Impaired gephyrin G-domain trimerization and phase separation in a patient with developmental epileptic encephalopathy

ABSTRACT: Epilepsy, a common neurological disorder is frequently linked to genetic variants in synaptic proteins. Here, we describe a de novo pathogenic missense variant in the gephyrin G-domain (G134R) identified in an individual with developmental delay, epileptic seizures, microcephaly, dysmorphic features and short stature. Functional analyses reveal that G134R disrupts higher-order oligomerization, leading to impaired liquid-liquid phase separation (LLPS) and synaptic clustering. Recombinant G134R-gephyrin variant forms lower oligomers and retains only 60% of its molybdenum cofactor (Moco) synthesis activity while binding to glycine receptor models is unaffected. In non-neuronal cells, G134R fails to oligomerize beyond dimers with Moco synthesis activity reduced to 5%. In neurons, G134R is unab

SUBMITTER: Emanuel, H. W. Bruckisch 

PROVIDER: S-SCDT-10_1038-S44321-026-00474-W | biostudies-other |

REPOSITORIES: biostudies-other