LY86-AS1 predicts poor prognosis and inhibits progression in non-small cell lung cancer by targeting the miR-132-3p/RB1CC1 axis.

The brain relies on a careful balance between excitatory and inhibitory signals to function normally. When this balance is disrupted, for example because inhibitory synapses fail to form properly, this can result in epilepsy, one of the most common neurological disorders worldwide. Many epilepsy cases are now known to arise from spontaneous mutations in single genes, but the precise molecular mechanisms often remain poorly understood, making diagnosis and treatment development difficult. In this study, we report a child born with epileptic seizures and developmental delay, caused by a single change in the gene encoding gephyrin, a key scaffolding protein that anchors inhibitory receptors at neuronal contacts. We show that this mutation (G134R) sits in a part of gephyrin called the G-domain and prevents the protein from assembling into the large molecular clusters it normally forms. Without this self-assembly, gephyrin cannot undergo the droplet-like condensation process that concentrates it at inhibitory synapses. In neurons, the mutant protein not only fails to do its job, but actively interferes with the healthy copy of gephyrin still present in the cell, a so-called dominant-negative effect, causing a near-complete breakdown of inhibitory synapse formation. These findings reframe how scientists and clinicians think about gephyrin-related disease, shifting attention to a part of the protein that was previously underappreciated. They explain why a single inherited mutation is sufficient to cause severe neurological symptoms and will aid the interpretation of newly discovered gephyrin variants in epilepsy diagnostic panels. Longer term, restoring gephyrin self-assembly emerges as a plausible therapeutic strategy for this and related forms of genetic epilepsy.