Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy.
Brain
; 147(9): 2983-2990, 2024 Sep 03.
Article
en En
| MEDLINE
| ID: mdl-38916065
ABSTRACT
Somatic mosaicism in a fraction of brain cells causes neurodevelopmental disorders, including childhood intractable epilepsy. However, the threshold for somatic mosaicism leading to brain dysfunction is unknown. In this study, we induced various mosaic burdens in focal cortical dysplasia type II (FCD II) mice, featuring mTOR somatic mosaicism and spontaneous behavioural seizures. The mosaic burdens ranged from approximately 1000 to 40 000 neurons expressing the mTOR mutant in the somatosensory or medial prefrontal cortex. Surprisingly, approximately 8000-9000 neurons expressing the MTOR mutant, extrapolated to constitute 0.08%-0.09% of total cells or roughly 0.04% of variant allele frequency in the mouse hemicortex, were sufficient to trigger epileptic seizures. The mutational burden was correlated with seizure frequency and onset, with a higher tendency for electrographic inter-ictal spikes and beta- and gamma-frequency oscillations in FCD II mice exceeding the threshold. Moreover, mutation-negative FCD II patients in deep sequencing of their bulky brain tissues revealed somatic mosaicism of the mTOR pathway genes as low as 0.07% in resected brain tissues through ultra-deep targeted sequencing (up to 20 million reads). Thus, our study suggests that extremely low levels of somatic mosaicism can contribute to brain dysfunction.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Epilepsias Parciales
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Serina-Treonina Quinasas TOR
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Mosaicismo
Límite:
Animals
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
Brain
Año:
2024
Tipo del documento:
Article