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Variantes bialélicas en CELSR1 causan malformaciones cerebrales, trastornos del neurodesarrollo y epilepsia en

Claudia M Bonardi^1,2, Rikke S Møller^1,3, Nuria Ruiz-Reig⁴

¹Danish Epilepsy Centre, Member of ERN-EpiCARE, Dianalund, Denmark.

Nature communications

|January 13, 2026

Resumen

Las variantes bialélicas en el gen CELSR1 causan un trastorno del neurodesarrollo con malformaciones cerebrales y discapacidad intelectual. Los modelos de ratón con deleción de Celsr1 muestran defectos cerebrales similares, lo que resalta la importancia de CELSR1.

Área de la Ciencia:

Genética y Neurociencia del Desarrollo

Sus antecedentes:

El gen CELSR1 es crucial para la vía de señalización de polaridad celular/tisular.
Codifica un receptor acoplado a proteína G de adhesión regulado en el desarrollo.

Objetivo del estudio:

Investigar el papel de CELSR1 en el neurodesarrollo humano.
Caracterizar el espectro fenotípico y la base genética de un trastorno del neurodesarrollo asociado con variantes de CELSR1.

Principales métodos:

Se utilizó la secuenciación del exoma completo para identificar variantes de CELSR1 en individuos afectados de cinco familias.
Se emplearon análisis bioinformáticos, modelado de proteínas y herramientas de predicción para evaluar la patogenicidad de las variantes.
Se generaron ratones knockout de Celsr1 para modelar el trastorno y estudiar los efectos funcionales.

Principales resultados:

Siete sujetos de cinco familias presentaron un trastorno del neurodesarrollo relacionado con variantes bialélicas de CELSR1 (cinco heterocigotos compuestos, uno homocigoto).
Las características fenotípicas incluyeron diversas malformaciones cerebrales (paquigiria, heterotopia, anomalías del cuerpo calloso, etc.), retraso del neurodesarrollo, discapacidad intelectual, problemas de comportamiento y epilepsia.
Los ratones knockout de Celsr1 exhibieron fenotipos que reflejan malformaciones cerebrales humanas, incluida la agenesia del cuerpo calloso, heterotopia periventricular y susceptibilidad a convulsiones.

Conclusiones:

Las variantes bialélicas de CELSR1 son patogénicas y causan un trastorno del neurodesarrollo distinto.
CELSR1 desempeña un papel crítico en el desarrollo embrionario y posnatal, particularmente en procesos dependientes de la polaridad.
El estudio destaca la importancia de CELSR1 en el desarrollo cerebral y proporciona información sobre los mecanismos moleculares subyacentes a los trastornos del neurodesarrollo relacionados.

Palabras clave:

CELSR1 malformaciones cerebrales trastornos del neurodesarrollo epilepsia variantes bialélicas discapacidad intelectual ratón Celsr1 knockout

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