Nonsense-mediated mRNA decay caused by a frameshift mutation in a large kindred of type 2 long QT syndrome

Ignatius Gerardo Zarraga, Li Zhang, Matthew R. Stump, Qiuming Gong, G. Michael Vincent, Zhengfeng Zhou

    Research output: Contribution to journalArticlepeer-review

    21 Scopus citations


    Background: Nonsense and frameshift mutations are common in congenital long QT syndrome type 2 (LQT2). We previously demonstrated that hERG nonsense mutations cause degradation of mutant mRNA by nonsense-mediated mRNA decay (NMD) and are associated with mild clinical phenotypes. The impact of NMD on the expression of hERG frameshift mutations and their phenotypic severity is not clear. Objective: The purpose of this study was to examine the role of NMD in the pathogenesis of a hERG frameshift mutation, P926AfsX14, identified in a large LQT2 kindred and characterize genotypephenotype correlations. Methods: Genetic screening was performed among family members. Phenotyping was performed by assessment of ECGs and LQTS-related cardiac events. The functional effect of P926AfsX14 was studied using hERG cDNA and minigene constructs expressed in HEK293 cells. Results: Significant cardiac events occurred in carriers of the P926AfsX14 mutation. When expressed from cDNA, the P926AfsX14 mutant channel was only mildly defective. However, when expressed from a minigene, the P926AfsX14 mutation caused a significant reduction in mutant mRNA, protein, and hERG current. Inhibition of NMD by RNA interference knockdown of up-frameshift protein 1 partially restored expression of mutant mRNA and protein and led to a significant increase in hERG current in the mutant cells. These results suggest that NMD is involved in the pathogenic mechanism of the P926AfsX14 mutation. Conclusion: Our findings suggest that the hERG frameshift mutation P926AfsX14 primarily results in degradation of mutant mRNA by the NMD pathway rather than production of truncated proteins. When combined with environmental triggers and genetic modifiers, LQT2 frameshift mutations associated with NMD can manifest with a severe clinical phenotype.

    Original languageEnglish (US)
    Pages (from-to)1200-1206
    Number of pages7
    JournalHeart Rhythm
    Issue number8
    StatePublished - Aug 2011


    • Long QT syndrome
    • Mutation
    • Nonsense-mediated mRNA decay
    • Patch clamp
    • Potassium channel

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)


    Dive into the research topics of 'Nonsense-mediated mRNA decay caused by a frameshift mutation in a large kindred of type 2 long QT syndrome'. Together they form a unique fingerprint.

    Cite this