Heterozygous variants in USP25 cause genetic generalized epilepsy

Area of Science:

• Neurogenetics
• Molecular Biology
• Epilepsy Research

Background:

• USP25 (ubiquitin-specific protease 25) is involved in neural development but its role in human diseases, particularly epilepsy, is undefined.
• Previous studies noted abnormal USP25 expression in Down's syndrome, hinting at its broader neurological relevance.
• Generalized epilepsy of unknown aetiology presents a significant diagnostic challenge, necessitating the identification of novel genetic factors.

Purpose of the Study:

• To investigate the potential association between USP25 gene variants and generalized epilepsy in a cohort of affected families.
• To elucidate the functional consequences of identified USP25 variants on protein function and neuronal activity.
• To determine the role of USP25 in epilepsy pathogenesis, considering both loss-of-function and gain-of-function mechanisms.

Main Methods:

• Trio-based whole exome sequencing was performed on 319 families with unexplained generalized epilepsy.
• USP25 variants were identified and analyzed for segregation with the epilepsy phenotype.
• Functional studies included mRNA/protein expression analysis, deubiquitinating activity assays, neuronal excitability measurements in vitro and in Usp25 knockout mice.

Main Results:

• Five heterozygous USP25 variants were identified in eight individuals from five families, with a significantly higher frequency than in population databases.
• USP25 variants were associated with early-onset generalized and febrile seizures, with some patients exhibiting intellectual disability.
• Functional analyses revealed that USP25 variants can lead to reduced expression, altered enzymatic activity, abnormal protein aggregation, and increased neuronal excitability, suggesting both loss-of-function and gain-of-function mechanisms.

Conclusions:

• Heterozygous variants in USP25 are significantly associated with generalized epilepsy, identifying USP25 as a potential predisposing gene for the disorder.
• USP25 plays a critical role in brain function, and its dysfunction, through either loss-of-function or gain-of-function mechanisms, can contribute to epileptogenesis.
• The findings highlight the importance of USP25 in neurological health and provide a basis for understanding the genetic underpinnings of certain epilepsy types.