Rectifying RNA splicing errors in hereditary neurodegenerative disease

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The normal pattern of human gene expression requires precise coordination between the transcriptional and RNA processing machineries (1). During and following transcription, nascent RNAs may be modified by 5′-end capping, splicing, and 3′-end cleavage/polyadenylation to generate the vast repertoire of gene products required for proper gene expression, from embryonic to late adult life. RNA splicing is a particularly critical step in this process because it generates the multitude of coding and noncoding RNAs required for specific cell and tissue functions. However, splicing is susceptible to processing errors as a result of regulation by numerous cis-acting sequences and transacting factors, and 5′ splice sites may be particularly vulnerable (2). Thus, it is not surprising that a large number of hereditary mutations result in abnormal splicing and disease (3⇓–5). One striking example is the sensory and autonomic neuropathy familial dysautonomia [FD, also known as Riley-Day syndrome or hereditary sensory and autonomic neuropathy type III (MIM 223900)], which is remarkably common in the Ashkenazi Jewish population with a carrier frequency of ∼1 in 30 (6). FD results from a homozygous mutation in intron 20 (IVS20 + 6T > C) of the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene, which encodes the IκB kinase complex-associated protein, that is predicted to disrupt interactions between IKBKAP pre-mRNA and U1 small nuclear ribonucleoprotein particle (snRNP), resulting in exon 20 skipping, frameshifting, and enhanced RNA turnover via the nonsense-mediated decay pathway (7) (Fig. 1A). Interestingly, the degree of exon …