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Desestabilización estructural de FRMD3 por una mutación en el dominio FERM causa enfermedad hipomielinizante a través

Diksha¹, Abhishek Kumar², Smita Saha³

¹All India Institute of Medical Sciences, Rishikesh 249203, India.

ACS chemical neuroscience

|January 21, 2026

Resumen

Una nueva variante del gen FRMD3 causa enfermedad hipomielinizante al desestabilizar la proteína, lo que lleva a la agregación y al deterioro de la función de los oligodendrocitos. Este descubrimiento identifica FRMD3 como un nuevo gen candidato para trastornos del neurodesarrollo.

Área de la Ciencia:

Neurogenética
Biología Molecular
Neurociencia del Desarrollo

Sus antecedentes:

Las enfermedades hipomielinizantes son trastornos raros del neurodesarrollo que afectan la formación o el mantenimiento de la mielina debido a factores genéticos.
La identificación de la base genética de estas afecciones es crucial para comprender los mecanismos de la enfermedad y desarrollar terapias.

Objetivo del estudio:

Investigar una nueva variante missense en el gen FRMD3 asociada con enfermedad hipomielinizante en un paciente pediátrico.
Elucidar los mecanismos moleculares por los cuales la variante FRMD3 conduce a la patología del neurodesarrollo.

Principales métodos:

Secuenciación genética para identificar la variante FRMD3 (c.898T > C; p.C300R).
Simulaciones de dinámica molecular y análisis biofísicos para evaluar la estructura y estabilidad de las proteínas.
Ensayos celulares (incluidos estudios de agregación y experimentos de rescate de FRMD3 en oligodendrocitos) para evaluar la función de las proteínas.
Análisis de interactoma y expresión de células únicas para mapear la localización e interacciones celulares de FRMD3.

Principales resultados:

La variante FRMD3 identificada (p.C300R) desestabiliza el dominio FERM, aumenta la agregación de proteínas y causa una localización errónea en modelos celulares.
La FRMD3 mutante altera la formación de neuritas de oligodendrocitos y no logra restaurar la expresión de proteínas de mielina (PLP1, MBP).
Se implica a FRMD3 en vías de tráfico de membranas y manejo de lípidos esenciales para la función de los oligodendrocitos.

Conclusiones:

FRMD3 es un nuevo gen candidato para enfermedades hipomielinizantes.
La desestabilización estructural y la agregación de FRMD3 alteran la función de los oligodendrocitos, lo que lleva a una alteración de la expresión de proteínas de mielina y a hipomielinización regional.
Este estudio destaca el papel crítico de la integridad estructural de las proteínas en los procesos del neurodesarrollo.

Palabras clave:

dominio FERM FRMD3 enfermedad hipomielinizante disfunción de oligodendrocitos agregación de proteínas

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