GAD1 (Glutamate Decarboxylase 1): A Key Enzyme in GABA Synthesis and Neurological Disorders
Explore the genomic, functional, and clinical significance of the GAD1 gene, including its role in GABAergic signaling, associated diseases, expression patterns, and mutation landscape.
Gene Information Card
| Symbol | GAD1 |
|---|---|
| Full Name | Glutamate Decarboxylase 1 |
| Gene Type | Protein-coding |
| Chromosomal Location | 2q31.1 |
| NCBI Gene ID | 2571 ncbi.nlm.nih.gov/gene/2571 |
| Ensembl ID | ENSG00000128683 |
| UniProt ID | Q99259 |
| OMIM ID | 605363 |
| HGNC ID | 4092 |
| Aliases | GAD67, FLJ45882, MGC161605, MGC161607 |
Description
The GAD1 gene encodes glutamate decarboxylase 1 (also known as GAD67), a pyridoxal phosphate-dependent enzyme that catalyzes the decarboxylation of glutamate to produce the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GAD1 is predominantly expressed in the central nervous system, where it plays a critical role in GABAergic neurotransmission. Alternative splicing results in multiple transcript variants; the predominant isoform is a 67 kDa protein. GAD1 is essential for normal brain development and function, and its dysregulation has been implicated in various neurological and psychiatric disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Schizophrenia | Reduced GAD1 expression leads to decreased GABA synthesis, contributing to excitatory/inhibitory imbalance in the prefrontal cortex. | Postmortem brain studies show decreased GAD1 mRNA and protein levels in cortical regions (e.g., Akbarian et al., 1995; Guidotti et al., 2000). |
| Bipolar Disorder | Altered GAD1 expression in the anterior cingulate cortex may disrupt GABAergic signaling, affecting mood regulation. | Gene expression studies report reduced GAD1 mRNA in bipolar disorder patients (e.g., Woo et al., 2004). |
| Epilepsy | Mutations or dysregulation of GAD1 may impair GABA synthesis, lowering seizure threshold. | Animal models and human studies link GAD1 variants to epilepsy susceptibility (e.g., Bu et al., 2001). |
| Autism Spectrum Disorder | GAD1 downregulation in the cerebellum and cortex may contribute to GABAergic dysfunction in autism. | Postmortem studies show reduced GAD1 expression in autistic brains (e.g., Fatemi et al., 2002). |
| Stiff-Person Syndrome | Autoantibodies against GAD1 (and GAD2) are associated with this autoimmune neurological disorder, though the gene itself is not mutated. | Serological studies demonstrate high anti-GAD antibody titers in patients (e.g., Solimena et al., 1988). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | High | Highest expression in cerebral cortex, hippocampus, and cerebellum. |
| Pancreas | Low | Expression in pancreatic islet cells (beta cells) but at lower levels than brain. |
| Testis | Low | Detectable expression in testicular tissue. |
| Kidney | Low | Minimal expression in kidney. |
| Liver | Not detected | No significant expression in liver. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | High | Neuronal-like cell line; used for GABAergic studies. |
| U87 (glioblastoma) | Moderate | Glial cell line; expression may reflect neuronal contamination. |
| HEK293 (embryonic kidney) | Low | Transfected for recombinant protein studies. |
| HeLa (cervical carcinoma) | Not detected | No endogenous expression. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs3749034 | SNP (intronic) | Minor allele frequency ~0.3 (global) | Associated with altered GAD1 expression in brain; linked to schizophrenia risk in some populations. |
| rs769391 | SNP (5' UTR) | Minor allele frequency ~0.2 | May affect transcription factor binding; implicated in bipolar disorder. |
| c.1123C>T (p.Arg375Cys) | Missense | Rare (MAF <0.01) | Reported in a patient with epilepsy; functional impact uncertain. |
| c.614A>G (p.Asn205Ser) | Missense | Rare | Found in autism spectrum disorder; may reduce enzyme activity. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in GAD1 are rare and often lethal in homozygous state; heterozygous mutations may lead to reduced GABA synthesis, contributing to epilepsy or neurodevelopmental disorders.
Gain of Function (GOF)
No clear gain-of-function mutations have been reported; increased GAD1 expression is generally not associated with disease.
Dominant Negative (DN)
Some missense mutations may exert dominant-negative effects by forming heterodimers with wild-type GAD1, reducing overall enzyme activity.
View complete mutation data：
Gene Ontology (GO)
| • glutamate decarboxylase activity (GO:0004351) | • 4-aminobutyrate transaminase activity (GO:0003867) |
| • glutamate metabolic process (GO:0006536) | • gamma-aminobutyric acid biosynthetic process (GO:0009450) |
| • chemical synaptic transmission (GO:0007268) | • plasma membrane (GO:0005886) |
| • cytoplasm (GO:0005737) | • cytosol (GO:0005829) |
Pathways
• GABAergic synapse (KEGG: hsa04727)
• Glutamate metabolism (KEGG: hsa00250)
• Neurotransmitter release cycle (Reactome: R-HSA-112310)
• GABA synthesis and release (Reactome: R-HSA-888590)
Protein Summary
The GAD1 protein (GAD67) is a 67 kDa enzyme that catalyzes the conversion of L-glutamate to GABA, the primary inhibitory neurotransmitter in the mammalian central nervous system. It requires the cofactor pyridoxal phosphate (PLP) for activity. GAD67 is responsible for the basal synthesis of GABA, whereas the related enzyme GAD65 (encoded by GAD2) is involved in activity-dependent GABA production. GAD67 is predominantly cytosolic and is expressed in GABAergic neurons, where it regulates neuronal excitability and synaptic plasticity. Post-translational modifications include phosphorylation and palmitoylation, which affect its stability and membrane association. Dysregulation of GAD67 is implicated in schizophrenia, bipolar disorder, and other neurological conditions.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GAD1 Knockout HEK293 Cell Line | EDJ-KQ2187 | Human | 2571 | Details Get a Quote |
| GAD1 Knockout HCT 116 Cell Line | EDJ-KQ22414 | Human | 2571 | Details Get a Quote |
| GAD1 Knockout HeLa Cell Line | EDJ-KQ22415 | Human | 2571 | Details Get a Quote |
| GAD1 Knockout A-549 Cell Line | EDJ-KQ61783 | Human | 2571 | Details Get a Quote |
Displaying Records 1 To 4 Of 4 Records
