19 results on '"Geburtig-Chiocchetti, Andreas"'
Search Results
2. Effects of hypoxia on RNA cargo in extracellular vesicles from human adipose-derived stromal/stem cells
- Author
-
Koch, Benjamin Florian, Geßner, Alec, Farmand, Samira, Fuhrmann, Dominik Christian, Geburtig-Chiocchetti, Andreas, Schubert, Ralf, Baer, Patrick C., Koch, Benjamin Florian, Geßner, Alec, Farmand, Samira, Fuhrmann, Dominik Christian, Geburtig-Chiocchetti, Andreas, Schubert, Ralf, and Baer, Patrick C.
- Abstract
Mesenchymal stromal/stem cells and their derivates are the most promising cell source for cell therapies in regenerative medicine. The application of extracellular vesicles (EVs) as cell-free therapeuticals requires particles with a maximum regenerative capability to enhance tissue and organ regeneration. The cargo of mRNA and microRNA (miR) in EVs after hypoxic preconditioning has not been extensively investigated. Therefore, the aim of our study was the characterization of mRNA and the miR loading of EVs. We further investigated the effects of the isolated EVs on renal tubular epithelial cells in vitro. We found 3131 transcripts to be significantly regulated upon hypoxia. Only 15 of these were downregulated, but 3116 were up-regulated. In addition, we found 190 small RNAs, 169 of these were miRs and 21 were piwi-interacting RNAs (piR). However, only 18 of the small RNAs were significantly altered, seven were miRs and 11 were piRs. Interestingly, all seven miRs were down-regulated after hypoxic pretreatment, whereas all 11 piRs were up-regulated. Gene ontology term enrichment and miR-target enrichment analysis of the mRNAs and miR were also performed in order to study the biological background. Finally, the therapeutic effect of EVs on human renal tubular epithelial cells was shown by the increased expression of three anti-inflammatory molecules after incubation with EVs from hypoxic pretreatment. In summary, our study demonstrates the altered mRNA and miR load in EVs after hypoxic preconditioning, and their anti-inflammatory effect on epithelial cells.
- Published
- 2022
3. The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors
- Author
-
Geburtig-Chiocchetti, Andreas, Yousaf, Afsheen, Waltes, Regina, Bernhard, Anka, Martinelli, Anne, Ackermann, Katharina, Haslinger, Denise, Rotter, Björn, Krezdorn, Nico, Konrad, Kerstin, Kohls, Gregor, Vetro, Agnes, Hervás, Amaia, Fernández-Rivas, Aranzazu, Freitag, Christine M., Geburtig-Chiocchetti, Andreas, Yousaf, Afsheen, Waltes, Regina, Bernhard, Anka, Martinelli, Anne, Ackermann, Katharina, Haslinger, Denise, Rotter, Björn, Krezdorn, Nico, Konrad, Kerstin, Kohls, Gregor, Vetro, Agnes, Hervás, Amaia, Fernández-Rivas, Aranzazu, and Freitag, Christine M.
- Abstract
Conduct Disorder (CD) is an impairing psychiatric disorder of childhood and adolescence characterized by aggressive and dissocial behavior. Environmental factors such as maternal smoking during pregnancy, socio-economic status, trauma, or early life stress are associated with CD. Although the number of females with CD is rising in Western societies, CD is under-researched in female cohorts. We aimed at exploring the epigenetic signature of females with CD and its relation to psychosocial and environmental risk factors. We performed HpaII sensitive genome-wide methylation sequencing of 49 CD girls and 50 matched typically developing controls and linear regression models to identify differentially methylated CpG loci (tags) and regions. Significant tags and regions were mapped to the respective genes and tested for enrichment in pathways and brain developmental processes. Finally, epigenetic signatures were tested as mediators for CD-associated risk factors. We identified a 12% increased methylation 5’ of the neurite modulator SLITRK5 (FDR = 0.0046) in cases within a glucocorticoid receptor binding site. Functionally, methylation positively correlated with gene expression in lymphoblastoid cell lines. At systems-level, genes (uncorr. P < 0.01) were associated with development of neurons, neurite outgrowth or neuronal developmental processes. At gene expression level, the associated gene-networks are activated perinatally and during early childhood in neocortical regions, thalamus and striatum, and expressed in amygdala and hippocampus. Specifically, the epigenetic signatures of the gene network activated in the thalamus during early childhood correlated with the effect of parental education on CD status possibly mediating its protective effect. The differential methylation patterns identified in females with CD are likely to affect genes that are expressed in brain regions previously indicated in CD. We provide suggestive evidence that protective effects are likely me
