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Fenotipo clínico y caracterización funcional de las mutaciones CASQ2 asociadas con taquicardia ventricular

Marina Raffaele di Barletta¹, Serge Viatchenko-Karpinski, Alessandra Nori

¹Molecular Cardiology, IRCCS Fondazione Maugeri, University of Pavia, Via Ferrata 8 27100, Pavia, Italy.

|August 16, 2006

Resumen

Se identificaron dos nuevas mutaciones en el gen de la calsequestrina cardíaca (CASQ2) en niños con taquicardia ventricular polimórfica catecolaminérgica (CPVT). Estas mutaciones interrumpen la regulación intracelular del calcio, lo que lleva a ritmos cardíacos peligrosos.

Área de la Ciencia:

Genética cardiovascular Genética cardiovascular Genética cardiovascular Genética cardiovascular Genética cardiovascular
Cardiología Molecular Cardiología Molecular
La arritmogénesis es la arritmogénesis.

Sus antecedentes:

Cuatro mutaciones en el gen de la calsequestrina cardíaca humana (CASQ2) están relacionadas con la taquicardia ventricular polimórfica catecolaminérgica (CPVT).
La comprensión de los mecanismos de la CPVT causada por mutaciones CASQ2 es limitada debido a la insuficiente caracterización in vitro de los mutantes identificados.

Objetivo del estudio:

Para identificar y caracterizar nuevas mutaciones CASQ2 asociadas con CPVT.
Investigar las consecuencias funcionales de estas mutaciones en el manejo de calcio de los miocitos cardíacos y la arritmogénesis.

Principales métodos:

Secuenciación genética para identificar mutaciones CASQ2 en pacientes CPVT.
Caracterización in vitro de la función de la proteína mutante CASQ2, incluida la unión al calcio.
Expresión de CASQ2 mutante en miocitos de rata para evaluar el almacenamiento de calcio en el retículo sarcoplásmico y los transitorios de calcio.
Estudios electrofisiológicos para evaluar el impacto de las mutaciones en los eventos aritmogénicos.

Principales resultados:

Se identificó una deleción homocigótica de 16-bp (CASQ2(G112+5X)) y una mutación heterocigótica compuesta (CASQ2(L167H)) en pacientes con CPVT.
CASQ2 ((G112+5X) exhibió un deterioro de la unión al calcio, mientras que ambos mutantes redujeron la capacidad de calcio del retículo sarcoplásmico en los miocitos.
Los miocitos que expresan mutantes mostraron transientes Ca2+ inducidos por I(Ca) reducidos y chispas espontáneas de Ca2+; el isoproterenol indujo retrasos después de las despolarizaciones en los miocitos que expresan CASQ2 (((G112+5X).

Conclusiones:

Las mutaciones identificadas CASQ2 (L167H) y CASQ2 (G112+5X) perjudican la función de los miocitos cardíacos al alterar la regulación del calcio.
Estas distintas anormalidades en el manejo del calcio intracelular contribuyen al desarrollo de taquiarritmias en pacientes con CPVT.
El estudio aclara los mecanismos moleculares subyacentes a la CPVT asociados con nuevas mutaciones CASQ2.

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