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La recombinación mitótica en pacientes con ictiosis causa la reversión de las mutaciones dominantes en KRT10
Keith A Choate1, Yin Lu, Jing Zhou
1Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA.
Science (New York, N.Y.)
|August 28, 2010
Resumen
La ictiosis con confeti, un raro trastorno de la piel, está relacionada con los clones de piel revertentes. Los investigadores identificaron mutaciones en el gen de la queratina 10 (KRT10) responsable de esta condición.
Área de la Ciencia:
- Genética La genética.
- Dermatología Dermatología dermatología.
- Biología celular Biología celular.
Sus antecedentes:
- La pérdida somática de alelos de tipo salvaje puede causar enfermedades, mientras que la pérdida de mutaciones de enfermedades puede revertir los fenotipos, aunque rara vez.
- La ictiosis con confeti es un trastorno cutáneo grave y esporádico caracterizado por distintos fenotipos cutáneos.
Objetivo del estudio:
- Para investigar las bases genéticas de la ictiosis con confeti.
- Identificar las mutaciones responsables de la enfermedad y comprender el mecanismo de la reversión somática.
Principales métodos:
- Análisis de clones revertentes en ictiosis con pacientes con confeti.
- Mapeo de la pérdida de heterocigosidad en el cromosoma 17q a través de la recombinación mitótica.
- Identificación y caracterización de mutaciones en el gen de la queratina 10 (KRT10).
Principales resultados:
- Se observaron miles de clones de piel normal revertentes en ictiosis con pacientes con confeti.
- La pérdida de heterocigosidad en el cromosoma 17q a través de la recombinación mitótica se identificó como el mecanismo para la reversión.
- Todas las mutaciones causantes de enfermedades identificadas fueron cambios de marco en KRT10, lo que lleva a una proteína de queratina 10 alterada que se localiza en el nucleolo.
Conclusiones:
- La alta frecuencia de la reversión somática sugiere una selección positiva de clones de células madre revertentes o una tasa elevada de recombinación mitótica en individuos afectados.
- Las mutaciones en KRT10 causan ictiosis con confeti al interrumpir la formación de la red de filamentos de queratina y la localización de proteínas.
- Comprender estos mecanismos proporciona información sobre las queratinopatías y el mosaicismo somático.
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