scholarly journals Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans

2017 ◽  
Author(s):  
Douglas R. Smith ◽  
Christine M. Stanley ◽  
Theodore Foss ◽  
Richard G. Boles ◽  
Kevin McKernan
Keyword(s):  
Genetic Variants ◽  
Rare Variants ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Brain Morphology ◽  
Molecular Testing ◽  
Diacylglycerol Lipase ◽  
Rare Genetic Variants ◽  
Type 1 Cannabinoid Receptor

AbstractRare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from up to 6.032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1), were found to be significantly associated with pain sensitivity (especially migraine), sleep and memory disorders - alone or in combination with anxiety - compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and developmental disorders, including abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

scholarly journals Rare variants association testing for a binary outcome when pooling individual level data from heterogeneous studies

2020 ◽  
Author(s):  
Tamar Sofer ◽  
Na Guo
Keyword(s):  
Genetic Variants ◽  
Error Control ◽  
Rare Variants ◽  
Score Test ◽  
Saddlepoint Approximation ◽  
Rare Allele ◽  
Association Testing ◽  
Type 1 Error ◽  
Rare Genetic Variants

AbstractWhole genome and exome sequencing studies are used to test the association of rare genetic variants with health traits. Many existing WGS efforts now aggregate data from heterogeneous groups, e.g. combining sets of individuals of European and African ancestries. We here investigate the statistical implications on rare variant association testing with a binary trait when combining together heterogeneous studies, defined as studies with potentially different disease proportion and different frequency of variant carriers. We study and compare in simulations the type 1 error control and power of the naïve Score test, the saddlepoint approximation to the score test (SPA test), and the BinomiRare test in a range of settings, focusing on low numbers of variant carriers. We show that type 1 error control and power patterns depend on both the number of carriers of the rare allele and on disease prevalence in each of the studies. We develop recommendations for association analysis of rare genetic variants. (1) The Score test is preferred when the case proportion in the sample is 50%. (2) Do not down-sample controls to balance case-control ratio, because it reduces power. Rather, use a test that controls the type 1 error. (3) Conduct stratified analysis in parallel with combined analysis. Aggregated testing may have lower power when the variant effect size differs between strata.

scholarly journals On the Role of Central Type-1 Cannabinoid Receptor Gene Regulation in Food Intake and Eating Behaviors

2021 ◽  
Vol 22 (1) ◽  
pp. 398
Author(s):  
Mariangela Pucci ◽  
Elizabeta Zaplatic ◽  
Maria Vittoria Micioni Di Bonaventura ◽  
Emanuela Micioni Di Bonaventura ◽  
Paolo De Cristofaro ◽  
...  
Keyword(s):  
Food Intake ◽  
Eating Behaviors ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Receptor Gene ◽  
Endocannabinoid System ◽  
Central Type ◽  
Type 1 Cannabinoid Receptor

Different neuromodulatory systems are involved in long-term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role. We here review current literature focusing on the role of the gene encoding type-1 cannabinoid receptors in the CNS and on the modulation of its expression by food intake and specific eating behaviors. We point out the importance to further investigate how environmental cues might have a role in the development of obesity as well as eating disorders through the transcriptional regulation of this gene in order to prevent or to treat these pathologies.

scholarly journals Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Muhammad Aslam ◽  
Nirosiya Kandasamy ◽  
Anwar Ullah ◽  
Nagarajan Paramasivam ◽  
Mehmet Ali Öztürk ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Variants ◽  
Rare Variants ◽  
Alpha Synuclein ◽  
Younger Age ◽  
Targeted Treatments ◽  
Genes Encoding ◽  
Rare Genetic Variants

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

scholarly journals Estrogens and Spermiogenesis: New Insights from Type 1 Cannabinoid Receptor Knockout Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Giovanna Cacciola ◽  
Teresa Chioccarelli ◽  
Silvia Fasano ◽  
Riccardo Pierantoni ◽  
Gilda Cobellis
Keyword(s):  
Cannabinoid Receptor ◽  
Morphological Changes ◽  
Terminal Differentiation ◽  
Environmental Chemicals ◽  
Complex Mechanism ◽  
Autocrine Factors ◽  
Estrogenic Effects ◽  
Male Gametes ◽  
Type 1 Cannabinoid Receptor

Spermatogenesis is a complex mechanism which allows the production of male gametes; it consists of mitotic, meiotic, and differentiation phases. Spermiogenesis is the terminal differentiation process during which haploid round spermatids undergo several biochemical and morphological changes, including extensive remodelling of chromatin and nuclear shape. Spermiogenesis is under control of endocrine, paracrine, and autocrine factors, like gonadotropins and testosterone. More recently, emerging pieces of evidence are suggesting that, among these factors, estrogens may have a role. To date, this is a matter of debate and concern because of the agonistic and antagonistic estrogenic effects that environmental chemicals may have on animal and human with damaging outcome on fertility. In this review, we summarize data which fuel this debate, with a particular attention to our recent results, obtained using type 1 cannabinoid receptor knockout male mice as animal model.

