Conséquence d'une carence gestationnelle en donneurs de méthyles sur l'expression des protéines clés de la neurostéroïdogenèse chez le rat

Early methyl-donor deficiency (MDD, folate and vitamin B12) produces hyperhomocysteinemia, cognitive and motor disorders in 21 days-old rat pups. These disorders are linked to an alteration of neurogenesis in the cerebellum and the hippocampus, which is closely linked to neurosteroidogenesis, defined as the local synthesis of steroids in brain. The aim of this work was to verify if these troubles are associated with an altered neurosteroidogenesis. This work led to several striking results, showing in particular the deleterious effects of the methyl donor deficiency on the steroidogenic pathway in the cerebellum, particularly vulnerable during postnatal development. This was confirmed by the reduced contents of estradiol and other neurosteroids, as a result of the decrease of the expression of StAR, TSPO and aromatase, as well as the estrogen receptors. These deleterious effects are associated to the impairment of AMPc dependent signaling pathway and the decrease of transcription factors, notably SF-1, which the presence in the cerebellar Purkinje cells had never been described previously. This response to the deficiency would be made according to a sexual dimorphism, since only the young deficient females were affected. Finally, these studies allowed us to show functional changes associated with the cellular and molecular damage observed in the olfactory bulbs, being traduced by a decrease of the olfactory discrimination. This could contribute to the growth retardation associated with the reduced body weight of the deficient animalsLa carence précoce en donneurs de méthyles (folates et vitamine B12) entraîne une hyperhomocystéinémie ainsi que des troubles cognitifs et de la coordination motrice chez les ratons de 21 jours. Ces troubles ont été reliés à une altération de la neurogenèse dans l'hippocampe et le cervelet, mécanisme étroitement relié à la neurostéroïdogenèse (NSG), définie par la synthèse locale de stéroïdes dans le cerveau. L'objectif principal de ce travail a été de déterminer si ces troubles étaient associés à une altération de la NSG. Ce travail a conduit à plusieurs résultats marquants, montrant notamment l'effet délétère de la carence gestationnelle en donneurs de méthyles sur la voie stéroïdogénique dans le cervelet, région cérébrale particulièrement vulnérable en période post-natale. Ceci s'est traduit par un effondrement du contenu en estradiol et autres neurostéroïdes, consécutivement à la diminution de l'expression de StAR, TSPO et de l'aromatase, ainsi que des récepteurs aux estrogènes. Ces effets délétères sont associés à une atteinte de la voie de signalisation dépendante de l'AMPc associée à l'activation du récepteur LHR, et la diminution de facteurs de transcription impliqués dans la régulation des gènes de la NSG, notamment SF-1, dont la présence dans les cellules de Purkinje du cervelet n'avait jamais été décrite auparavant. Cette réponse à la carence se ferait selon un dimorphisme sexuel, puisque seules les jeunes femelles nées de mères carencées étaient affectées. Enfin, ces études ont permis la mise en évidence d'altérations fonctionnelles associées aux dommages cellulaires et moléculaires observés dans les bulbes olfactifs (BO), se traduisant par une diminution des fonctions de la discrimination olfactive. Ceci pourrait contribuer au retard de croissance associé au poids corporel réduit mesuré chez les animaux carencé

Consequences of early methyl-donor deficiency on the expression of key proteins of neurosteroidogenesis in the brain of rat

