Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: UMLS:C0036341 (
schizophrenia
)
60,220
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures. 2339 57
Involvement of the gamma-aminobutyric acid (GABA)-ergic system in
schizophrenia
pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining
schizophrenia
risk is unknown. We therefore tested the association of 375 tagged SNPs in genes derived from the GABAergic system, such as GABA
A
receptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese
schizophrenia
case-control samples (n=2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABA
A
receptor subunit genes and the
GPHN
gene with
schizophrenia
, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (P
allele
=0.002; uncorrected) and rs1157122 (P
allele
=0.006; uncorrected) showed top hits, followed by rs723432 (P
allele
=0.007; uncorrected) in the
GPHN
gene. All three were significantly associated with
schizophrenia
and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not
GPHN
were significantly associated with
schizophrenia
. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in
schizophrenia
susceptibility. These results warrant further investigations to replicate the association of GABRA1 and
GPHN
with
schizophrenia
and to discern the precise mechanisms of disease pathophysiology.
...
PMID:Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia. 2807 5