- Published
- 2022
4. Epigenetic regulation of inflammation by microRNAs in post-infectious bronchiolitis obliterans
- Author
-
Duecker, Ruth P.., de Mir-Messa, Inés, Jerkic, Silvija-Pera, Kochems, Annalena, Gottwald, Gabriele, Moreno Galdó, Antonio, Rosewich, Martin, Gronau, Lucia, Zielen, Stefan, Geburtig-Chiocchetti, Andreas, Kreyenberg, Hermann, Schubert, Ralf, and Universitat Autònoma de Barcelona
- Subjects
Inflammation ,Post-infectious bronchiolitis obliterans ,Fibrosis ,Microrna - Abstract
Post-infectious bronchiolitis obliterans (PiBO) is a rare, chronic disease initiated by severe infection and followed by perpetuating inflammation and obliteration of the small airways. MicroRNAs (miRNAs) have been proposed to play a central role as epigenetic regulators, which control resolution and prevent the uncontrolled progress of inflammation. The aim of this study was to define biomarkers on the level of post-transcriptional gene regulation in order to characterise PiBO. A total of 39 patients with well-defined PiBO and 31 controls from two centres, Barcelona, Spain, and Frankfurt, Germany, were analysed by next-generation sequencing (NGS). The evaluation of the biological targets of the miRNAs was performed by pathway enrichment analysis and protein-protein interaction network analysis respectively. Patients with PiBO had significantly lower lung function values and increased airway inflammation in induced sputum as indicated by total cell counts, neutrophils, IL-1β, IL-6, IL-8 and TGF-β compared to controls. Next-generation sequencing analysis revealed a total of 22 dysregulated miRNAs, which passed significance threshold for P adj ≤ 0.001 with 17 being upregulated and 5 being downregulated. Of these dysregulated miRNAs, miR-335-5p, miR-186-5p, miR-30b-5p and miR-30c-5p were further validated using qRT-PCR. Interestingly, these miRNAs are functionally implicated in cytokine-cytokine receptor interaction, TGF-β signalling and FoxO signalling pathway and significantly correlated with lung function values (FEV1). Our results demonstrate an aberrant miRNA expression profile in PiBO, which impacts pathways responsible for the regulation of inflammation and fibrosis. The defined miRNAs are useful biomarkers and should be assessed as potential target in the field of miRNA therapeutics. We identified dysregulated miRNAs, which impact pathways for inflammatory cytokines and TGF-β signalling in post-infectious bronchiolitis obliterans. The miRNAs reflect bronchial inflammation and fibrosis and could be considered as novel biomarkers supporting diagnosis and treatment options.
- Published
- 2022
5. Epigenetic regulation of inflammation by microRNAs in post‐infectious bronchiolitis obliterans
- Author
-
Duecker, Ruth P, primary, De Mir Messa, Ines, additional, Jerkic, Silvija‐Pera, additional, Kochems, Annalena, additional, Gottwald, Gabriele, additional, Moreno‐Galdó, Antonio, additional, Rosewich, Martin, additional, Gronau, Lucia, additional, Zielen, Stefan, additional, Geburtig‐Chiocchetti, Andreas, additional, Kreyenberg, Hermann, additional, and Schubert, Ralf, additional
- Published
- 2022
- Full Text
- View/download PDF
6. Correction: SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study
- Author
-
Farrow, Elizabeth, Geburtig-Chiocchetti, Andreas, Rogers, Jack C., Pauli, Ruth, Raschle, Nora Maria, Gonzalez-Madruga, Karen, Smaragdi, Areti, Martinelli, Anne, Kohls, Gregor, Stadler, Christina, Konrad, Kerstin, Fairchild, Graeme, Freitag, Christine M., Chechlacz, Magdalena, De Brito, Stephane A., Farrow, Elizabeth, Geburtig-Chiocchetti, Andreas, Rogers, Jack C., Pauli, Ruth, Raschle, Nora Maria, Gonzalez-Madruga, Karen, Smaragdi, Areti, Martinelli, Anne, Kohls, Gregor, Stadler, Christina, Konrad, Kerstin, Fairchild, Graeme, Freitag, Christine M., Chechlacz, Magdalena, and De Brito, Stephane A.
- Abstract
Correction to: Translational Psychiatry https://doi.org/10.1038/s41398-021-01609-y, published online 24 September 2021 Since the publication of the article the authors have noticed mistakes in the text, figures, tables and supplementary materials. The authors apologize for these errors, which have now been corrected in the original article. Please note that these changes do not affect the results of the paper or their interpretation.
