Abstract
Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting the function and/or expression of splicing factors, including the core snRNP proteins. Variants in the genes encoding proteins of the U5 snRNP cause two distinct and tissue-specific human disease phenotypes – variants in PRPF6, PRPF8, and SNRP200 are associated with retinitis pigmentosa (RP), while variants in EFTUD2 and TXNL4A cause the craniofacial disorders mandibulofacial dysostosis Guion-Almeida type (MFDGA) and Burn-McKeown syndrome (BMKS), respectively. Furthermore, recurrent somatic mutations or changes in the expression levels of a number of U5 snRNP proteins (PRPF6, PRPF8, EFTUD2, DDX23, and SNRNP40) have been associated with human cancers. How and why variants in ubiquitously expressed spliceosome proteins required for pre-mRNA splicing in all human cells result in tissue-restricted disease phenotypes is not clear. Additionally, why variants in different, yet interacting, proteins making up the same core spliceosome snRNP result in completely distinct disease outcomes – RP, craniofacial defects or cancer – is unclear. In this review, we define the roles of different U5 snRNP proteins in RP, craniofacial disorders and cancer, including how disease-associated genetic variants affect pre-mRNA splicing and the proposed disease mechanisms. We then propose potential hypotheses for how U5 snRNP variants cause tissue specificity resulting in the restricted and distinct human disorders.
Highlights
The vast majority of human genes contain introns which interrupt the coding exons
We have reviewed the association between the U5 small nuclear ribonucleoprotein complexes (snRNPs) and human disease
The association of certain U5 snRNP proteins with cancer, including proteins linked to retinitis pigmentosa (RP) or craniofacial defects, introduces an additional layer of complexity as mutations in and/or altered expression levels of the same protein can have very different phenotypic outcomes
Summary
The vast majority of human genes contain introns which interrupt the coding exons. Genes are transcribed into precursor messenger RNA (pre-mRNA) which contain introns that must be removed in the nucleus, in the process of pre-mRNA splicing. Links between somatic mutations in and/or altered expression of several of the U5 snRNP proteins (including those associated with craniofacial or retinal phenotypes) and human cancers have been established (Table 1).
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