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Biallelic gephyrin variants lead to impaired GABAergic inhibition in a patient with developmental and epileptic encephalopathy
- Source :
- Human molecular genetics
- Publication Year :
- 2021
- Publisher :
- Oxford University Press (OUP), 2021.
-
Abstract
- Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition is linked to epilepsy. Gephyrin (Geph) is the principal scaffolding protein at inhibitory synapses and is essential for postsynaptic clustering of glycine (GlyRs) and GABA type A receptors. Consequently, gephyrin is crucial for maintaining the relationship between excitation and inhibition in normal brain function and mutations in the gephyrin gene (GPHN) are associated with neurodevelopmental disorders and epilepsy. We identified bi-allelic variants in the GPHN gene, namely the missense mutation c.1264G > A and splice acceptor variant c.1315-2A > G, in a patient with developmental and epileptic encephalopathy. We demonstrate that the splice acceptor variant leads to nonsense-mediated mRNA decay. Furthermore, the missense variant (D422N) alters gephyrin structure, as examined by analytical size exclusion chromatography and circular dichroism-spectroscopy, thus leading to reduced receptor clustering and sensitivity towards calpain-mediated cleavage. In addition, both alterations contribute to an observed reduction of inhibitory signal transmission in neurons, which likely contributes to the pathological encephalopathy.
- Subjects :
- Scaffold protein
Biology
Inhibitory postsynaptic potential
Epilepsy
Postsynaptic potential
Genetics
medicine
Humans
Missense mutation
Receptor
Molecular Biology
Genetics (clinical)
Brain Diseases
Gephyrin
Membrane Proteins
General Medicine
Receptors, GABA-A
medicine.disease
Cell biology
Chemistry
Synapses
biology.protein
Human medicine
Receptor clustering
Carrier Proteins
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....180886e444ed6f6878cab9428fe64b24