Introduction La lipodystrophie congénitale généralisée de Berardinelli-Seip (BSCL) est caractérisée par une absence de tissu adipeux et une insulino-résistance sévère. Elle est souvent liée à ...l’altération bi-allélique de BSCL2 codant la seipine de fonction encore inconnue. Matériels et méthodes Nous avons caractérisé le phénotype métabolique des souris-Bscl2−/− et développé un modèle de fibroblastes embryonnaires (MEFs) capables de se différencier in vitro en adipocytes. Résultats La microtomographie à rayon-X montre que les souris-Bscl2−/− sont lipodystrophiques dès l’âge de 6 semaines, avec une baisse de 80 % des taux de leptine et d’adiponectine. Les données in vitro indiquent que l’absence de tissu adipeux serait due à la combinaison d’un défaut d’adipogenèse et de lipolyse. Seulement 10 % des MEFs-Bscl2−/− se différencient en adipocytes (vs 80 % pour les MEFs-sauvages) avec une réduction de l’induction de l’expression de PPAR ? et de son gène cible AP2. Ces défauts de différenciation sont réversés par la rosiglitazone. Dans les adipocytes-Bscl2−/−, l’hydrolyse des triglycérides est augmentée de 3 fois (p < 0,05). Les tests métaboliques démontrent que les souris-Bscl2−/− sont intolérantes au glucose et insulino-résistantes. Alors que ces souris sont hyperglycémiques à l’état nourri (1.88 ± 0,44 vs 1.22 ± 0,13 g/L, p < 0,05), leur glycémie s’abaisse après 12 h de jeûne (0,95 ± 0,07 vs 1.27 ± 0,08 g/L, p < 0,001). Le jeûne s’accompagne également d’une perte de poids sévère (2.50 ± 0,62 vs 0,86 ± 0,58 g) et d’une hypothermie (35.3 ± 0,6 vs 37.2 ± 0,2°C; p < 0,0005). De façon surprenante, les souris-Bscl2−/− sont hypotriglycéridémiques à l’état nourri, avec une chute supplémentaire de 80 % des triglycérides après 12 h de jeûne (vs 45 % chez les souris sauvages, p < 0,0001). Cette hypotriglycéridémie n’est pas liée à une baisse de la production hépatique des VLDL ni à une augmentation de l’activité lipase. Conclusion Nos données montrent que la seipine joue un rôle clé dans l’adipogenèse et la capacité de stockage des adipocytes mais aussi dans l’adaptabilité au jeûne.
Aims/hypothesis
Mutations in
BSCL
2/seipin cause Berardinelli–Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin ...resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype.
Methods
Bscl2
−/−
mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation.
Results
As observed in humans,
Bscl2
−/−
mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However,
Bscl2
−/−
mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in
Bscl2
−/−
MEFs. In vivo treatment of
Bscl2
−/−
mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice.
Conclusions/interpretation
Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in
Bscl2
−/−
mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.
Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the ...Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma.
To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls.
The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ~0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown.
Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.
Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between ...circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR = 1.49 95%CI1.18-1.88; p = 0.0008) and rs782931 in RORA (OR = 1.31 95%CI1.12-1.54; p = 0.0006) and BD. Then we used a "reverse phenotyping approach" to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p = 0.04) and languid circadian type (p = 0.01), whereas rs782931 was associated with rigid circadian type (p = 0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.
Background: Factor VIII (FVIII) and von Willebrand factor (VWF) are two known quantitative risk factors for venous thromboembolism (VTE). Objectives: To identify new loci that could contribute to VTE ...susceptibility and to modulating FVIII and/or VWF levels. Patients/Methods: A pedigree linkage analysis was first performed in five extended French‐Canadian families, including 253 individuals, to identify genomic regions linked to FVIII or VWF levels. Identified regions were further explored using ‘in silico’ genome‐wide association studies (GWAS) data on VTE (419 patients and 1228 controls), and two independent case‐control studies (MARTHA and FARIVE) for VTE, gathering 1166 early‐onset patients and 1408 healthy individuals. Single nucleotide polymorphisms (SNPs) associated with VTE risk were further investigated in relation to plasma levels of FVIII and VWF in a cohort of 108 healthy nuclear families. Results: Four main linkage regions were identified, among which the well‐characterized ABO locus, the recently identified STAB 2 gene, and a third one, on chromosome 6q13‐14, harbouring four non‐redundant SNPs, associated with VTE at P < 10−4 in the GWAS dataset. The association of one of these SNPs, rs9363864, with VTE was further replicated in the MARTHA and FARIVE studies. The rs9363864‐AA genotype was associated with a lower risk for VTE (OR = 0.58 0.42–0.80, P = 0.0005) but mainly in non‐carriers of the FV Leiden mutation. This genotype was further found to be associated with the lowest levels of FVIII (P = 0.006) and VWF (P = 0.001). Conclusions: The BAI3 locus where the rs9363864 maps is a new candidate for VTE risk.
Recent advances have been made in the genetics of two human communication skills: speaking and reading. Mutations of the FOXP2 gene cause a severe form of language impairment and orofacial dyspraxia, ...while single-nucleotide polymorphisms (SNPs) located within a KIAA0319/TTRAP/THEM2 gene cluster and affecting the KIAA0319 gene expression are associated with reading disability. Neuroimaging studies of clinical populations point to partially distinct cerebral bases for language and reading impairments. However, alteration of FOXP2 and KIAA0319/TTRAP/THEM2 polymorphisms on typically developed language networks has never been explored. Here, we genotyped and scanned 94 healthy subjects using fMRI during a reading task. We studied the correlation of genetic polymorphisms with interindividual variability in brain activation and functional asymmetry in frontal and temporal cortices. In FOXP2, SNPs rs6980093 and rs7799109 were associated with variations of activation in the left frontal cortex. In the KIAA0319/TTRAP/THEM2 locus, rs17243157 was associated with asymmetry in functional activation of the superior temporal sulcus (STS). Interestingly, healthy subjects bearing the KIAA0319/TTRAP/THEM2 variants previously identified as enhancing the risk of dyslexia showed a reduced left-hemispheric asymmetry of the STS. Our results confirm that both FOXP2 and KIAA0319/TTRAP/THEM2 genes play an important role in human language development, but probably through different cerebral pathways. The observed cortical effects mirror previous fMRI results in developmental language and reading disorders, and suggest that a continuum may exist between these pathologies and normal interindividual variability.
To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation ...in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 × 10−17), 8q24.21 (rs4295627, CCDC26; P = 2.34 × 10−18), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 × 10−15), 20q13.33 (rs6010620, RTEL1; P = 2.52 × 10−12) and 11q23.3 (rs498872, PHLDB1; P = 1.07 × 10−8). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 ...transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
Transplantation tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This tolerance is donor Ag specific and depends on a population of CD4(+) ...regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired tolerance was dominant, such that naive monospecific T cells were not able to override tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining transplantation tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.
Colour sidedness is a dominantly inherited phenotype of cattle characterized by the polarization of pigmented sectors on the flanks, snout and ear tips. It is also referred to as 'lineback' or ...'witrik' (which means white back), as colour-sided animals typically display a white band along their spine. Colour sidedness is documented at least since the Middle Ages and is presently segregating in several cattle breeds around the globe, including in Belgian blue and brown Swiss. Here we report that colour sidedness is determined by a first allele on chromosome 29 (Cs(29)), which results from the translocation of a 492-kilobase chromosome 6 segment encompassing KIT to chromosome 29, and a second allele on chromosome 6 (Cs(6)), derived from the first by repatriation of fused 575-kilobase chromosome 6 and 29 sequences to the KIT locus. We provide evidence that both translocation events involved circular intermediates. This is the first example, to our knowledge, of a phenotype determined by homologous yet non-syntenic alleles that result from a novel copy-number-variant-generating mechanism.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
