Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures

Abstract

The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions.

Assessment and modulation of cortical inhibition using transcranial magnetic stimulation

“…This conclusion is of clinical relevance since changes of the human gene locus for gephyrin are linked with an increased risk to develop autism, schizophrenia and epilepsy (Lionel et al, 2013). Together with the studies described above, these results show that rTMS is able to mediate long-term changes of inhibitory neurotransmission consistent with rTMS-induced disinhibition.…”

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…NMDA receptors are trafficked to and anchored at the PSD by numerous proteins including PSD95, neuregulin, and SAP102. (Barnes, 2000;Lionel et al, 2013;Weickert et al, 2004). Similar to the DISC1 and neuregulin1 knockout mice, PSD95 homozygous KO's are not lethal, and the heterozygous animals share prepulse inhibition, hyperactivity, and enhanced LTP phenotypes (Desbonnet et al, 2009;Dyck et al, 2009;Kato et al, 2010;Le Greves et al, 2006;Yao et al, 2004).…”

Gephyrin: a central GABAergic synapse organizer

“…107 DISEASE IMPLICATIONS OF GEPHYRIN Some neurological disorders have been linked to gephyrin dysfunctions (e.g., stiff-person syndrome (Moersch-Woltman), hyperekplexia, temporal lobe epilepsy, molybdenum cofactor deficiency, autism and schizophrenia). [108][109][110][111][112][113] These diseases may be partly attributed to defects in the glycinergic system, which can be easily understood given the role of gephyrin in GlyR clustering. Gephyrin levels are reduced in the brains of patients suffering from Alzheimer's disease, but its direct involvement in this disorder has not yet been fully explored.…”

“…114,115 Intriguingly, temporal lobe epilepsy has been linked to abnormal operation of the gephyrin splicing machinery. 113 More specifically, cellular stresses (e.g., alkalosis) increase the proportions of gephyrin splice variants lacking exons encoding the G domain, potentially altering the activity of gephyrin clustering. 116 These results suggest that targeting the alternative splicing of gephyrin could provide a possible therapeutic strategy against the above-listed diseases.…”