Stop-codon and C-terminal nonsense mutations are associated with a lower risk of cardiac events in patients with long QT syndrome type 1
| Autor: | Coeli M. Lopes, Martin H. Ruwald, Arthur J. Moss, Jayson R. Baman, Xiaorong Xu Parks, Wataru Shimizu, Scott McNitt, Jørgen K. Kanters, Wojciech Zareba, Christian Jons, Arthur A.M. Wilde |
|---|---|
| Přispěvatelé: | Amsterdam Cardiovascular Sciences, Cardiology |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine medicine.medical_specialty Adolescent Romano-Ward Syndrome Long QT syndrome Nonsense mutation Mutation Missense 030204 cardiovascular system & hematology medicine.disease_cause Risk Assessment QT interval Gastroenterology Syncope Article Frameshift mutation 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine medicine Humans Missense mutation Frameshift Mutation Proportional Hazards Models Genetics Mutation business.industry Wild type Prognosis medicine.disease Heart Arrest Romano–Ward syndrome Death Sudden Cardiac 030104 developmental biology Codon Nonsense KCNQ1 Potassium Channel Codon Terminator Female Cardiology and Cardiovascular Medicine business |
| Zdroj: | Heart rhythm, 13(1), 122-131. Elsevier |
| ISSN: | 1547-5271 |
| Popis: | Background In long QT syndrome type 1 (LQT1), the location and type of mutations have been shown to affect the clinical outcome. Although haploinsufficiency, including stop-codon and frameshift mutations, has been associated with a lower risk of cardiac events in patients with LQT1, nonsense mutations have been presumed functionally equivalent. Objective The purpose of this study was to evaluate clinical differences between patients with nonsense mutations. Methods The study sample comprised 1090 patients with genetically confirmed mutations. Patients were categorized into 5 groups, depending on mutation type and location: missense not located in the high-risk cytoplasmic loop (c-loop) (n = 698), which is used as reference; missense c-loop (n = 192); stop-codon (n = 67); frameshift (n = 39); and others (n = 94). The primary outcome was a composite end point of syncope, aborted cardiac arrest, and long QT syndrome–related death (cardiac events). Outcomes were evaluated using the multivariate Cox proportional hazards regression analysis. Standard patch clamp techniques were used. Results Compared to patients with missense non–c-loop mutations, the risk of cardiac events was reduced significantly in patients with stop-codon mutations (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.34–0.96; P = .035), but not in patients with frameshift mutations (HR 1.01; 95% CI 0.58–1.77; P = .97). Our data suggest that currents of the most common stop-codon mutant channel (Q530X) were larger than those of haploinsufficient channels (wild type: 42 ± 6 pA/pF, n=20; Q530X+wild type: 79 ± 14 pA/pF, n=20; P Conclusion Stop-codon mutations are associated with a lower risk of cardiac events in patients with LQT1, while frameshift mutations are associated with the same risk as the majority of the missense mutations. Our data indicate functional differences between these previously considered equivalent mutation subtypes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|