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Prader–Willi Syndrome: An Example of Genomic Imprinting
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Besides imprinted genes in the 15q11–q13 region, three gamma amino butyric acid receptor genes (GABRB3, GABRA5, and GABRG3) and the P gene for pigment production are located toward the telomere end of the 15q11–q13 region (5). The expression status of the GABA receptor genes has recently been studied with microarray technology and reported to have a paternal bias of expression (more expression from the paternal allele than from the maternal allele) that may impact on the phenotype (24). Mouse models for PWS, whereby the human chromosome equivalent (15q11–q13) located on mouse chromosome 7 is deleted, have also been produced and their phenotypes have also been described (25). By studying the phenotype of these mice with equivalent genetic anomalies seen in humans, a better understanding of the role of specific genes causing PWS will be gained. In addition, studies with animal models (e.g., transgenic knockout mice) involving single genes, such as SNRPN, have shown that loss of a single specific candidate gene does not necessarily correlate with the PWS phenotype. Therefore, PWS is termed a contiguous gene syndrome with several genes involved.
Cleft Lip and Palate
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
Eman Allam, Ahmed Ghoneima, Katherine Kula
CLP is etiologically heterogeneous, with complex genetic and environmental interactions. It is essential to distinguish between isolated nonsyndromic cases and those clefts associated with particular syndromes, as both are considered etiologically distinct. More than 350 specific genetic syndromes are identified as being associated with CLP [12,13]. Advances in segregation analysis, genetic linkage, and association studies, as well as twin studies, have made it possible to identify major genetic factors related to clefts [12–14]. Three classes of genes are suggested to play a role in the susceptibility to clefting: (1) genes involved in the process of palate development, specifically the transforming growth factors alpha and beta (TGFα, TGFβ 2, TGFβ 3); (2) genes identified in transgenic animal models with clefts, such as the Msx1, Msx2, Gabrb3, and Ap-2 genes; and (3) genes involved in certain biological activities that are linked to CLP pathogenesis, such as xenobiotic metabolism (CYP1A1, glutathione S-transferase μ1 [GSTM1], N-acetyltransferase [NAT2]), and nutrient metabolism (methylene tetrahydrofolate reductase [MTHFR], retinoic acid receptor [RAR-α], and folate receptor [FOLR1]). Candidate gene studies on CLP cases associated with Van der Woude (VWS) syndrome have also provided strong evidence for the involvement of the interferon regulatory factor 6 (IRF6) gene in cleft development. VWS is an autosomal dominant disorder that is considered to be the most important model for isolated CLP [15–17].
Precision medicine in stroke and other related neurological diseases
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Anjana Munshi, Vandana Sharma, Sulena Singh
The understanding of mechanisms of neuronal alteration and maintenance of their molecular signatures during disease progression is a major requirement for clinically correct diagnosis of neurological disease. Numerous diagnostic investigations, including imaging techniques, are opted by concerned clinicians for prediction and analysis of the disease. Apart from these diagnostic measures, genomic profiling is one of the cornerstones of precision or personalized therapy, which not only forecasts the susceptibility to disease but also predicts the best possible treatment for the individual patient. Many genes, including ATP binding cassette subfamily A member 7 (ABCA7), bridging integrator 1 (BIN1), complement receptor 1 (CR1), phospholipase D3 gene (PLD3), and phosphatidylinositol-binding clathrin assembly protein gene (PICALM), have been revealed to contribute toward the excess burden of deleterious coding mutations in Alzheimer's disease (Ma et al., 2014; Jiang et al., 2014; Tan et al., 2014b; Cacace et al., 2015; Vardarajan et al., 2015). In the epileptic encephalopathies, trio exome sequencing has identified that genes UDP-N-acetylglucosaminyltransferase subunit (ALG), gamma-aminobutyric acid type a receptor β3 gene (GABRB3), dynamin 1 (DNM1), hyperpolarization activated cyclic nucleotide gated potassium channel 1 (HCN1), glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), gamma-aminobutyric acid type A receptor alpha1 subunit (GABRA1), G protein subunit alpha O1 (GNAO1), potassium sodium-activated channel subfamily T member 1 (KCNT1), sodium voltage-gated channel alpha subunit 2 (SCN2A), sodium voltage-gated channel alpha subunit 8 (SCN8A), and solute carrier family 35 member A2 (SLC35A2) are associated with epileptogenesis. Many of the proteins encoded by these genes have been found to be associated with synaptic transmission (Epi, 2015).
