OBSCN undergoes extensive alternative splicing during human cardiac and skeletal muscle development

Abstract

Background Highly expressed in skeletal muscles, the gene Obscurin (i.e. OBSCN) has 121 non-overlapping exons and codes for some of the largest known mRNAs in human genome. Furthermore, it is known to play an essential role in muscle development and function. Mutations within OBSCN are known to cause several hypertrophic cardiomyopathies and muscular disorders. OBSCN undergoes extensive and complex alternative splicing, which is the main reason that its splicing regulation associated with skeletal and cardiac muscle development has not previously been thoroughly studied. Methods We analyzed RNA-Seq data from skeletal and cardiac muscles extracted from 41 postnatal individuals and 6 fetuses. We applied the intron/exon level splicing analysis software IntEREst to study the splicing of OBSCN in the studied samples. The differential splicing analysis was adjusted for batch effects. Our comparisons reveal the splicing variations in OBSCN, between the human skeletal and cardiac muscle, as well as between post-natal muscle (skeletal and cardiac) and the pre-natal equivalent muscle. Results We detected several splicing regulations located in 5’end, 3’ end, and the middle of OBSCN that are associated with human cardiac or skeletal muscle development. Many of these alternative splicing events have not previously been reported. Conclusions We conclude that the splicing of OBSCN is extensively regulated during the human skeletal/cardiac muscle development. We developed an interactive visualization tool that can be used by clinicians and researchers to study the inclusion of specific OBSCN exons in pre- and postnatal cardiac and skeletal muscles (as well as their differential splicing statistics). The human skeletal/cardiac muscle development OBSCN exon inclusion map is available at https://gacatag.shinyapps.io/OBSCN_PSIVIS/. These findings are essential for an accurate pre- and postnatal diagnosis and prognosis of OBSCN exonic variants.