Sök i SwePub databas

  Utökad sökning

Träfflista för sökning "L773:0964 6906 "

Sökning: L773:0964 6906

Sortera/gruppera träfflistan
  • Acevedo, Nathalie, et al. (författare)
  • Risk of childhood asthma is associated with CpG-site polymorphisms, regional DNA methylation and mRNA levels at the GSDMB/ORMDL3 locus
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 24:3, s. 90-875
  • Tidskriftsartikel (refereegranskat)abstract
    • Single-nucleotide polymorphisms (SNPs) in GSDMB (Gasdermin B) and ORMDL3 (ORMDL sphingolipid biosynthesis regulator 3) are strongly associated with childhood asthma, but the molecular alterations contributing to disease remain unknown. We investigated the effects of asthma-associated SNPs on DNA methylation and mRNA levels of GSDMB and ORMDL3. Genetic association between GSDMB/ORMDL3 and physician-diagnosed childhood asthma was confirmed in the Swedish birth-cohort BAMSE. CpG-site SNPs (rs7216389 and rs4065275) showed differences in DNA methylation depending on carrier status of the risk alleles, and were significantly associated with methylation levels in two CpG sites in the 5' UTR (untranslated region) of ORMDL3. In the Swedish Search study, we found significant differences in DNA methylation between asthmatics and controls in five CpG sites; after adjusting for lymphocyte and neutrophil cell counts, three remained significant: one in IKZF3 [IKAROS family zinc finger 3 (Aiolos); cg16293631] and two in the CpG island (CGI) of ORMDL3 (cg02305874 and cg16638648). Also, cg16293631 and cg02305874 correlated with mRNA levels of ORMDL3. The association between methylation and asthma was independent of the genotype in rs7216389, rs4065275 and rs12603332. Both SNPs and CpG sites showed significant associations with ORMDL3 mRNA levels. SNPs influenced expression independently of methylation, and the residual association between methylation and expression was not mediated by these SNPs. We found a differentially methylated region in the CGI shore of ORMDL3 with six CpG sites less methylated in CD8(+) T-cells. In summary, this study supports that there are differences in DNA methylation at this locus between asthmatics and controls; and both SNPs and CpG sites are independently associated with ORMDL3 expression.
  • Adhikari, Deepak, et al. (författare)
  • Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes
  • 2012
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; , s. 1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Previous studies have shown that deletions of Cdk3, Cdk4 or Cdk6 in mice result in viable animals with normal oocyte maturation, indicating that these Cdks are not essential for the meiotic maturation of oocytes. In addition, conventional knockout of Cdk1 and Cdk2 leads to embryonic lethality and postnatal follicular depletion, respectively, making it impossible to study the functions of Cdk1 and Cdk2 in oocyte meiosis. In this study, we generated conditional knockout mice with oocyte-specific deletions of Cdk1 and Cdk2. We showed that the lack of Cdk1, but not of Cdk2, leads to female infertility due to a failure of the resumption of meiosis in the oocyte. Re-introduction of Cdk1 mRNA into Cdk1-null oocytes largely resumed meiosis. Thus, Cdk1 is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. We also found that Cdk1 maintains the phosphorylation status of protein phosphatase 1 and lamin A/C in oocytes in order for meiosis resumption to occur.
  • Adhikari, Deepak, et al. (författare)
  • Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles
  • 2010
  • Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 19:3, s. 397-410
  • Tidskriftsartikel (refereegranskat)abstract
    • To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.
  • Aguila, Monica, et al. (författare)
  • AAV-mediated ERdj5 overexpression protects against P23H rhodopsin toxicity
  • 2020
  • Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 29:8, s. 1310-1318