- Published
- 2021
7. SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study
- Author
-
Farrow, Elizabeth, Geburtig-Chiocchetti, Andreas, Rogers, Jack C., Pauli, Ruth, Raschle, Nora Maria, Gonzalez-Madruga, Karen, Smaragdi, Areti, Martinelli, Anne, Kohls, Gregor, Stadler, Christina, Konrad, Kerstin, Fairchild, Graeme, Freitag, Christine M., Chechlacz, Magdalena, De Brito, Stephane A., Farrow, Elizabeth, Geburtig-Chiocchetti, Andreas, Rogers, Jack C., Pauli, Ruth, Raschle, Nora Maria, Gonzalez-Madruga, Karen, Smaragdi, Areti, Martinelli, Anne, Kohls, Gregor, Stadler, Christina, Konrad, Kerstin, Fairchild, Graeme, Freitag, Christine M., Chechlacz, Magdalena, and De Brito, Stephane A.
- Abstract
Conduct disorder (CD), a psychiatric disorder characterized by a repetitive pattern of antisocial behaviors, results from a complex interplay between genetic and environmental factors. The clinical presentation of CD varies both according to the individual’s sex and level of callous-unemotional (CU) traits, but it remains unclear how genetic and environmental factors interact at the molecular level to produce these differences. Emerging evidence in males implicates methylation of genes associated with socio-affective processes. Here, we combined an epigenome-wide association study with structural neuroimaging in 51 females with CD and 59 typically developing (TD) females to examine DNA methylation in relation to CD, CU traits, and gray matter volume (GMV). We demonstrate an inverse pattern of correlation between CU traits and methylation of a chromosome 1 region in CD females (positive) as compared to TD females (negative). The identified region spans exon 1 of the SLC25A24 gene, central to energy metabolism due to its role in mitochondrial function. Increased SLC25A24 methylation was also related to lower GMV in multiple brain regions in the overall cohort. These included the superior frontal gyrus, dorsolateral prefrontal cortex, supramarginal gyrus, secondary visual cortex and ventral posterior cingulate cortex, which are regions that have previously been implicated in CD and CU traits. While our findings are preliminary and need to be replicated in larger samples, they provide novel evidence that CU traits in females are associated with methylation levels in a fundamentally different way in CD and TD individuals, which in turn may relate to observable variations in GMV across the brain.
- Published
- 2021
8. Genetische Risikofaktoren und ihre Auswirkungen auf die neurale Entwicklung bei Autismus-Spektrum-Störungen
- Author
-
Freitag, Christine M., Geburtig-Chiocchetti, Andreas, Haslinger, Denise, Yousaf, Afsheen, Waltes, Regina, Freitag, Christine M., Geburtig-Chiocchetti, Andreas, Haslinger, Denise, Yousaf, Afsheen, and Waltes, Regina
- Abstract
Die Ätiologie der Autismus-Spektrum-Störungen (ASS) ist in genetischen Risikofaktoren sowie der Interaktion von genetischen und biologisch wirksamen Umweltrisikofaktoren begründet. ASS werden aufgrund von Verhaltensmerkmalen, nämlich bleibend eingeschränkter sozialer Kommunikation, sowie durch stereotypes Verhalten, sensorische und Sonderinteressen diagnostiziert. Hinsichtlich des genetischen Hintergrundes besteht eine hohe genetische Heterogenität, d. h., die genetischen Ursachen sind vielfältig und individuell oft sehr unterschiedlich ausgeprägt. Allerdings konvergieren diese Ursachen in bestimmten biologischen Mechanismen und überlappenden biologischen Endstrecken, deren Veränderung sehr wahrscheinlich den autismusspezifischen Verhaltensmerkmalen zugrunde liegt. Die vorliegende, selektive Literaturübersicht summiert die genetischen Befunde und fokusiert sich insbesondere auf Mechanismen und Endstrecken, die aufgrund der neueren Forschung immer besser charakterisiert werden. Der Artikel schließt mit Hinweisen zur klinischen Relevanz der aktuellen Befunde sowie offenen Fragen der translationalen Forschung., Autism spectrum disorders are etiologically based on genetic and specific gene x biologically relevant environmental risk factors. They are diagnosed based on behavioral characteristics, such as impaired social communication and stereotyped, repetitive behavior and sensory as well as special interests. The genetic background is heterogeneous, i. e., it comprises diverse genetic risk factors across the disorder and high interindividual differences of specific genetic risk factors. Nevertheless, risk factors converge regarding underlying biological mechanisms and shared pathways, which likely cause the autism-specific behavioral characteristics. The current selective literature review summarizes differential genetic risk factors and focuses particularly on mechanisms and pathways currently being discussed by international research. In conclusion, clinically relevant aspects and open translational research questions are presented.
