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Interacción Epistática Humana Controla el Splicing de IL7R y Aumenta el Riesgo de Esclerosis Múltiple

Gaddiel Galarza-Muñoz¹, Farren B S Briggs², Irina Evsyukova³

¹Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Center for RNA Biology, Duke University, Durham, NC 27710, USA; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.

|March 25, 2017

Resumen

Los investigadores identificaron a DDX39B como un regulador clave del empalme del receptor alfa de la interleucina-7 (IL7R), que tiene un impacto en el riesgo de esclerosis múltiple (EM). Las variantes genéticas en DDX39B influyen en la susceptibilidad a la EM al afectar el empalme del exón 6 de IL7R.

Área de la Ciencia:

Neuroinmunología
Genética molecular
Enfermedades autoinmunes

Sus antecedentes:

La esclerosis múltiple (EM) es una enfermedad autoinmune dirigida al sistema nervioso central (SNC).
El aumento del riesgo de EM está relacionado con el receptor alfa de la interleucina-7 soluble (sIL7R) derivado del empalme alternativo del exón IL7R 6.
La base genética de la EM implica interacciones complejas y mecanismos de regulación.

Objetivo del estudio:

Identificar nuevos reguladores del empalme del exón IL7R 6.
Investigar el papel de la ARN helicasa DDX39B en la patogénesis de la EM.
Elucidar las interacciones genéticas y funcionales que influyen en el riesgo de EM.

Principales métodos:

Análisis de empalme de ARN
Estudios de asociación genética
Ensayos funcionales de las variantes genéticas
Análisis de la epistasis

Principales resultados:

DDX39B fue identificado como un activador del empalme del exón 6 de IL7R, reprimiendo así la producción de sIL7R.
Una variante genética en el 5' UTR de DDX39B se asoció con una traducción reducida de DDX39B y un mayor riesgo de EM.
Se observó una epistasis genética y funcional significativa entre las variantes DDX39B y las variantes alélicas del exón 6 de IL7R.

Conclusiones:

DDX39B actúa como un regulador crucial del empalme del exón 6 de IL7R.
Las variaciones genéticas en DDX39B contribuyen al riesgo de EM a través de la modulación del splicing de IL7R.
Este estudio demuestra la epistasis biológica en humanos, proporcionando información mecanicista sobre la etiología de la EM.

Palabras clave:

En el caso de los vehículos de motor:El número IL7R empalme alternativo Trastornos autoinmunes La epistasis Asociación genética esclerosis múltiple

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