Rasgos no ventriculares, clínicos y funcionales de la mutación RyR2 R420Q causante de taquicardia ventricular polimórfica catecolaminérgica / Non-ventricular, clinical, and functional features of the ryr2 r420q mutation causing catecholaminergic polymorphic ventricular tachycardia

Introducción y objetivos: La taquicardia ventricular polimórfica catecolaminérgica es una enfermedad maligna que se debe a mutaciones en las proteínas que controlan la homeostasis del Ca2+. Aunque el fenotipo se caracteriza por arritmias ventriculares polimórficas desencadenadas por el estrés, no se han caracterizado plenamente las arritmias supraventriculares que en ocasiones las acompañan. Métodos: Veinticinco miembros de una familia española en la que había habido varias muertes súbitas fueron evaluados mediante electrocardiograma, pruebas de esfuerzo y prueba de desenmascaramiento con adrenalina opcionalmente. Se realizó secuenciación selectiva deRyR2 en un miembro afectado y un cribado en cascada al resto de la familia. Se generó la mutación RyR2R420Q en células HEK-293 mediante mutagénesis dirigida, con objeto de realizar estudios funcionales in vitro. Resultados: Las pruebas de esfuerzo desenmascararon taquicardia ventricular polimórfica catecolaminérgica en 8 familiares (sensibilidad del 89%; valor predictivo positivo del 100%; valor predictivo negativo del 93%), todos ellos portadores de una mutación heterocigota RyR2R420Q, que estaba presente también en el caso probando y en una chica joven sin prueba de esfuerzo, lo que corresponde a una penetrancia del 91% al final del seguimiento. Es de destacar que en los pacientes se identificó bradicardia sinusal, arritmias auriculares y de la unión y/u ondas U gigantes tras esfuerzo. Tras la permeabilización y en las células intactas, las células que expresaban RyR2R420Q mostraron un pico de liberación de Ca2+ menor que el de las célulasRyR2 no mutado o wild-type. Sin embargo, a una concentración de Ca2+ intracelular fisiológica, equivalente a la concentración citosólica diastólica, las células RyR2R420Q liberaban más Ca2+ y oscilaban con mayor rapidez que las células con RyR2 no mutado o wild-type. Conclusiones: La mutación missense RyR2R420Q se identificó en el extremo aminoterminal del gen RyR2 en esta familia muy sintomática. Es de destacar que esta mutación se asocia a bradicardia sinusal, arritmias auriculares y de la unión y ondas U gigantes. En conjunto, los estudios de expresión heteróloga funcional indican que la mutación RyR2R420Q causa un comportamiento aberrante del canal, con pérdida o ganancia de función, según cuál sea la concentración de Ca2+ intracelular citosólica

Introduction and objectives: Catecholaminergic polymorphic ventricular tachycardia is a malignant disease, due to mutations in proteins controlling Ca2+ homeostasis. While the phenotype is characterized by polymorphic ventricular arrhythmias under stress, supraventricular arrhythmias may occur and are not fully characterized. Methods: Twenty-five relatives from a Spanish family with several sudden deaths were evaluated with electrocardiogram, exercise testing, and optional epinephrine challenge. Selective RyR2 sequencing in an affected individual and cascade screening in the rest of the family was offered. The RyR2R420Q mutation was generated in HEK-293 cells using site-directed mutagenesis to conduct in vitro functional studies. Results: The exercise testing unmasked catecholaminergic polymorphic ventricular tachycardia in 8 relatives (sensitivity = 89%; positive predictive value = 100%; negative predictive value = 93%), all of them carrying the heterozygous RyR2R420Q mutation, which was also present in the proband and a young girl without exercise testing, a 91% penetrance at the end of the follow-up. Remarkably, sinus bradycardia, atrial and junctional arrhythmias, and/or giant post-effort U-waves were identified in patients. Upon permeabilization and in intact cells, the RyR2R420Q expressing cells showed a smaller peak of Ca2+ release than RyR2 wild-type cells. However, at physiologic intracellular Ca2+ concentration, equivalent to the diastolic cytosolic concentration, the RyR2R420Q released more Ca2+ and oscillated faster than RyR2 wild-type cells. Conclusions The missense RyR2R420Q mutation was identified in the N-terminus of the RyR2 gene in this highly symptomatic family. Remarkably, this mutation is associated with sinus bradycardia, atrial and junctional arrhythmias, and giant U-waves. Collectively, functional heterologous expression studies suggest that the RyR2R420Q behaves as an aberrant channel, as a loss- or gain-of-function mutation depending on cytosolic intracellular Ca2+ concentration

Una nueva mutación en el gen del receptor de la rianodina ( RyR2 C2277R) como causa de taquicardia ventricular polimórfica catecolaminérgica / A new mutation in the ryanodine receptor 2 gene (RyR2 C2277R) as a cause catecholaminergic polymorphic ventricular tachycardia

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Non-ventricular, Clinical, and Functional Features of the RyR2(R420Q) Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia.

INTRODUCTION AND OBJECTIVES: Catecholaminergic polymorphic ventricular tachycardia is a malignant disease, due to mutations in proteins controlling Ca(2+) homeostasis. While the phenotype is characterized by polymorphic ventricular arrhythmias under stress, supraventricular arrhythmias may occur and are not fully characterized. METHODS: Twenty-five relatives from a Spanish family with several sudden deaths were evaluated with electrocardiogram, exercise testing, and optional epinephrine challenge. Selective RyR2 sequencing in an affected individual and cascade screening in the rest of the family was offered. The RyR2(R420Q) mutation was generated in HEK-293 cells using site-directed mutagenesis to conduct in vitro functional studies. RESULTS: The exercise testing unmasked catecholaminergic polymorphic ventricular tachycardia in 8 relatives (sensitivity = 89%; positive predictive value = 100%; negative predictive value = 93%), all of them carrying the heterozygous RyR2(R420Q) mutation, which was also present in the proband and a young girl without exercise testing, a 91% penetrance at the end of the follow-up. Remarkably, sinus bradycardia, atrial and junctional arrhythmias, and/or giant post-effort U-waves were identified in patients. Upon permeabilization and in intact cells, the RyR2(R420Q) expressing cells showed a smaller peak of Ca(2+) release than RyR2 wild-type cells. However, at physiologic intracellular Ca(2+) concentration, equivalent to the diastolic cytosolic concentration, the RyR2(R420Q) released more Ca(2+) and oscillated faster than RyR2 wild-type cells. CONCLUSIONS: The missense RyR2(R420Q) mutation was identified in the N-terminus of the RyR2 gene in this highly symptomatic family. Remarkably, this mutation is associated with sinus bradycardia, atrial and junctional arrhythmias, and giant U-waves. Collectively, functional heterologous expression studies suggest that the RyR2(R420Q) behaves as an aberrant channel, as a loss- or gain-of-function mutation depending on cytosolic intracellular Ca(2+) concentration.