- Published
- 2021
9. Energy metabolism disturbances in cell models of PARK2 CNV carriers with ADHD
- Author
-
Palladino, Viola Stella, Geburtig-Chiocchetti, Andreas, Frank, Lukas, Haslinger, Denise, McNeill, Rhiannon, Radtke, Franziska, Till, Andreas, Haupt, Simone, Brüstle, Oliver, Günther, Katharina, Edenhofer, Frank, Hoffmann, Per, Reif, Andreas, Kittel-Schneider, Sarah, Palladino, Viola Stella, Geburtig-Chiocchetti, Andreas, Frank, Lukas, Haslinger, Denise, McNeill, Rhiannon, Radtke, Franziska, Till, Andreas, Haupt, Simone, Brüstle, Oliver, Günther, Katharina, Edenhofer, Frank, Hoffmann, Per, Reif, Andreas, and Kittel-Schneider, Sarah
- Abstract
The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.
- Published
- 2020
10. Risk stratification for bipolar disorder using polygenic risk scores among young high-risk adults
- Author
-
Biere, Silvia, Kranz, Thorsten Manfred, Matura, Silke, Petrova, Kristiyana, Streit, Fabian, Geburtig-Chiocchetti, Andreas, Grimm, Oliver, Brum, Murielle, Brunkhorst-Kanaan, Nathalie, Oertel, Viola, Malyshau, Aliaksandr, Pfennig, Andrea, Bauer, Michael, Schulze, Thomas Gerd, Kittel-Schneider, Sarah, Reif, Andreas, Biere, Silvia, Kranz, Thorsten Manfred, Matura, Silke, Petrova, Kristiyana, Streit, Fabian, Geburtig-Chiocchetti, Andreas, Grimm, Oliver, Brum, Murielle, Brunkhorst-Kanaan, Nathalie, Oertel, Viola, Malyshau, Aliaksandr, Pfennig, Andrea, Bauer, Michael, Schulze, Thomas Gerd, Kittel-Schneider, Sarah, and Reif, Andreas
- Abstract
Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD. Methods: A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes. Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls. Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.
- Published
- 2020
11. Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder
- Author
-
Yousaf, Afsheen, Waltes, Regina, Haslinger, Denise, Klauck, Sabine M., Duketis, Eftichia, Sachse, Michael, Voran, Anette, Biscaldi, Monica, Schulte-Rüther, Martin, Cichon, Sven, Nöthen, Markus Maria, Ackermann, Jörg, Koch, Ina, Freitag, Christine M., Geburtig-Chiocchetti, Andreas, Yousaf, Afsheen, Waltes, Regina, Haslinger, Denise, Klauck, Sabine M., Duketis, Eftichia, Sachse, Michael, Voran, Anette, Biscaldi, Monica, Schulte-Rüther, Martin, Cichon, Sven, Nöthen, Markus Maria, Ackermann, Jörg, Koch, Ina, Freitag, Christine M., and Geburtig-Chiocchetti, Andreas
- Abstract
Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h2SNP = 0.2–0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3–3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits—partially replicating previous findings—and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.
- Published
- 2020
12. Knockdown of the ADHD candidate gene Diras2 in murine hippocampal primary cells
- Author
-
Grünewald, Lena, Geburtig-Chiocchetti, Andreas, Weber, Heike, Scholz, Claus-Jürgen, Schartner, Christoph, Freudenberg, Florian, Reif, Andreas, Grünewald, Lena, Geburtig-Chiocchetti, Andreas, Weber, Heike, Scholz, Claus-Jürgen, Schartner, Christoph, Freudenberg, Florian, and Reif, Andreas
- Abstract
Objective: The DIRAS2 gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by DIRAS2. Method: Using short hairpin RNAs, we downregulated Diras2 in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. Results: Diras2 knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. Conclusion: Our findings show that Diras2 affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that DIRAS2 is linked to etiological processes underlying ADHD. (J. of Att. Dis. 2021; 25(4) 572-583).
- Published
- 2019
13. Drug-resistant juvenile myoclonic epilepsy: Misdiagnosis of progressive myoclonus epilepsy
- Author
-
Ferlazzo, Edoardo, Martin, Sarah, Strzelczyk, Adam, Lindlar, Silvia, Krause, Kristina, Reif, Philipp Sebastian, Menzler, Katja, Geburtig-Chiocchetti, Andreas, Rosenow, Felix, Knake, Susanne, Klein, Karl Martin, Ferlazzo, Edoardo, Martin, Sarah, Strzelczyk, Adam, Lindlar, Silvia, Krause, Kristina, Reif, Philipp Sebastian, Menzler, Katja, Geburtig-Chiocchetti, Andreas, Rosenow, Felix, Knake, Susanne, and Klein, Karl Martin
- Abstract
Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability (p = 0.025), cognitive impairment (p < 0.001), febrile seizures in first-degree relatives (p = 0.023) and prominent dialeptic seizures (p = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.