La carence précoce en donneurs de méthyles (folates et vitamine B12) entraîne une hyperhomocystéinémie ainsi que des troubles cognitifs et de la coordination motrice chez les ratons de 21 jours. Ces troubles ont été reliés à une altération de la neurogenèse dans l'hippocampe et le cervelet, mécanisme étroitement relié à la neurostéroïdogenèse (NSG), définie par la synthèse locale de stéroïdes dans le cerveau. L'objectif principal de ce travail a été de déterminer si ces troubles étaient associés à une altération de la NSG. Ce travail a conduit à plusieurs résultats marquants, montrant notamment l'effet délétère de la carence gestationnelle en donneurs de méthyles sur la voie stéroïdogénique dans le cervelet, région cérébrale particulièrement vulnérable en période post-natale. Ceci s'est traduit par un effondrement du contenu en estradiol et autres neurostéroïdes, consécutivement à la diminution de l'expression de StAR, TSPO et de l'aromatase, ainsi que des récepteurs aux estrogènes. Ces effets délétères sont associés à une atteinte de la voie de signalisation dépendante de l'AMPc associée à l'activation du récepteur LHR, et la diminution de facteurs de transcription impliqués dans la régulation des gènes de la NSG, notamment SF-1, dont la présence dans les cellules de Purkinje du cervelet n'avait jamais été décrite auparavant. Cette réponse à la carence se ferait selon un dimorphisme sexuel, puisque seules les jeunes femelles nées de mères carencées étaient affectées. Enfin, ces études ont permis la mise en évidence d'altérations fonctionnelles associées aux dommages cellulaires et moléculaires observés dans les bulbes olfactifs (BO), se traduisant par une diminution des fonctions de la discrimination olfactive. Ceci pourrait contribuer au retard de croissance associé au poids corporel réduit mesuré chez les animaux carencésEarly methyl-donor deficiency (MDD, folate and vitamin B12) produces hyperhomocysteinemia, cognitive and motor disorders in 21 days-old rat pups. These disorders are linked to an alteration of neurogenesis in the cerebellum and the hippocampus, which is closely linked to neurosteroidogenesis, defined as the local synthesis of steroids in brain. The aim of this work was to verify if these troubles are associated with an altered neurosteroidogenesis. This work led to several striking results, showing in particular the deleterious effects of the methyl donor deficiency on the steroidogenic pathway in the cerebellum, particularly vulnerable during postnatal development. This was confirmed by the reduced contents of estradiol and other neurosteroids, as a result of the decrease of the expression of StAR, TSPO and aromatase, as well as the estrogen receptors. These deleterious effects are associated to the impairment of AMPc dependent signaling pathway and the decrease of transcription factors, notably SF-1, which the presence in the cerebellar Purkinje cells had never been described previously. This response to the deficiency would be made according to a sexual dimorphism, since only the young deficient females were affected. Finally, these studies allowed us to show functional changes associated with the cellular and molecular damage observed in the olfactory bulbs, being traduced by a decrease of the olfactory discrimination. This could contribute to the growth retardation associated with the reduced body weight of the deficient animal

Conséquence d'une carence gestationnelle en donneurs de méthyles sur l'expression des protéines clés de la neurostéroïdogenèse chez le rat

La carence précoce en donneurs de méthyles (folates et vitamine B12) entraîne une hyperhomocystéinémie ainsi que des troubles cognitifs et de la coordination motrice chez les ratons de 21 jours. Ces troubles ont été reliés à une altération de la neurogenèse dans l'hippocampe et le cervelet, mécanisme étroitement relié à la neurostéroïdogenèse (NSG), définie par la synthèse locale de stéroïdes dans le cerveau. L'objectif principal de ce travail a été de déterminer si ces troubles étaient associés à une altération de la NSG. Ce travail a conduit à plusieurs résultats marquants, montrant notamment l'effet délétère de la carence gestationnelle en donneurs de méthyles sur la voie stéroïdogénique dans le cervelet, région cérébrale particulièrement vulnérable en période post-natale. Ceci s'est traduit par un effondrement du contenu en estradiol et autres neurostéroïdes, consécutivement à la diminution de l'expression de StAR, TSPO et de l'aromatase, ainsi que des récepteurs aux estrogènes. Ces effets délétères sont associés à une atteinte de la voie de signalisation dépendante de l'AMPc associée à l'activation du récepteur LHR, et la diminution de facteurs de transcription impliqués dans la régulation des gènes de la NSG, notamment SF-1, dont la présence dans les cellules de Purkinje du cervelet n'avait jamais été décrite auparavant. Cette réponse à la carence se ferait selon un dimorphisme sexuel, puisque seules les jeunes femelles nées de mères carencées étaient affectées. Enfin, ces études ont permis la mise en évidence d'altérations fonctionnelles associées aux dommages cellulaires et moléculaires observés dans les bulbes olfactifs (BO), se traduisant par une diminution des fonctions de la discrimination olfactive. Ceci pourrait contribuer au retard de croissance associé au poids corporel réduit mesuré chez les animaux carencésEarly methyl-donor deficiency (MDD, folate and vitamin B12) produces hyperhomocysteinemia, cognitive and motor disorders in 21 days-old rat pups. These disorders are linked to an alteration of neurogenesis in the cerebellum and the hippocampus, which is closely linked to neurosteroidogenesis, defined as the local synthesis of steroids in brain. The aim of this work was to verify if these troubles are associated with an altered neurosteroidogenesis. This work led to several striking results, showing in particular the deleterious effects of the methyl donor deficiency on the steroidogenic pathway in the cerebellum, particularly vulnerable during postnatal development. This was confirmed by the reduced contents of estradiol and other neurosteroids, as a result of the decrease of the expression of StAR, TSPO and aromatase, as well as the estrogen receptors. These deleterious effects are associated to the impairment of AMPc dependent signaling pathway and the decrease of transcription factors, notably SF-1, which the presence in the cerebellar Purkinje cells had never been described previously. This response to the deficiency would be made according to a sexual dimorphism, since only the young deficient females were affected. Finally, these studies allowed us to show functional changes associated with the cellular and molecular damage observed in the olfactory bulbs, being traduced by a decrease of the olfactory discrimination. This could contribute to the growth retardation associated with the reduced body weight of the deficient animalsMETZ-SCD (574632105) / SudocNANCY1-Bib. numérique (543959902) / SudocNANCY2-Bibliotheque electronique (543959901) / SudocNANCY-INPL-Bib. électronique (545479901) / SudocSudocFranceF