  • Tidskriftsartikel (refereegranskat)abstract
    • Rhodopsin misfolding caused by the P23H mutation is a major cause of autosomal dominant retinitis pigmentosa (adRP). To date, there are no effective treatments for adRP. The BiP co-chaperone and reductase ERdj5 (DNAJC10) is part of the endoplasmic reticulum (ER) quality control machinery, and previous studies have shown that overexpression of ERdj5 in vitro enhanced the degradation of P23H rhodopsin, whereas knockdown of ERdj5 increased P23H rhodopsin ER retention and aggregation. Here, we investigated the role of ERdj5 in photoreceptor homeostasis in vivo by using an Erdj5 knockout mouse crossed with the P23H knock-in mouse and by adeno-associated viral (AAV) vector-mediated gene augmentation of ERdj5 in P23H-3 rats. Electroretinogram (ERG) and optical coherence tomography of Erdj5(-/-) and P23H(+/-):Erdj5(-/-) mice showed no effect of ERdj5 ablation on retinal function or photoreceptor survival. Rhodopsin levels and localization were similar to those of control animals at a range of time points. By contrast, when AAV2/8-ERdj5-HA was subretinally injected into P23H-3 rats, analysis of the full-field ERG suggested that overexpression of ERdj5 reduced visual function loss 10 weeks post-injection (PI). This correlated with a significant preservation of photoreceptor cells at 4 and 10 weeks PI. Assessment of the outer nuclear layer (ONL) morphology showed preserved ONL thickness and reduced rhodopsin retention in the ONL in the injected superior retina. Overall, these data suggest that manipulation of the ER quality control and ER-associated degradation factors to promote mutant protein degradation could be beneficial for the treatment of adRP caused by mutant rhodopsin.
  • Ahlqvist, Emma, et al. (författare)
  • High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice
  • 2011
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 20:15, s. 3031-3041
  • Tidskriftsartikel (refereegranskat)abstract
    • Resolving the genetic basis of complex diseases like rheumatoid arthritis will require knowledge of the corresponding diseases in experimental animals to enable translational functional studies. Mapping of quantitative trait loci in mouse models of arthritis, such as collagen-induced arthritis (CIA), using F-2 crosses has been successful, but can resolve loci only to large chromosomal regions. Using an inbred-outbred cross design, we identified and fine-mapped CIA loci on a genome-wide scale. Heterogeneous stock mice were first intercrossed with an inbred strain, B10.Q, to introduce an arthritis permitting MHCII haplotype. Homozygous H2(q) mice were then selected to set up an F-3 generation with fixed major histocompatibility complex that was used for arthritis experiments. We identified 26 loci, 18 of which are novel, controlling arthritis traits such as incidence of disease, severity and time of onset and fine-mapped a number of previously mapped loci.
  • Ahola-Erkkilä, Sofia, et al. (författare)
  • Ketogenic diet slows down mitochondrial myopathy progression in mice
  • 2010
  • Ingår i: ; 19:10, s. 1974-1984
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies.
  • Albagha, Omar M E, et al. (författare)
  • Linkage disequilibrium between polymorphisms in the human TNFRSF1B gene and their association with bone mass in perimenopausal women
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906. ; 11:19, s. 95-2289
  • Tidskriftsartikel (refereegranskat)abstract
    • Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met-Arg) and three SNPs (G593A, T598G, and T620C) in the 3'UTR of the gene. The 3'UTR SNPs were in strong linkage disequilibrium (LD) with each other (P<0.00001), and the exon 6 SNP was in LD with G593A and T598G (P<0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593-T598-C620 haplotype (n=85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n=1155; P<0.00008) and this remained significant after correcting for confounding factors and multiple testing (P<0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3'UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.