- Published
- 2019
14. Generation of human induced pluripotent stem cell lines (hiPSC) from one bipolar disorder patient carrier of a DGKH risk haplotype and one non-risk-variant-carrier bipolar disorder patient
- Author
-
Palladino, Viola Stella, Subrata, Nadia Omega Cipta, Geburtig-Chiocchetti, Andreas, McNeill, Rhiannon, Hoffmann, Per, Reif, Andreas, and Kittel-Schneider, Sarah
- Subjects
Bipolar Disorder ,lcsh:Biology (General) ,Haplotypes ,Reverse Transcriptase Polymerase Chain Reaction ,Induced Pluripotent Stem Cells ,Humans ,Cell Differentiation ,ddc:610 ,lcsh:QH301-705.5 ,Cells, Cultured ,Skin - Abstract
Fibroblasts were isolated from skin biopsies from two patients with bipolar I disorder. One patient was a 26 year old female carrying a risk haplotype in the DGKH (diacylglycerol kinase eta) gene and the other was a non-carrier 27 year old male. Patient fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) by using a Sendai virus vector. DGKH-risk haplotype and non-risk haplotype hiPSCs showed expression of pluripotency markers and were able to differentiate into cells of the three germ layers. These cell models are useful to investigate the role of risk gene variants in bipolar disorder.Resource table.Unlabelled TableUnique stem cell lines identifierKGUi001-AKGUi002-AAlternative names of stem cell linesAR1023 hiPSC (KGUi001-A)AR1034 hiPSC (KGUi002-A)InstitutionDepartment of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt Am Main, GermanyContact information of distributorDr. Sarah Kittel-Schneider, sarah.kittel-schneider@kgu.deType of cell linesiPSCOriginHumanCell SourceDermal fibroblastsClonalityClonalMethod of reprogrammingSendai virusMultiline rationaleSame disease non-isogenic cell linesGene modificationNoType of modificationN/AAssociated diseaseBipolar DisorderGene/locusSNPs DGKH (rs994856/rs9525580/rs9525584 GAT haplotype; GG/AG/TT) and NON-GAT haplotype (AG/GG/CT); 13q14.11Method of modificationN/AName of transgene or resistanceN/AInducible/constitutive systemN/ADate archived/stock dateMay 2018Cell line repository/bankN/AEthical approvalEthics committee University of Würzburg, 10.06.2011, Ethical approval number 96/11Ethics committee University of Frankfurt, 04.3.2015, Ethical approval number 425/14
- Published
- 2018
- Full Text
- View/download PDF
15. Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model
- Author
-
Haslinger, Denise, Waltes, Regina, Yousaf, Afsheen, Lindlar, Silvia, Schneider, Ines, Lim, Chai K., Tsai, Meng-Miao, Garvalov, Boyan K., Acker-Palmer, Amparo, Krezdorn, Nicolas, Rotter, Björn, Acker, Till, Guillemin, Gilles J., Fulda, Simone, Freitag, Christine M., Geburtig-Chiocchetti, Andreas, Haslinger, Denise, Waltes, Regina, Yousaf, Afsheen, Lindlar, Silvia, Schneider, Ines, Lim, Chai K., Tsai, Meng-Miao, Garvalov, Boyan K., Acker-Palmer, Amparo, Krezdorn, Nicolas, Rotter, Björn, Acker, Till, Guillemin, Gilles J., Fulda, Simone, Freitag, Christine M., and Geburtig-Chiocchetti, Andreas
- Abstract
