Genetic variations in GABA metabolism and epilepsy

Feng, Yan; Wei, Zihan; Liu, Chao; Li, Guo-Yan; Qiao, Xiaomu; Gan, Yajing; Zhang, Chuchu; Deng, Yanchun

doi:10.1016/j.seizure.2022.07.007

Cited by 29 publications

(21 citation statements)

References 59 publications

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“…The GAD1 gene is located on 2q31.1, has 21 exons, and encodes the GAD67 enzyme, which converts L-glutamate to GABA. 3 As a result of mutation, the leucine amino acid has been replaced by phenylalanine, which has a bigger side chain. The mutation is located in the PLP-binding domain, which is important for…”

Section: Gyration Analysismentioning

confidence: 99%

“…1,2 GABA is produced from the decarboxylation of glutamate by the glutamate decarboxylase (GAD) enzyme. 3 There are two isoforms of the GAD enzyme, including GAD67 and GAD65, which are encoded by two distinct GAD1 and GAD2 genes, respectively. 4 GADs for catalysis in their active site demand the pyridoxal phosphate (PLP) cofactor, which is derived from vitamin B6.…”

Section: Introductionmentioning

confidence: 99%

“…4 GADs for catalysis in their active site demand the pyridoxal phosphate (PLP) cofactor, which is derived from vitamin B6. 3 The two isoforms share nearly 70% similarity in their amino acid sequences, and most of their difference occurs in their N-terminal domain, which determines the distinct sub-cellular location of each isoform. 5,6 GAD67 is a ubiquitously expressed and constitutively active isoform that preferentially synthesizes cytoplasmic GABA and provides more than 90% of GABA in the human CNS.…”

Section: Introductionmentioning

confidence: 99%

“…GABA is involved in different biological functions, including the formation of the human neural network during embryonic development, regulating synaptic transmission, locomotor activity, learning, reproduction, circadian rhythms, and the prevention of insomnia and depression 1,2 . GABA is produced from the decarboxylation of glutamate by the glutamate decarboxylase (GAD) enzyme 3 . There are two isoforms of the GAD enzyme, including GAD67 and GAD65, which are encoded by two distinct GAD1 and GAD2 genes, respectively 4 .…”

Section: Introductionmentioning

confidence: 99%

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Developmental and epileptic encephalopathy 89: A novel bi‐allelic variant, molecular dynamics simulation, and a comprehensive clinical and molecular profile

2023

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Objective: Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult central nervous system, plays an important role during embryonic neural network formation. GAD67 is the rate-limiting enzyme in GABA synthesis, and its deficiency leads to developmental and epileptic encephalopathy 89 (DEE 89). Patients who suffered from this syndrome generally manifested severe to profound neurodevelopmental delay, seizures, and often congenital anomalies such as the cleft palate or/and omphalocele. Up to now, only three papers on this syndrome have been published, and our knowledge about the disease's clinical course and pathophysiology is in its infancy. Methods:We used whole-exome sequencing (WES) and multiple in-silico tools to detect a potential causative variant in a patient with severe neurodevelopmental delay and refractory epilepsy. Moreover, by molecular docking and molecular dynamics simulation, we investigate the effect of the candidate variant on the GAD67 function and structure.

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Section: Gyration Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Developmental and epileptic encephalopathy 89: A novel bi‐allelic variant, molecular dynamics simulation, and a comprehensive clinical and molecular profile

2023

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“…Researchers found out that the gut microbiota is a key factor in the progression of chronic liver disease, while the gut microbiota (e.g., Enterococcus and Escherichia coli ) in patients with liver cirrhosis has significant changes compared to healthy individuals ( Hussain et al, 2020 ; Ren et al, 2021 ). Moreover, Escherichia coli can produce an active amino acid GABA through the metabolic pathway ( Altaib et al, 2022 ), which can activate glucose metabolism in the brain, improve brain function and impact epileptic seizures via the genetic pathway ( Feng et al, 2022 ). Epilepsy is another of the third most common chronic neurological disorder worldwide, which usually suffers from depression, anxiety, obsessive-compulsive disorder, migraine and other disorders ( Löscher et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Identifying microbe-disease association based on graph convolutional attention network: Case study of liver cirrhosis and epilepsy

Shi

Li²,

Wang³

et al. 2023

Front. Neurosci.

