<scp><i>GABRG1</i></scp> variant as a potential novel cause of epileptic encephalopathy, hypotonia, and global developmental delay

Williams, Aaron M.; Cooney, Erin; Segal, Gabrielle; Narayanan, Swetha; Morand, Megan; Agadi, Satish

doi:10.1002/ajmg.a.62969

Cited by 5 publications

(5 citation statements)

References 31 publications

(31 reference statements)

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“…GABRG1 encoded a gamma subunit of the GABAA receptor (gamma-aminobutyric acid type A receptor) [ 62 ]. The GABA system usually acts as an inhibitory neurotransmitter to regulate the activities of the central nervous system [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

Key mRNAs and lncRNAs of pituitary that affect the reproduction of FecB + + small tail han sheep

Yang,

Tang,

et al. 2024

BMC Genomics

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Background The pituitary directly regulates the reproductive process through follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Transcriptomic research on the pituitaries of ewes with different FecB (fecundity Booroola) genotypes has shown that some key genes and lncRNAs play an important role in pituitary function and sheep fecundity. Our previous study found that ewes with FecB + + genotypes (without FecB mutation) still had individuals with more than one offspring per birth. It is hoped to analyze this phenomenon from the perspective of the pituitary transcriptome. Results The 12 Small Tail Han Sheep were equally divided into polytocous sheep in the follicular phase (PF), polytocous sheep in the luteal phase (PL), monotocous sheep in the follicular phase (MF), and monotocous sheep in the luteal phase (ML). Pituitary tissues were collected after estrus synchronous treatment for transcriptomic analysis. A total of 384 differentially expressed genes (DEGs) (182 in PF vs. MF and 202 in PL vs. ML) and 844 differentially expressed lncRNAs (DELs) (427 in PF vs. MF and 417 in PL vs. ML) were obtained from the polytocous-monotocous comparison groups in the two phases. Functional enrichment analysis showed that the DEGs in the two phases were enriched in signaling pathways known to play an important role in sheep fecundity, such as calcium ion binding and cAMP signaling pathways. A total of 1322 target relationship pairs (551 pairs in PF vs. MF and 771 pairs in PL vs. ML) were obtained for the target genes prediction of DELs, of which 29 DEL-DEG target relationship pairs (nine pairs in PF vs. MF and twenty pairs in PL vs. ML). In addition, the competing endogenous RNA (ceRNA) networks were constructed to explore the regulatory relationships of DEGs, and some important regulatory relationship pairs were obtained. Conclusion According to the analysis results, we hypothesized that the pituitary first receives steroid hormone signals from the ovary and uterus and that VAV3 (Vav Guanine Nucleotide Exchange Factor 3), GABRG1 (Gamma-Aminobutyric Acid A Receptor, Gamma 1), and FNDC1 (Fibronectin Type III Domain Containing 1) played an important role in this process. Subsequently, the reproductive process was regulated by gonadotropins, and IGFBP1 (Insulin-like Growth Factor Binding Protein 1) was directly involved in this process, ultimately affecting litter size. In addition, TGIF1 (Transforming Growth Factor-Beta-Induced Factor 1) and TMEFF2 (Transmembrane Protein With EGF Like And Two Follistatin Like Domains 2) compensated for the effect of the FecB mutation and function by acting on TGF-β/SMAD signaling pathway, an important pathway for sheep reproduction. These results provided a reference for understanding the mechanism of multiple births in Small Tail Han Sheep without FecB mutation.

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Section: Discussionmentioning

confidence: 99%

Key mRNAs and lncRNAs of pituitary that affect the reproduction of FecB + + small tail han sheep

Yang,

Tang,

et al. 2024

BMC Genomics

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“…SCI-mediated downregulated genes include the NMDA/GABA receptor family and the potassium channel genes. Of the three GABA receptors examined, strain differences were most prominent for Gabrg1 (Gamma-Aminobutyric Acid Type A Receptor Subunit Gamma1), which has been implicated in epilepsy [56,57] and alcoholism [58,59], as well as with depression and suicide behavior [60]. Among the potassium channels genes, strain differences were most prominent in Kcnv2 (Potassium Voltage-Gated Channel Modifier Subfamily V Member 2) and Lrrc26 (Leucine Rich Repeat Containing 26), which has been implicated in chronic neuropathic pain [61].…”

Section: Discussionmentioning

confidence: 99%

Dissecting Genetic Mechanisms of Differential Locomotion, Depression, and Allodynia after Spinal Cord Injury in Three Mouse Strains