Characterizing the diversity of MHC conserved extended haplotypes using families from the United Arab Emirates

Aside from its anthropological relevance, the characterization of the allele frequencies of genes in the human Major Histocompatibility Complex (MHC) and the combination of these alleles that make up MHC conserved extended haplotypes (CEHs) is necessary for histocompatibility matching in transplantation as well as mapping disease association loci. The structure and content of the MHC region in Middle Eastern populations remain poorly characterized, posing challenges when establishing disease association studies in ethnic groups that inhabit the region and reducing the capacity to translate genetic research into clinical practice. This study was conceived to address a gap of knowledge, aiming to characterize CEHs in the United Arab Emirates (UAE) population through segregation analysis of high-resolution, pedigree-phased, MHC haplotypes derived from 41 families. Twenty per cent (20.5%) of the total haplotype pool derived from this study cohort were identified as putative CEHs in the UAE population. These consisted of CEHs that have been previously detected in other ethnic groups, including the South Asian CEH 8.2 [HLA- C*07:02-B*08:01-DRB1*03:01-DQA1*05:01-DQB1*02:01 (H.F. 0.094)] and the common East Asian CEH 58.1 [HLA- C*03:02-B*58:01-DRB1*03:01- DQA1*05:01-DQB1*02:01 (H.F. 0.024)]. Additionally, three novel CEHs were identified in the current cohort, including HLA- C*15:02-B*40:06-DRB1*16:02-DQB1*05:02 (H.F. 0.035), HLA- C*16:02-B*51:01-DRB1*16:01-DQA1*01:02-DQB1*05:02 (H.F. 0.029), and HLA- C*03:02-B*58:01-DRB1*16:01-DQA1*01:02-DQB1*05:02 (H.F. 0.024). Overall, the results indicate a substantial gene flow with neighbouring ethnic groups in the contemporary UAE population including South Asian, East Asian, African, and European populations. Importantly, alleles and haplotypes that have been previously associated with autoimmune diseases (e.g., Type 1 Diabetes) were also present. In this regard, this study emphasizes that an appreciation for ethnic differences can provide insights into subpopulation-specific disease-related polymorphisms, which has remained a difficult endeavour

Association between type 2 diabetes mellitus TCF7L2 gene variants in the Emirati population: Genetics of diabetes in the United Arab Emirates

© 2020 Wiley Periodicals, Inc. Objective: Type 2 diabetes mellitus (T2DM) has a multifactorial etiology involving a complex interplay between genes and the environment. The prevalence of T2DM among the countries of the Gulf Corporation Council (GCC), including the United Arab Emirates (UAE), ranks among the top 15 in the world. A number of studies have shown an increase in T2DM risk for the “TT” genotype at the rs4506565 and rs12255372 Single Nucleotide Polymorphisms (SNP) of the TCF7L2 gene. However, the association between TCF7L2 and T2DM still needs to be investigated in the UAE population. Therefore, this study analyzed the potential associations with rs4506565 and rs12255372 in UAE subjects. Methods: For this case-control study, T2DM patients (n = 890) and healthy subjects (n = 686) were genotyped using a Taqman Real-Time PCR assay. Statistical analysis was performed with the resulting data using the R (version 3.3.1) and STATA (version 13) software packages. Results: The rs12255372 SNP was significantly associated with T2DM (OR = 1.16, 95% CI = 1.00-1.34; P =.042). However, no significant association was found for the rs4506565 SNP (P =.120). After gender stratification, a significant association was found for both SNPs in males (Prs4506565 =.009 and Prs12255372 =.021). Interestingly, we found the interaction between the SNP rs4506565 with gender alone (P =.032) and in conjunction with BMI and age (P =.036) confers associations with T2DM. Conclusions: These findings suggest that the genetic variants of the TCF7L2 gene are associated with an increased susceptibility to T2DM, especially in Emirati males. Our study also highlights the impact of biological and environmental risk factors including age, BMI, and gender on the genetic susceptibility to T2DM