Background: Altered neuronal development is discussed as the underlying pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 genes within this region, quinolinate phosphoribosyltransferase (QPRT) showed the strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma cells. We hypothesized a causal relation between this tryptophan metabolism-related enzyme and neuronal differentiation. We thus analyzed the effect of QPRT on the differentiation of SH-SY5Y and specifically focused on neuronal morphology, metabolites of the tryptophan pathway, and the neurodevelopmental transcriptome. Methods: The gene dosage-dependent change of QPRT expression following Chr16p11.2 deletion was investigated in a lymphoblastoid cell line (LCL) of a deletion carrier and compared to his non-carrier parents. Expression of QPRT was tested for correlation with neuromorphology in SH-SY5Y cells. QPRT function was inhibited in SH-SY5Y neuroblastoma cells using (i) siRNA knockdown (KD), (ii) chemical mimicking of loss of QPRT, and (iii) complete CRISPR/Cas9-mediated knock out (KO). QPRT-KD cells underwent morphological analysis. Chemically inhibited and QPRT-KO cells were characterized using viability assays. Additionally, QPRT-KO cells underwent metabolite and whole transcriptome analyses. Genes differentially expressed upon KO of QPRT were tested for enrichment in biological processes and co-regulated gene-networks of the human brain. Results: QPRT expression was reduced in the LCL of the deletion carrier and significantly correlated with the neuritic complexity of SH-SY5Y. The reduction of QPRT altered neuronal morphology of differentiated SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal upon induction of neuronal differentiation, but not proliferation. The QPRT-associated tryptophan pathway was not affected by KO. At the transcriptome lev
- Published
- 2018
16. A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets
- Author
-
Almeida, Francisca F., Tognarelli, Sara, Marçais, Antoine, Kueh, Andrew J., Friede, Miriam Elisabeth, Liao, Yang, Willis, Simon N., Luong, Kylie, Faure, Fabrice, Mercier, Francois E., Galluso, Justine, Firth, Matthew, Narni-Mancinelli, Emilie, Rais, Bushra, Scadden, David T., Spallotta, Francesco, Weil, Sandra, Giannattasio, Ariane, Kalensee, Franziska, Zöller, Tobias, Huntington, Nicholas D., Schleicher, Ulrike, Geburtig-Chiocchetti, Andreas, Ugolini, Sophie, Herold, Marco, Shi, Wei, Koch, Joachim, Steinle, Alexander, Vivier, Eric, Walzer, Thierry, Belz, Gabrielle T., Ullrich, Evelyn, Almeida, Francisca F., Tognarelli, Sara, Marçais, Antoine, Kueh, Andrew J., Friede, Miriam Elisabeth, Liao, Yang, Willis, Simon N., Luong, Kylie, Faure, Fabrice, Mercier, Francois E., Galluso, Justine, Firth, Matthew, Narni-Mancinelli, Emilie, Rais, Bushra, Scadden, David T., Spallotta, Francesco, Weil, Sandra, Giannattasio, Ariane, Kalensee, Franziska, Zöller, Tobias, Huntington, Nicholas D., Schleicher, Ulrike, Geburtig-Chiocchetti, Andreas, Ugolini, Sophie, Herold, Marco, Shi, Wei, Koch, Joachim, Steinle, Alexander, Vivier, Eric, Walzer, Thierry, Belz, Gabrielle T., and Ullrich, Evelyn
- Abstract
NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.
- Published
- 2018
17. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
- Author
-
Pinto, Dalila, Delaby, Elsa, Merico, Daniele, Barbosa, Mafalda, Merikangas, Alison, Klei, Lambertus, Thiruvahindrapuram, Bhooma, Xu, Xiao, Ziman, Robert, Wang, Zhuozhi, Vorstman, Jacob A. S., Thompson, Ann P., Regan, Regina, Pilorge, Marion, Pellecchia, Giovanna, Pagnamenta, Alistair T., Oliveira, Bárbara, Marshall, Christian R., Magalhães, Tiago R., Lowe, Jennifer K., Howe, Jennifer L., Griswold, Anthony J., Gilbert, John, Duketis, Eftichia, Dombroski, Beth A., Jonge, Maretha de, Cuccaro, Michael L., Crawford, Emily L., Correia, Catarina T., Conroy, Judith, Conceição, Inȇs C., Geburtig-Chiocchetti, Andreas, Casey, Jillian