Molecular diagnosis & therapy · 2012
Variants of the lamin A/C (LMNA) gene in non-valvular atrial fibrillation patients: a possible pathogenic role of the Thr528Met mutation.
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Saj Michal, Dabrowski Rafal, Labib Sarah, Jankowska Agnieszka, Szperl Malgorzata, Broda Grazyna, Szwed Hanna, Tesson Frederique, Bilinska Zofia T, Ploski Rafal
Аннотация
BACKGROUND AND OBJECTIVE: Lamin A/C (LMNA) gene mutations cause dilated cardiomyopathy, often accompanied by conduction disturbances. Our aim was to search for LMNA mutations in individuals with atrial fibrillation.
METHODS: A cohort of Polish subjects (N = 103) with non-valvular atrial fibrillation with a high (48.5%) prevalence of conduction system disturbances was screened for LMNA variants by direct DNA sequencing.
RESULTS: We found a single non-synonymous variant (Thr528Met) in a 72-year-old patient with normal left ventricular function and episodes of advanced atrioventricular block. One of his two mutation-carrying daughters had episodes of type I second-degree atrioventricular block on a 24-hour Holter ECG and peak exercise arrhythmia. Interpretation of cardiac anomalies observed in the other daughter was complicated by thyroid insufficiency. A Thr528Met weak pathogenic effect was supported by transient transfections of C2C12 mouse myoblasts and computationally. Another interesting variant was Ile26Ile (c.78C>T), found in a New York Heart Association class III patient with a depressed left ventricular ejection fraction (30%), left bundle branch block, and a family history of heart disease. Ile26Ile was absent in 246 healthy individuals and was computationally predicted to interfere with splicing.
CONCLUSION: LMNA mutations are not a frequent cause of atrial fibrillation even when conduction disease is present. Unlike the majority of LMNA mutations clearly associated with a severe clinical phenotype and a poor prognosis, Thr528Met results in a more subtle pathogenic effect, while Ile26Ile should be considered as a variant of unknown significance.
METHODS: A cohort of Polish subjects (N = 103) with non-valvular atrial fibrillation with a high (48.5%) prevalence of conduction system disturbances was screened for LMNA variants by direct DNA sequencing.
RESULTS: We found a single non-synonymous variant (Thr528Met) in a 72-year-old patient with normal left ventricular function and episodes of advanced atrioventricular block. One of his two mutation-carrying daughters had episodes of type I second-degree atrioventricular block on a 24-hour Holter ECG and peak exercise arrhythmia. Interpretation of cardiac anomalies observed in the other daughter was complicated by thyroid insufficiency. A Thr528Met weak pathogenic effect was supported by transient transfections of C2C12 mouse myoblasts and computationally. Another interesting variant was Ile26Ile (c.78C>T), found in a New York Heart Association class III patient with a depressed left ventricular ejection fraction (30%), left bundle branch block, and a family history of heart disease. Ile26Ile was absent in 246 healthy individuals and was computationally predicted to interfere with splicing.
CONCLUSION: LMNA mutations are not a frequent cause of atrial fibrillation even when conduction disease is present. Unlike the majority of LMNA mutations clearly associated with a severe clinical phenotype and a poor prognosis, Thr528Met results in a more subtle pathogenic effect, while Ile26Ile should be considered as a variant of unknown significance.