Vitamin D receptor gene polymorphisms among Emirati patients with type 2 diabetes mellitus

© 2017 Elsevier Ltd At a prevalence rate close to 19.5%, the UAE has one of the highest rates of Type 2 Diabetes Mellitus (T2DM) in the world. Genome wide association studies (GWAS) have led to the identification of several genetic variants that are associated with T2DM. Recently, genes involved in vitamin D metabolism have gained interest because of the association between vitamin D deficiency (VDD) and increased risk for T2DM. Among these, the Vitamin D receptor (VDR) gene is a good candidate for T2DM susceptibility. The aim of this study was to investigate the association between VDR polymorphisms and T2DM among a representative sample of the Emirati population. In this cross sectional study, two hundred and sixty four patients with T2DM and ninety-one healthy controls were enrolled. The study population was genotyped for the three VDR gene mutations, TaqI (rs731236), FokI (rs2228570) and BsmI (rs1544410). VDR alleles and haplotypes were compared between patients and their healthy controls. The mean age of the T2DM cohort was 60 ± 11.59 years and 48.21 ± 12.17 years for the healthy controls. The G-allele and GG genotype of rs2228570 and T-allele and TT genotype of rs1544410 SNPs were associated with T2DM. In regards to T2DM-related metabolic complications, the AG and GG genotypes of rs731236 were significantly associated with higher total cholesterol (p = 0.011) and LDL-cholesterol (p = 0.009) levels in the patients with T2DM. In contrast, the CT genotype of rs1544410 was significantly associated with lower BMI (p = 0.031) and the TT genotype was associated with lower LDL-cholesterol level (p = 0.007). The frequency of AAT and GGC haplotypes was also different between groups (p = 0.014; p = 0.032, respectively), implying that these haplotypes of the VDR gene are associated with the susceptibility to T2DM in the Emirati population. To conclude, an association between SNPs in the VDR gene (except for rs731236) and T2DM per se was demonstrated. The rs731236 variant was shown to be associated with high cholesterol and LDL-cholesterol levels in T2DM patients, while rs1544410 was associated with lower BMI and lower LDL cholesterol levels. Our results imply that alleles and haploypes of the VDR gene are associated with the susceptibility to T2DM in the Emirati population

Folate- and vitamin B-12-deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor alpha

Deficiency in the methyl donors vitamin B-12 and folate during pregnancy and postnatal life impairs proper brain development. We studied the consequences of this combined deficiency on cerebellum plasticity in offspring from rat mothers subjected to deficient diet during gestation and lactation and in rat neuroprogenitor cells expressing cerebellum markers. The major proteomic change in cerebellum of 21-d-old deprived females was a 2.2-fold lower expression of synapsins, which was confirmed in neuroprogenitors cultivated in the deficient condition. A pathway analysis suggested that these proteomic changes were related to estrogen receptor a (ER-alpha)/Src tyrosine kinase. The influence of impaired ER-alpha pathway was confirmed by abnormal negative geotaxis test at d 19-20 and decreased phsophorylation of synapsins in deprived females treated by ER-alpha antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP). This effect was consistent with 2-fold decreased expression and methylation of ER-a and subsequent decreased ER-alpha/PPAR-gamma coactivator 1 alpha (PGC-1 alpha) interaction in deficiency condition. The impaired ER-a pathway led to decreased expression of synapsins through 2-fold decreased EGR-1/Zif-268 transcription factor and to 1.7-fold reduced Src-dependent phosphorylation of synapsins. The treatment of neuroprogenitors with either MPP or PP1 (4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-N-(4-phenoxyphenyl)-4-quinazolinamine, SKI-1, Src-11) Src inhibitor produced similar effects. In conclusion, the deficiency during pregnancy and lactation impairs the expression of synapsins through a deregulation of ER-alpha pathwa