P., Cai, Guiqing, Cabrol, Christelle, Bolshakova, Nadia, Bacchelli, Elena, Anney, Richard, Gallinger, Steven, Cotterchio, Michelle, Casey, Graham, Zwaigenbaum, Lonnie, Wittemeyer, Kerstin, Wing, Kirsty, Wallace, Simon, Engeland, Herman van, Tryfon, Ana, Thomson, Susanne, Soorya, Latha, Roge, Bernadette, Roberts, Wendy, Poustka, Fritz, Mouga, Susana, Minshew, Nancy J., McInnes, L. Alison, McGrew, Susan G., Lord, Catherine, Leboyer, Marion, Le Couteur, Ann, Kolevzon, Alexander, González, Patricia Jiménez, Jacob, Suma, Holt, Richard, Guter, Stephen J., Green, Jonathan, Green, Andrew, Gillberg, Christopher, Fernandez, Bridget A., Duque, Frederico, Delorme, Richard, Dawson, Geraldine, Chaste, Pauline, Café, Cátia, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F., Bölte, Sven, Bernier, Raphael, Baird, Gillian, Bailey, Anthony J., Anagnostou, Evdokia, Almeida, Joana, Wijsman, Ellen M., Vieland, Veronica J., Vicente, Astrid M., Schellenberg, Gerard D., Pericak-Vance, Margaret Ann, Paterson, Andrew D., Parr, Jeremy R., Oliveira, Guiomar, Nurnberger, John I., Monaco, Anthony P., Maestrini, Elena, Klauck, Sabine M., Hakonarson, Hakon, Haines, Jonathan L., Geschwind, Daniel H., Freitag, Christine M., Folstein, Susan E., Ennis, Sean, Coon, Hilary, Battaglia, Agatino, Szatmari, Peter, Sutcliffe, James S., Hallmayer, Joachim, Gill, Michael, Cook, Edwin H., Buxbaum, Joseph D., Devlin, Bernie, Gallagher, Louise, Betancur, Catalina, Scherer, Stephen W., Pinto, Dalila, Delaby, Elsa, Merico, Daniele, Barbosa, Mafalda, Merikangas, Alison, Klei, Lambertus, Thiruvahindrapuram, Bhooma, Xu, Xiao, Ziman, Robert, Wang, Zhuozhi, Vorstman, Jacob A. S., Thompson, Ann P., Regan, Regina, Pilorge, Marion, Pellecchia, Giovanna, Pagnamenta, Alistair T., Oliveira, Bárbara, Marshall, Christian R., Magalhães, Tiago R., Lowe, Jennifer K., Howe, Jennifer L., Griswold, Anthony J., Gilbert, John, Duketis, Eftichia, Dombroski, Beth A., Jonge, Maretha de, Cuccaro, Michael L., Crawford, Emily L., Correia, Catarina T., Conroy, Judith, Conceição, Inȇs C., Geburtig-Chiocchetti, Andreas, Casey, Jillian P., Cai, Guiqing, Cabrol, Christelle, Bolshakova, Nadia, Bacchelli, Elena, Anney, Richard, Gallinger, Steven, Cotterchio, Michelle, Casey, Graham, Zwaigenbaum, Lonnie, Wittemeyer, Kerstin, Wing, Kirsty, Wallace, Simon, Engeland, Herman van, Tryfon, Ana, Thomson, Susanne, Soorya, Latha, Roge, Bernadette, Roberts, Wendy, Poustka, Fritz, Mouga, Susana, Minshew, Nancy J., McInnes, L. Alison, McGrew, Susan G., Lord, Catherine, Leboyer, Marion, Le Couteur, Ann, Kolevzon, Alexander, González, Patricia Jiménez, Jacob, Suma, Holt, Richard, Guter, Stephen J., Green, Jonathan, Green, Andrew, Gillberg, Christopher, Fernandez, Bridget A., Duque, Frederico, Delorme, Richard, Dawson, Geraldine, Chaste, Pauline, Café, Cátia, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F., Bölte, Sven, Bernier, Raphael, Baird, Gillian, Bailey, Anthony J., Anagnostou, Evdokia, Almeida, Joana, Wijsman, Ellen M., Vieland, Veronica J., Vicente, Astrid M., Schellenberg, Gerard D., Pericak-Vance, Margaret Ann, Paterson, Andrew D., Parr, Jeremy R., Oliveira, Guiomar, Nurnberger, John I., Monaco, Anthony P., Maestrini, Elena, Klauck, Sabine M., Hakonarson, Hakon, Haines, Jonathan L., Geschwind, Daniel H., Freitag, Christine M., Folstein, Susan E., Ennis, Sean, Coon, Hilary, Battaglia, Agatino, Szatmari, Peter, Sutcliffe, James S., Hallmayer, Joachim, Gill, Michael, Cook, Edwin H., Buxbaum, Joseph D., Devlin, Bernie, Gallagher, Louise, Betancur, Catalina, and Scherer, Stephen W.
