| 1 | Pharmacogenet. Genomics 2008 Apr 18: 317-23 |
|---|---|
| PMID | 18334916 |
| Title | Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. |
| Abstract | Neuroleptic-induced迟发的维yskinesia (TD) is an involuntary movement disorder that develops in patients who have undergone long-term treatment with antipsychotic medications, and its etiology is unclear. In this study, a genome-wide association screening was done to identify the pathway(s) in which genetic variations influence susceptibility to neuroleptic-induced TD. Screening with Sentrix Human-1 Genotyping BeadChip (Illumina, San Diego, California, USA) was done for 50 Japaneseschizophreniapatients with treatment-resistant TD and 50 Japaneseschizophreniapatients without TD. A total of 40 573 single nucleotide polymorphisms that were not in linkage disequilibrium with each other and were located in the exonic and intronic regions of 13 307 genes were analyzed. After gene-based corrections, P values for allelic associations were subjected to canonical pathway-based analyses with Ingenuity Pathway Analysis software (Ingenuity Systems, Inc., Redwood City, California, USA). Eight genes (ABAT, ALDH9A1, GABRA3, GABRA4, GABRB2, GABRAG3,GPHN，和SLC6A11）包含基于基因校正的等位基因P值小于0.05的多态性。它们在属于γ-氨基丁酸（GABA）受体信号通路的33个基因中显着汇总（p = 0.00007，校正后p = 0.01）。在SLC6A11（GABA Transporter 3）（总样本中的P = 0.0004）中，在36例TD患者和136例TD患者的独立样本中复制了关联，GABRB2（beta-2 beta-2 beta-2亚基）在总样本中= 0.00007）和GABRG3（GABA-A受体的γ-3亚基）（总样本中的p = 0.0006）。 The results suggest that the GABA receptor signaling pathway may be involved in genetic susceptibility to treatment-resistant TD, at least in a subgroup of Japanese patients withschizophrenia. The present results suggest that benzodiazepines may be considered as possible treatment option for TD. |
| SCZ关键字 | schizophrenia |
| 2 | Hum. Mol. Genet. 2013 May 22: 2055-66 |
| PMID | 23393157 |
| Title | Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures. |
| Abstract | TheGPHNgene 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),schizophreniaand epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally splicedGPHNmRNA 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,schizophreniaor seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons ofGPHN在14q23.3染色体上。跨缺失的共同重叠区域包含3-5外显子，对应于Gephyrin蛋白的G域。这些发现，以及先前关于纯合的报道GPHNmutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of theGPHNmutation 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. |
| SCZ关键字 | schizophrenia |
| 3 | Neurobiol. Dis. 2014 Jul 67: 88-96 |
| PMID | 24561070 |
| Title | Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy. |
| Abstract | Gephyrin is a postsynaptic scaffolding protein, essential for the clustering of glycine and ?-aminobutyric acid type-A receptors (GABAARs) at inhibitory synapses. An impairment of GABAergic synaptic inhibition represents a key pathway of epileptogenesis. Recently, exonic microdeletions in the gephyrin (GPHN) gene have been associated with neurodevelopmental disorders including autism spectrum disorder,schizophreniaand epileptic seizures. Here we report the identification of novel exonicGPHNmicrodeletions in two patients with idiopathic generalized epilepsy (IGE), representing the most common group of genetically determined epilepsies. The identifiedGPHNmicrodeletions involve exons 5-9 (?5-9) and 2-3 (?2-3), both affecting the gephyrin G-domain. Molecular characterization of theGPHN?5-9 variant demonstrated that it perturbs the clustering of regular gephyrin at inhibitory synapses in cultured mouse hippocampal neurons in a dominant-negative manner, resulting in a significant loss of ?2-subunit containing GABAARs.GPHN?2-3 causes a frameshift resulting in a premature stop codon (p.V22Gfs*7) leading to haplo-insufficiency of the gene. Our results demonstrate that structural exonic microdeletions affecting theGPHNgene constitute a rare genetic risk factor for IGE and other neuropsychiatric disorders by an impairment of the GABAergic inhibitory synaptic transmission. |
| SCZ关键字 | schizophrenia |