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<p>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 unable to form synaptic clusters and exerts a dominant-negative effect on WT-gephyrin, severely disrupting inhibitory synapse formation. Our findings highlight a critical role for the G-domain in gephyrin self-assembly and LLPS, shifting the focus from the E-domain-centric view of gephyrin function and providing a novel molecular mechanism for epilepsy linked to G-domain mutations.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Emanuel H W Bruckisch,
  • Marcelo de Melo Aragão,
  • Thais dos Santos Rohde,
  • Ann-Kathrin Huber,
  • Mateus de Oliveira Torres,
  • Günter Schwarz,
  • Filip Liebsch

摘要

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 unable to form synaptic clusters and exerts a dominant-negative effect on WT-gephyrin, severely disrupting inhibitory synapse formation. Our findings highlight a critical role for the G-domain in gephyrin self-assembly and LLPS, shifting the focus from the E-domain-centric view of gephyrin function and providing a novel molecular mechanism for epilepsy linked to G-domain mutations.