Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy

Abstract

Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition plays an important role in neurological disorders. Gephyrin is a central player at inhibitory postsynapses, directly binds and organizes GABAA and glycine receptors (GABAARs and GlyRs), and is thereby indispensable for normal inhibitory neurotransmission. Additionally, gephyrin catalyzes the synthesis of the molybdenum cofactor (MoCo) in peripheral tissue. We identified a de novo missense mutation (G375D) in the gephyrin gene (GPHN) in a patient with epileptic encephalopathy resembling Dravet syndrome. Although stably expressed and correctly folded, gephyrin‐G375D was non‐synaptically localized in neurons and acted dominant‐negatively on the clustering of wild‐type gephyrin leading to a marked decrease in GABAAR surface expression and GABAergic signaling. We identified a decreased binding affinity between gephyrin‐G375D and the receptors, suggesting that Gly375 is essential for gephyrin–receptor complex formation. Surprisingly, gephyrin‐G375D was also unable to synthesize MoCo and activate MoCo‐dependent enzymes. Thus, we describe a missense mutation that affects both functions of gephyrin and suggest that the identified defect at GABAergic synapses is the mechanism underlying the patient's severe phenotype.

S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

“…Cortical neurons (DIV 10) were cultivated in a 6C). The sequence of events identified in this study is supported by previous findings of maladaptive changes in gephyrin function as a pathogenic factor in epilepsy (40,41,46,47).…”

Critical roles of αII spectrin in brain development and epileptic encephalopathy

“…Gephyrin is required for the organization, stability, and clustering of GABA A Rs (37,38). Genetic mutations in both GABA A Rs and gephyrin have been identified in different epilepsy syndromes, including severe epileptic encephalopathies (39)(40)(41)(42)(43)(44). Our data suggest that defective gephyrin clustering and GABAergic innervation of cortical pyramidal neurons contribute to the pathogenesis of EIEE5, providing further evidence that inhibitory transmission plays critical roles in EIEEs.…”

10.2174/1381612823666170809115827

“…Every attempt to stop or reduce the medication led to seizure recurrence. The missense mutation was shown to abolish both postsynaptic clustering with subsequent impairment of GABAergic synapse function, and synthesis of the molybdenum cofactor, which is vital for the function of molybdo-enzymes, without affecting the structure and folding of the protein [438].…”