missplicing

Missplicing refers to errors in the splicing of pre-mRNA, a process that removes introns and joins exons to produce mature messenger RNA. In missplicing, exons may be skipped, introns retained, or cryptic splice sites used, resulting in transcripts that differ from the normal sequence. Such aberrant splicing can alter the encoded protein, disrupt regulatory elements, or trigger nonsense-mediated decay of the transcript.

Missplicing arises from cis-acting mutations at canonical splice sites or regulatory sequences, such as exonic or intronic splicing enhancers and silencers, and from mutations or altered expression of trans-acting splicing factors. It can also occur due to changes in RNA secondary structure or cellular conditions that affect spliceosome assembly. In diseases, especially cancer and inherited disorders, dysregulation of splicing factors or mutations in splicing components are common drivers.

The consequences of missplicing include loss of protein function, production of dominant-negative or gain-of-function variants, and reduced protein levels via decay pathways. Missplicing is implicated in a broad range of conditions; for example, spinal muscular atrophy involves mis-splicing of SMN1/SMN2 transcripts, and certain muscular dystrophies involve exon-skipping events in dystrophin.

Detection and study typically use RNA sequencing, RT-PCR, and minigene assays to identify aberrant transcripts and assess splice-site strength. Therapeutic approaches include antisense oligonucleotides that modulate splicing, small molecule modulators of the spliceosome, and genome-editing strategies aimed at restoring normal splicing patterns.