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De la interpretación de variantes al descubrimiento estructural: Un nuevo dominio de unión a zinc en PARS2

Célia Hoebeke¹, Camille Engel², Claire-Marine Berat³

¹Departement of Neuropediatrics and Reference Centre for Inborn Errors of Metabolism, La-Timone Children Hospital, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, 13385 Marseille cedex 05, France.

|February 20, 2026

Resumen

La deficiencia de la prolil-tRNA sintasa mitocondrial (PARS2) puede causar trastornos neurológicos. Los investigadores identificaron un nuevo dominio de unión a zinc en PARS2, lo que mejora la clasificación de variantes y amplía la comprensión de las enfermedades genéticas relacionadas.

Área de la Ciencia:

Bioquímica
Genética
Neurociencia

Sus antecedentes:

Las aminoacil-tRNA sintetasas (aaRS) son enzimas cruciales para la síntesis de proteínas.
Las aaRS mitocondriales (ARS2) tienen dominios extra pobremente caracterizados, lo que complica los diagnósticos genéticos.
Las variantes patogénicas en genes ARS2 causan diversos trastornos neurológicos.

Objetivo del estudio:

Investigar la causa de la encefalopatía epiléptica en dos pacientes con variantes bialélicas de PARS2.
Caracterizar una nueva variante en PARS2 previamente predicha como "probablemente benigna".
Mejorar la comprensión de la estructura, función y predicción de patogenicidad de ARS2.

Principales métodos:

Evaluación fenotípica de pacientes.
Modelado comparativo de la estructura de proteínas.
Análisis de conservación de secuencias específico de clado.

Principales resultados:

Ambos pacientes presentaron características clínicas consistentes con deficiencia de PARS2.
Se identificó una nueva variante de PARS2 dentro de un dominio de unión a zinc (ZBD) previamente no reconocido.
Este ZBD es estructuralmente similar al ZBD en ProRS citosólico.

Conclusiones:

El estudio revela un ZBD crítico en la prolil-tRNA sintasa mitocondrial (PARS2).
Los hallazgos resaltan las limitaciones en la predicción de la patogenicidad de variantes de ARS2 utilizando herramientas actuales.
Este trabajo amplía el espectro genotípico de los trastornos relacionados con PARS2 y describe fenotipos asociados.

Palabras clave:

Aminoacil-tRNA sintetasas Encefalopatía epiléptica PARS2 Dominio de unión a zinc

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