Evaluation of serum MicroRNA expression profiles in patients with panic disorder
Published in Psychiatry and Clinical Psychopharmacology, 2019
Fikret Poyraz Çökmüş, Erol Özmen, Tunç Alkin, Muhammet Burak Batir, Fethi Sırrı Çam
GABA, the major inhibitory neurotransmitter in the central nervous system, is thought to play an important role in the development of anxiety and panic attacks. A study indicated that stress-associated anxiety and depression suicide risk was elevated in carriers of the GABRA6 rs3219151 T allele [35]. Neurochemical mechanisms that interrupt GABAergic activity can cause anxiety [36,37] and various GABAergic drugs are effective in panic [38,39]. As a result of our study, we determined that miR-1297 and miR-4465 were upregulated in PD group compared with the HCs. These two miRNAs can be expected to regulate gene regions linked to benzodiazepines, which are potent anti-panic drugs. In addition, the gene regions that they affect regulate both benzodiazepine-sensitive GABAA receptors and benzodiazepine-insensitive GABAA receptors. Alcohol, binds to benzodiazepine-insensitive GABAA receptors [40] known to exhibit anxiolytic properties, and the association of alcohol use disorders in patients with PD is common [41,42]. In an alcohol withdrawal study, downregulation of GABRA4 expression is mediated in part by the induction of specific microRNAs [43]. Another study investigating candidate gene regions of PD, 8 of the GABAA receptor subtypes investigated were not associated with PD [44]. Another study found that GABRA5 and GABRB3 were associated with PD [45]. There are more studies investigating the relationship of PD with GABAAA receptor subtypes [46,47]. However, the results are inconsistent and new studies targeting the GABAergic system, GABAA receptor subtypes, and the miRNAs affecting them may be relevant in PD.
Prader-Willi syndrome and Angelman syndrome: Visualisation of the molecular pathways for two chromosomal disorders
Published in The World Journal of Biological Psychiatry, 2019
Friederike Ehrhart, Kelly J. M. Janssen, Susan L. Coort, Chris T. Evelo, Leopold M. G. Curfs
The last pathway section contains four genes that are involved in PWS as well as in AS (Figure 10). Although, they are not imprinted in the same way as the PWS- and AS-causing genes, which would lead to a complete loss of the gene product, the gene doses are reduced. GABRB3 is the main actor here, as it stimulates the transcription of GABRA5, GABRG3 and OCA2 (Delahanty et al. 2016). GABRB3, GABRA5 and GABRG3 all encode a subunit of the GABA(A) receptor. Expression of GABRB3 was found in embryonic stem cells and neural crest stem cells (Delahanty et al. 2016). These cells are known to give rise to various cells, including melanocytes. What role GABRB3 plays in the differentiation of those stem cells is unknown, visualised by dashed lines in the pathway. A lack of subunit β-3 impairs the function of the GABA(A) receptor, causing problems in rapid inhibitory synaptic transmission in the central nervous system (Homanics et al. 1997). This can lead to epilepsy, cleft palate and hypersensitive behaviour, especially in the case of AS together with the loss of UBE3A induced dysfunction of the GABAergic neurons (Greer et al. 2010; Judson et al. 2016). Loss of GABRA5 and GABRG3 also impair GABA(A) receptor function (and there is recent evidence that the GABA levels are also decreased in PWS patients (Rice et al. 2016)). This mechanism could also play a role in the development of these disorders in humans, but this has not yet been proven. OCA2 encodes the P-protein, which is known to be important in the production of melanin (Delahanty et al. 2016). The loss of GABRB3 alone causes expression of OCA2 to be impaired, leading to hypopigmentation. In PWS and AS, both genes are deleted, probably enhancing that effect.
A double-blind, placebo-controlled, randomised-designed GABA tea study in children diagnosed with autism spectrum conditions: a feasibility study clinical trial registration: ISRCTN 72571312
Published in Nutritional Neuroscience, 2021
Penelope Hannant, Sarah Cassidy, Derek Renshaw, Anna Joyce
In addition to these pathological abnormalities of the cerebellum and basal ganglia in ASC, neurological differences are also present. Purkinje and MSN cells release the inhibitory neurotransmitter, GABA, which is key in sensory discrimination [15]. GABA is considered essential to reducing and inhibiting sensory feedback and decreases the firing of neurons, regulating brain excitability [68]. Variations in GABAergic transmission have been associated with sleep disorders [69] and hyper-excitable states such as anxiety and epilepsy [70–71]. GABAergic functioning has also been implicated in tactile reactivity and performance [72–73]. Significant reductions of 63% and 61% respectively in GABAA receptors and the glutamic acid decarboxylase protein (GAD) (the enzyme responsible for converting glutamate into GABA) have been found in ASC in comparison to controls [74–75]. GABA levels have also been shown to be lower in the auditory and motor cortices of children with ASC [16]. In addition, increased glutamate levels in blood and platelets have been found in ASC subjects, suggesting impaired conversion of glutamate to GABA [74,76]. Moreover, a key candidate gene for ASC is the GABA receptor gene, GABRB3 [77–78]. Furthermore, a study by Green et al. [79] demonstrated that participants with ASC also showed stronger activation of the amygdala towards sensory stimuli, which is thought to perform a pivotal role in emotion processing and decision-making; GABAergic neurons are also present in the amygdala [17,80]. It is noteworthy that GABA is a neurotransmitter of enteric neurons in the mammalian gastrointestinal tract [81] and GABAA receptors are influenced greatly by testosterone levels [82], where both gastrointestinal difficulties [83] and exposure to high concentrations of testosterone levels prenatally [84] are associated with ASC. Thus, establishing and maintaining a balance between the inhibitory and excitatory responses in this key neural pathway appears to be intrinsically linked to ASC [85].