  • Almqvist, E, et al. (författare)
  • Ancestral differences in the distribution of the delta 2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes : insights into the genetic evolution of Huntington disease.
  • 1995
  • Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 4:2, s. 207-14
  • Tidskriftsartikel (refereegranskat)abstract
    • This study addresses genetic factors associated with normal variation of the CAG repeat in the Huntington disease (HD) gene. To achieve this, we have studied patterns of variation of three trinucleotide repeats in the HD gene including the CAG and adjacent CCG repeats as well as a GAG polymorphism at residue 2642 (delta 2642). We have previously demonstrated that variation in the CCG repeat is associated with variation of the CAG repeat length on normal chromosomes. Here we show that differences in the GAG trinucleotide polymorphism at residue 2642 is also significantly correlated with CAG size on normal chromosomes. The B allele which is associated with higher CAG repeat lengths on normal chromosomes is markedly enriched on affected chromosomes. Furthermore, this glutamic acid polymorphism shows significant variation in different ancestries and is absent in chromosomes of Japanese, Black and Chinese descent. Haplotype analysis of both the CCG and delta 2642 polymorphisms have indicated that both are independently associated with differences in CAG length on normal chromosomes. These findings lead to a model for the genetic evolution of new mutations for HD preferentially occurring on normal chromosomes with higher CAG repeat lengths and a CCG repeat length of seven and/or a deletion of the glutamic acid residue at delta 2642. This study also provides additional evidence for genetic contributions to demographic differences in prevalence rates for HD.
Skapa referenser, mejla, bekava och länka
Typ av publikation
tidskriftsartikel (323)
forskningsöversikt (1)
Typ av innehåll
refereegranskat (321)
övrigt vetenskapligt (3)
Andersen, Peter M. (12)
Uitterlinden, Andre ... (12)
Riboli, Elio (11)
Groop, Leif (11)
Johansson, Åsa (11)
Easton, Douglas F. (11)
visa fler...
Gyllensten, Ulf (11)
Chanock, Stephen J (10)
Diver, W. Ryan (10)
Kraft, Peter (10)
Hunter, David J. (10)
Petersén, Åsa (10)
Johansson, Bertil (9)
Hofman, Albert (9)
Ingelsson, Erik (9)
Andrulis, Irene L. (9)
Franks, Paul W (8)
Kere, J (8)
Melander, Olle (8)
Haiman, Christopher ... (8)
Albanes, Demetrius (8)
Hopper, John L. (8)
Schmutzler, Rita K. (8)
Brundin, Patrik (8)
Fioretos, Thoas (8)
Wang, Zhaoming (8)
Chang-Claude, Jenny (7)
Khaw, Kay-Tee (7)
Tjonneland, Anne (7)
Riboli, E. (7)
Henderson, Brian E (7)
Neuhausen, Susan L (7)
Chanock, SJ (7)
Syvänen, Ann-Christi ... (7)
Vineis, Paolo (7)
Chasman, Daniel I. (7)
Ingelsson, E (7)
Spurdle, Amanda B. (7)
Benitez, Javier (7)
Diver, WR (7)
Kraft, P (7)
Le Marchand, Loïc (7)
Virtamo, Jarmo (7)
Almqvist, E (7)
Gieger, Christian (7)
Sinilnikova, Olga M. (7)
Couch, Fergus J. (7)
Hayward, Caroline (7)
Polašek, Ozren (7)
Rivadeneira, Fernand ... (7)
visa färre...
Lunds universitet (107)
Karolinska Institutet (91)
Uppsala universitet (79)
Umeå universitet (50)
Göteborgs universitet (30)
Linköpings universitet (15)
visa fler...
Stockholms universitet (14)
Ersta Sköndal Bräcke högskola (6)
Örebro universitet (4)
Jönköping University (2)
Högskolan i Skövde (2)
Linnéuniversitetet (2)
Kungliga Tekniska Högskolan (1)
Mittuniversitetet (1)
Gymnastik- och idrottshögskolan (1)
Sveriges Lantbruksuniversitet (1)
visa färre...
Engelska (323)
Odefinierat språk (1)
Forskningsämne (UKÄ/SCB)
Medicin och hälsovetenskap (190)
Naturvetenskap (30)
Samhällsvetenskap (1)


pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy