Audrezet M.-P.,Institut Universitaire de France |
Corbiere C.,University Hospital Necker Enfants Malades |
Lebbah S.,University Hospital Necker Enfants Malades |
Moriniere V.,University Hospital Necker Enfants Malades |
And 25 more authors.
Journal of the American Society of Nephrology | Year: 2016
Prenatal forms of autosomal dominant polycystic kidney disease (ADPKD) are rare but can be recurrent in some families, suggesting a common genetic modifying background. Few patients have been reported carrying, in addition to the familial mutation, variation(s) in polycystic kidney disease 1 (PKD1) or HNF1 homeobox B (HNF1B), inherited from the unaffected parent, or biallelic polycystic kidney and hepatic disease 1 (PKHD1) mutations. To assess the frequency of additional variations in PKD1, PKD2, HNF1B, andPKHD1 associated with the familialPKDmutation in earlyADPKD, these four geneswere screened in 42 patients with earlyADPKD in 41 families. Two patientswere associatedwith de novo PKD1 mutations. Forty patients occurred in 39 families with known ADPKD and were associated with PKD1 mutation in 36 families and with PKD2 mutation in two families (no mutation identified in one family). Additional PKD variation(s) (inherited from the unaffected parent when tested) were identified in 15 of 42 patients (37.2%), whereas these variations were observed in 25 of 174 (14.4%,P=0.001)patientswith adultADPKD.NoHNF1Bvariations or PKHD1biallelicmutationswere identified.These results suggestthat,at least insomepatients, the severity of the cystic disease is inversely correlated with the level of polycystin 1 function.
Daroux M.,Research Division |
Daroux M.,Regional University Hospital of Lille |
Prevost G.,Research Division |
Prevost G.,Regional University Hospital of Lille |
And 8 more authors.
Diabetes and Metabolism | Year: 2010
Glycation is the process whereby sugars bind to the free amine residues of proteins. These newly formed modified molecular species are known as 'advanced glycation end-products', or AGEs. AGE toxicity may occur through at least three mechanisms: interaction with the receptor for AGEs (RAGE); tissue deposition; and in situ glycation. AGEs trigger proinflammatory, profibrotic and procoagulant cellular responses that are capable of damaging tissues, often targeting particular organs. In diabetic patients, the conditions needed to promote AGE formation are all present, and are further accentuated by accompanying renal failure. The aim of this review is to outline the involvement of AGEs in the various forms of renal pathology associated with diabetic and non-diabetic nephropathies. AGEs are present in all renal compartments in diabetic patients, including the vessels, glomeruli, tubules and interstitium. Many cell types may be activated-specifically, endothelial, tubular and mesangial cells, and podocytes. AGEs play a major role in the accumulation of extracellular matrix, as occurs in diabetic glomerulosclerosis, and are also involved in most diabetic (renovascular, microangiopathic and glomerular) and non-diabetic renal injury associated with progressive glomerulosclerosis and ageing. © 2009 Elsevier Masson SAS. All rights reserved.
Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: A meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium
Ma Y.,Boston University |
Ma Y.,U.S. Department of Agriculture |
Follis J.L.,University of St. Thomas, Texas |
Smith C.E.,U.S. Department of Agriculture |
And 45 more authors.
American Journal of Clinical Nutrition | Year: 2016
Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression. Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation. Design: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids.We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium. Results: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = 20.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 1021). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 1018) and lower circulating EPA (β = 21.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = 22.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = 20.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = 20.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05). Conclusion: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation. © 2016 American Society for Nutrition.
Carpentier C.,University of Lille Nord de France |
Carpentier C.,Regional University Hospital of Lille |
Ghanem D.,University of Lille Nord de France |
Ghanem D.,Regional University Hospital of Lille |
And 27 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014
The splicing of the microtubule-associated protein Tau is regulated during development and is found to be deregulated in a growing number of pathological conditions such as myotonic dystrophy type I (DM1), in which a reduced number of isoforms is expressed in the adult brain. DM1 is caused by a dynamic and unstable CTG repeat expansion in the DMPK gene, resulting in an RNA bearing long CUG repeats (n>50) that accumulates in nuclear foci and sequesters CUG-binding splicing factors of the muscleblind-like (MBNL) family, involved in the splicing of Tau pre-mRNA among others. However, the precise mechanism leading to Tau mis-splicing and the role of MBNL splicing factors in this process are poorly understood. We therefore used new Tau minigenes that we developed for this purpose to determine how MBNL1 and MBNL2 interact to regulate Tau exon 2 splicing. We demonstrate that an intronic region 250 nucleotides downstream of Tau exon 2 contains cis-regulatory splicing enhancers that are sensitive to MBNL and that bind directly to MBNL1. Both MBNL1 and MBNL2 act as enhancers of Tau exon 2 inclusion. Intriguingly, the interaction of MBNL1 and MBNL2 is required to fully reverse the mis-splicing of Tau exon 2 induced by the trans-dominant effect of long CUG repeats, similar to the DM1 condition. In conclusion, both MBNL1 and MBNL2 are involved in the regulation of Tau exon 2 splicing and the mis-splicing of Tau in DM1 is due to the combined inactivation of both. © 2014 Elsevier B.V.
PubMed | Regional University Hospital of Lille, Lancaster University, Northeastern University, University College London and Imperial College London
Type: | Journal: Scientific reports | Year: 2016
The impaired maturation of bone-forming osteoblasts results in reduced bone formation and subsequent bone weakening, which leads to a number of conditions such as osteogenesis imperfecta (OI). Transplantation of human fetal mesenchymal stem cells has been proposed as skeletal anabolic therapy to enhance bone formation, but the mechanisms underlying the contribution of the donor cells to bone health are poorly understood and require further elucidation. Here, we show that intraperitoneal injection of human amniotic mesenchymal stem cells (AFSCs) into a mouse model of OI (oim mice) reduced fracture susceptibility, increased bone strength, improved bone quality and micro-architecture, normalised bone remodelling and reduced TNF and TGF sigalling. Donor cells engrafted into bones and differentiated into osteoblasts but importantly, also promoted endogenous osteogenesis and the maturation of resident osteoblasts. Together, these findings identify AFSC transplantation as a countermeasure to bone fragility. These data have wider implications for bone health and fracture reduction.