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The interactions between the microbiota and the human host can affect the physiological functions of organs (such as the brain, liver, gut, etc.). Accumulating investigations indicate that the imbalance of microbial community is closely related to the occurrence and development of diseases. Thus, the identification of potential links between microbes and diseases can provide insight into the pathogenesis of diseases. In this study, we propose a deep learning framework (MDAGCAN) based on graph convolutional attention network to identify potential microbe-disease associations. In MDAGCAN, we first construct a heterogeneous network consisting of the known microbe-disease associations and multi-similarity fusion networks of microbes and diseases. Then, the node embeddings considering the neighbor information of the heterogeneous network are learned by applying graph convolutional layers and graph attention layers. Finally, a bilinear decoder using node embedding representations reconstructs the unknown microbe-disease association. Experiments show that our method achieves reliable performance with average AUCs of 0.9778 and 0.9454 ± 0.0038 in the frameworks of Leave-one-out cross validation (LOOCV) and 5-fold cross validation (5-fold CV), respectively. Furthermore, we apply MDAGCAN to predict latent microbes for two high-risk human diseases, i.e., liver cirrhosis and epilepsy, and results illustrate that 16 and 17 out of the top 20 predicted microbes are verified by published literatures, respectively. In conclusion, our method displays effective and reliable prediction performance and can be expected to predict unknown microbe-disease associations facilitating disease diagnosis and prevention.

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Enhanced production of gamma‐aminobutyric acid in fermented carrot juice by utilizing pectin hydrolysate derived from pomegranate waste

Devecioglu,

Kara,

Tapan

et al. 2024

Food Science & Nutrition

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In this study, a functional fermented beverage enriched with gamma‐aminobutyric acid (GABA) was produced. To achieve this, the prebiotic abilities of pectin obtained from pomegranate peel and its enzymatic hydrolysates were evaluated. Additionally, a functional fermented beverage enriched with GABA was produced by fermenting carrot juice with pectin hydrolysates. First, pectin was obtained at a yield of 8.91% from pomegranate peels. Pectinase‐catalyzed hydrolysis of the obtained pectin was applied using different enzyme concentrations and hydrolysis times, and the effect of these hydrolysates on the growth of Levilactobacillus brevis was determined. Although the Fourier transform infrared (FT‐IR) spectra of the resulting hydrolysates were similar, their degree of esterification compared to that of pectin was statistically different (p < .05). Considering the viability analysis and GABA production of L. brevis in the liquid medium supplemented with pectin or its hydrolysate, the hydrolysate obtained by treatment with 400 μL enzyme for 2 h and having a high glucose content (216.80 mg/100 g) was selected for application in fermented carrot juice. During fermentation (24, 48, and 72 h), a remarkable change was observed, especially in the amounts of lactic acid and malic acid, while the amount of GABA in carrot juice varied between 25 and 46 mg/mL and increased with the increase in hydrolysate concentration. It was observed that the total phenolic content and antioxidant activity of carrot juice were highly affected by the hydrolysate concentration. This study demonstrated that pectin hydrolysate obtained from food waste could be a potential prebiotic and could be used in the production of a functional beverage with improved GABA content.

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Genetic variations in GABA metabolism and epilepsy

Cited by 29 publications

References 59 publications

Developmental and epileptic encephalopathy 89: A novel bi‐allelic variant, molecular dynamics simulation, and a comprehensive clinical and molecular profile

Developmental and epileptic encephalopathy 89: A novel bi‐allelic variant, molecular dynamics simulation, and a comprehensive clinical and molecular profile

Identifying microbe-disease association based on graph convolutional attention network: Case study of liver cirrhosis and epilepsy

Enhanced production of gamma‐aminobutyric acid in fermented carrot juice by utilizing pectin hydrolysate derived from pomegranate waste

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