Yang,

Matyas,

et al. 2024

Cells

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Strain differences have been reported for motor behaviors, and only a subset of spinal cord injury (SCI) patients develop neuropathic pain, implicating genetic or genomic contribution to this condition. Here, we evaluated neuropsychiatric behaviors in A/J, BALB/c, and C57BL/6 male mice and tested genetic or genomic alterations following SCI. A/J and BALB/c naive mice showed significantly less locomotor activity and greater anxiety-like behavior than C57BL/6 mice. Although SCI elicited locomotor dysfunction, C57BL/6 and A/J mice showed the best and the worst post-traumatic recovery, respectively. Mild (m)-SCI mice showed deficits in gait dynamics. All moderate/severe SCI mice exhibited similar degrees of anxiety/depression. mSCI in BALB/c and A/J mice resulted in depression, whereas C57BL/6 mice did not exhibit depression. mSCI mice had significantly lower mechanical thresholds than their controls, indicating high cutaneous hypersensitivity. C57BL/6, but not A/J and BLAB/c mice, showed significantly lower heat thresholds than their controls. C57BL/6 mice exhibited spontaneous pain. RNAseq showed that genes in immune responses and wound healing were upregulated, although A/J mice showed the largest increase. The cell cycle and the truncated isoform of trkB genes were robustly elevated in SCI mice. Thus, different genomics are associated with post-traumatic recovery, underscoring the likely importance of genetic factors in SCI.

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“…For GABAR complex signaling pathway (Supplementary Table 7), only eight genes showed differential expression between epilepsy and control groups, with GABRG3 and GABRG1 under-studied in epilepsy. 48 GABRG3 was significantly up-regulated in the L2_4_CUX2_YWHAH, PVALB_RGS5, and SST_PENK subtypes. The L2_4_CUX2_YWHAH and PVALB_RGS5 subtypes exhibited the highest number of significantly altered genes (with an avg _log2 (FC) > 1 or < -1 and p < 0.05) in the above three receptor pathways, and suggest that these We performed additional analysis on the neuronal development signaling pathways (GO:0048666) in the identified 34 neuronal subtypes.…”

Section: Epilepsy-related Signaling Pathways and Novel Epilepsy-relat...mentioning

confidence: 90%

Prominent contributions of selective neuronal subtypes to pediatric drug-resistant focal dysplasia

Zhang

Lin

Zhu

et al. 2023

Preprint

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About 75% cases of epilepsy begin during childhood, and 10 - 30% of pediatric epilepsy patients are resistant to drug treatment. The predominant seizure type in children is focal cortical dysplasia (FCD) which is highly associated with drug-resistant epilepsy, but its underlying cause is poorly understood. We performed single-cell RNA sequencing and patch-clamp recording on fresh brain tissues obtained from pediatric FCD patients shortly after surgery to reveal critical factors contributing to FCD. We report that known epilepsy genes or significant transcriptomic alterations occur in only a few neuronal subgroups, suggesting that epilepsy-associated neurons cluster into only a few neuronal subtypes. These epilepsy-subtypes displayed significant epilepsy-related transcriptomic alterations, especially in the genes associated with excitation/inhibition balance and neuron functional signal pathways. Among eight epilepsy-subtypes, L2_4_CUX2_YWHAH and PVALB_RGS5 subtypes showed the most prominent alterations in FCD patient tissues. Supporting PV-neurons being important, recording from fast-spiking/parvalbumin-containing neurons in acute FCD patient brain slices revealed reduced excitatory synaptic inputs, implicating lower activity in these neurons and fewer synaptic inputs onto them. A higher percentage of mitochondria genes, and likely higher activity in the pathways associated with oxidative phosphorylation and ATP biosynthetic process, was observed in the epilepsy-subtypes, suggesting a high energy expenditure in them. Interestingly, the activity of the above two pathways in most epilepsy-subtypes was lower in the FCD patients, suggesting these subtypes may be more vulnerable to energy deficit in epilepsy. Altogether, transcriptomics is significantly altered in only a few neuronal subtypes in pediatric FCD patient brains. These selective epilepsy-subtypes may play prominent roles in the genesis of pediatric drug-resistant seizure and targeting them may provide new treatment options.

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GABRG1 variant as a potential novel cause of epileptic encephalopathy, hypotonia, and global developmental delay

Cited by 5 publications

References 31 publications

Key mRNAs and lncRNAs of pituitary that affect the reproduction of FecB + + small tail han sheep

Key mRNAs and lncRNAs of pituitary that affect the reproduction of FecB + + small tail han sheep

Dissecting Genetic Mechanisms of Differential Locomotion, Depression, and Allodynia after Spinal Cord Injury in Three Mouse Strains

Prominent contributions of selective neuronal subtypes to pediatric drug-resistant focal dysplasia

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