Open AccessSimultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy
Author(s) -
Dejanovic Borislav,
Djémié Tania,
Grünewald Nora,
Suls Arvid,
Kress Vanessa,
Hetsch Florian,
Craiu Dana,
Zemel Matthew,
Gormley Padhraig,
Lal Dennis,
Myers Candace T,
Mefford Heather C,
Palotie Aarno,
Helbig Ingo,
Meier Jochen C,
De Jonghe Peter,
Weckhuysen Sarah,
Schwarz Guenter
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201505323
Subject(s) - gephyrin , epilepsy , medicine , function (biology) , brain function , neuroscience , cardiology , biology , microbiology and biotechnology , genetics , amino acid , glycine receptor , glycine
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 GABA A and glycine receptors ( GABA A R s 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 GABA A R surface expression and GABA ergic 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 GABA ergic synapses is the mechanism underlying the patient's severe phenotype.