formation is a stepwise assembly model, which has been supported by numerous
doi:10.1080/15476286.2016.1191735 pmid:27302685 pmcid:PMC5449078 fatcat:se5grromiffbfohvfwhmnyc2g4