Astroglial type-1 cannabinoid receptor (CB1): A new player in the tripartite synapse

Neuroscience ◽  
2016 ◽  
Vol 323 ◽  
pp. 35-42 ◽  
Author(s):  
J.F. Oliveira da Cruz ◽  
L.M. Robin ◽  
F. Drago ◽  
G. Marsicano ◽  
M. Metna-Laurent
Keyword(s):  
Cannabinoid Receptor ◽  
Tripartite Synapse ◽  
Type 1 Cannabinoid Receptor

Anandamide regulates the expression of GnRH1, GnRH2, and GnRH-Rs in frog testis

2012 ◽  
Vol 303 (4) ◽  
pp. E475-E487 ◽  
Author(s):  
Rosanna Chianese ◽  
Vincenza Ciaramella ◽  
Donatella Scarpa ◽  
Silvia Fasano ◽  
Riccardo Pierantoni ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Rana Esculenta ◽  
Sexual Cycle ◽  
Human Testis ◽  
Biosynthetic Enzyme ◽  
Endogenous Production ◽  
Cb1 Antagonist ◽  
Type 1 Cannabinoid Receptor

Gonadotropin-releasing hormone (either GnRH1 or GnRH2) exerts a local activity in vertebrate testis, including human testis. Relationships between endocannabinoid (eCB) and GnRH systems in gonads have never been elucidated in any species so far. To reveal a cross-talk between eCBs and GnRH at testicular level, we characterized the expression of GnRH ( GnRH1 and GnRH2) as well as GnRH receptor ( GnRH-R1, -R2, and -R3) mRNA in the testis of the anuran amphibian Rana esculenta during the annual sexual cycle; furthermore, the corresponding transcripts were localized inside the testis by in situ hybridization. The possible endogenous production of the eCB, anandamide (AEA), was investigated in testis by analyzing the expression of its biosynthetic enzyme, Nape-pld. Incubations of testis pieces with AEA were carried out in the postreproductive period (June) and in February, when a new spermatogenetic wave takes place. In June, AEA treatment significantly decreased GnRH1 and GnRH-R2 mRNA, stimulated the transcription of GnRH2 and GnRH-R1, and did not affect GnRH-R3 expression. In February, AEA treatment upregulated GnRH2 and GnRH-R3 mRNA, downregulated GnRH-R2, and did not affect GnRH1 and GnRH-R1 expression. These effects were mediated by type 1 cannabinoid receptor ( CB1) since they were fully counteracted by SR141716A (Rimonabant), a selective CB1 antagonist. In conclusion, eCB system modulates GnRH activity in frog testis during the annual sexual cycle in a stage-dependent fashion.

scholarly journals Type 1 cannabinoid receptor modulates water deprivation-induced homeostatic responses

2015 ◽  
Vol 309 (11) ◽  
pp. R1358-R1368 ◽  
Author(s):  
Silvia G. Ruginsk ◽  
Fernanda M. V. Vechiato ◽  
Ernane T. Uchoa ◽  
Lucila L. K. Elias ◽  
Jose Antunes-Rodrigues
Keyword(s):  
Mrna Expression ◽  
Water Deprivation ◽  
Energy Homeostasis ◽  
Cannabinoid Receptor ◽  
Plasma Concentrations ◽  
Hydration Status ◽  
Potential Candidate ◽  
Mrna Levels ◽  
Type 1 Cannabinoid Receptor

The present study investigated the type 1 cannabinoid receptor (CB1R) as a potential candidate to mediate the homeostatic responses triggered by 24 h of water deprivation, which constitutes primarily a hydroelectrolytic challenge and also significantly impacts energy homeostasis. The present results demonstrated for the first time that CB1R mRNA expression is increased in the hypothalamus of water-deprived (WD) rats. Furthermore, the administration of ACEA, a CB1R selective agonist, potentiated WD-induced dipsogenic effect, whereas AM251, a CB1R antagonist, attenuated not only water but also salt intake in response to WD. In parallel with the modulation of thirst and salt appetite, we confirmed that CB1Rs are essential for the development of appropriated neuroendocrine responses. Although the administration of ACEA or AM251 did not produce any effects on WD-induced arginine vasopressin (AVP) secretion, oxytocin (OXT) plasma concentrations were significantly decreased in WD rats treated with ACEA. At the genomic level, ACEA significantly decreased AVP and OXT mRNA expression in the hypothalamus of WD rats, whereas AM251 potentiated both basal and WD-induced stimulatory effects on the transcription of AVP and OXT genes. In addition, we showed that water deprivation alone upregulated proopiomelanocortin, Agouti-related peptide, melanin-concentrating hormone, and orexin A mRNA levels in the hypothalamus, and that CB1Rs regulate main central peptidergic pathways controlling food intake, being that most of these effects were also significantly influenced by the hydration status. In conclusion, the present study demonstrated that CB1Rs participate in the homeostatic responses regulating fluid balance and energy homeostasis during water deprivation.

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