Vulnerable exons, like ACADM exon 5, are highly dependent on maintaining a correct balance between splicing enhancers and silencers. Issue 2 (30th December 2021)

• Record Type: Journal Article
• Authors: Holm, Lise L.; Doktor, Thomas K.; Hansen, Michael B.; Petersen, Ulrika S. S.; Andresen, Brage S.
• Is Part Of: Human mutation. Volume 43:Issue 2(2022)
• Page Start: 253
• Page End: 265
• Publication Date: 2021-12-30
• Subjects: aberrant splicing -- exonic splicing mutations -- fatty acid oxidation -- MCAD deficiency -- newborn screening -- pre‐mRNA splicing -- splicing enhancer -- splicing silencer; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24321
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: It is now widely accepted that aberrant splicing of constitutive exons is often caused by mutations affecting cis ‐acting splicing regulatory elements, but there is a misconception that all exons have an equal dependency on splicing regulatory elements and thus a similar susceptibility to aberrant splicing. We investigated exonic mutations in ACADM exon 5 to experimentally examine their effect on splicing and found that 7 out of 11 tested mutations affected exon inclusion, demonstrating that this constitutive exon is particularly vulnerable to exonic splicing mutations. Employing ACADM exon 5 and 6 as models, we demonstrate that the balance between splicing enhancers and silencers, flanking intron length, and flanking splice site strength are important factors that determine exon definition and splicing efficiency of the exon in question. Our study shows that two constitutive exons in ACADM have different inherent vulnerabilities to exonic splicing mutations. This suggests that in silico prediction of potential pathogenic effects on splicing from exonic mutations may be improved by also considering the inherent vulnerability of the exon. Moreover, we show that single nucleotide polymorphism that affect either of two different exonic splicing silencers, located far apart in exon 5, all protect against both immediately flanking and more distant exonic splicing mutations. Abstract : ACADM exon 5 illustrates that vulnerability to splicing mutations is context dependent.