- Abstract
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
- Published
- 2014
18. Protein signatures of oxidative stress response in a patient specific cell line model for autism
- Author
-
Geburtig-Chiocchetti, Andreas, Haslinger, Denise, Boesch, Maximilian, Karl, Thomas, Wiemann, Stefan, Freitag, Christine M., Poustka, Fritz, Scheibe, Burghardt, Bauer, Johann W., Hintner, Helmut, Breitenbach, Michael, Kellermann, Josef, Lottspeich, Friedrich, Klauck, Sabine M., Breitenbach-Koller, Lore, Geburtig-Chiocchetti, Andreas, Haslinger, Denise, Boesch, Maximilian, Karl, Thomas, Wiemann, Stefan, Freitag, Christine M., Poustka, Fritz, Scheibe, Burghardt, Bauer, Johann W., Hintner, Helmut, Breitenbach, Michael, Kellermann, Josef, Lottspeich, Friedrich, Klauck, Sabine M., and Breitenbach-Koller, Lore
- Abstract
Background: Known genetic variants can account for 10% to 20% of all cases with autism spectrum disorders (ASD). Overlapping cellular pathomechanisms common to neurons of the central nervous system (CNS) and in tissues of peripheral organs, such as immune dysregulation, oxidative stress and dysfunctions in mitochondrial and protein synthesis metabolism, were suggested to support the wide spectrum of ASD on unifying disease phenotype. Here, we studied in patient-derived lymphoblastoid cell lines (LCLs) how an ASD-specific mutation in ribosomal protein RPL10 (RPL10[H213Q]) generates a distinct protein signature. We compared the RPL10[H213Q] expression pattern to expression patterns derived from unrelated ASD patients without RPL10[H213Q] mutation. In addition, a yeast rpl10 deficiency model served in a proof-of-principle study to test for alterations in protein patterns in response to oxidative stress. Methods: Protein extracts of LCLs from patients, relatives and controls, as well as diploid yeast cells hemizygous for rpl10, were subjected to two-dimensional gel electrophoresis and differentially regulated spots were identified by mass spectrometry. Subsequently, Gene Ontology database (GO)-term enrichment and network analysis was performed to map the identified proteins into cellular pathways. Results: The protein signature generated by RPL10[H213Q] is a functionally related subset of the ASD-specific protein signature, sharing redox-sensitive elements in energy-, protein- and redox-metabolism. In yeast, rpl10 deficiency generates a specific protein signature, harboring components of pathways identified in both the RPL10[H213Q] subjects' and the ASD patients' set. Importantly, the rpl10 deficiency signature is a subset of the signature resulting from response of wild-type yeast to oxidative stress. Conclusions: Redox-sensitive protein signatures mapping into cellular pathways with pathophysiology in ASD have been identified in both LCLs carrying the ASD-specific mut
- Published
- 2014
19. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of Autism spectrum disorders
- Author
-
Leblond, Claire S., Heinrich, Jutta, Delorme, Richard, Proepper, Christian, Betancur, Catalina, Huguet, Guillaume, Konyukh, Marina, Chaste, Pauline, Ey, Elodie, Rastam, Maria, Anckarsäter, Henrik, Nygren, Gudrun, Gillberg, I. Carina, Melke, Jonas, Toro, Roberto, Regnault, Beatrice, Fauchereau, Fabien, Mercati, Oriane, Lemière, Nathalie, Skuse, David, Poot, Martin, Holt, Richard, Monaco, Anthony P., Järvelä, Irma, Kantojärvi, Katri, Vanhala, Raija, Curran, Sarah, Collier, David A., Bolton, Patrick F., Geburtig-Chiocchetti, Andreas, Klauck, Sabine M., Poustka, Fritz, Freitag, Christine M., Waltes, Regina, Kopp, Marnie, Duketis, Eftichia, Bacchelli, Elena, Minopoli, Fiorella, Ruta, Liliana, Battaglia, Agatino, Mazzone, Luigi, Maestrini, Elena, Sequeira, Ana F., Oliveira, Barbara, Vicente, Astrid M., Oliveira, Guiomar, Pinto, Dalila, Scherer, Stephen W., Zelenika, Diana, Delepine, Marc, Lathrop, Mark, Bonneau, Dominique, Guinchat, Vincent, Devillard, Françoise, Assouline, Brigitte, Mouren, Marie-Christine, Leboyer, Marion, Gillberg, Christopher, Böckers, Tobias M., Bourgeron, Thomas, Leblond, Claire S., Heinrich, Jutta, Delorme, Richard, Proepper, Christian, Betancur, Catalina, Huguet, Guillaume, Konyukh, Marina, Chaste, Pauline, Ey, Elodie, Rastam, Maria, Anckarsäter, Henrik, Nygren, Gudrun, Gillberg, I. Carina, Melke, Jonas, Toro, Roberto, Regnault, Beatrice, Fauchereau, Fabien, Mercati, Oriane, Lemière, Nathalie, Skuse, David, Poot, Martin, Holt, Richard, Monaco, Anthony P., Järvelä, Irma, Kantojärvi, Katri, Vanhala, Raija, Curran, Sarah, Collier, David A., Bolton, Patrick F., Geburtig-Chiocchetti, Andreas, Klauck, Sabine M., Poustka, Fritz, Freitag, Christine M., Waltes, Regina, Kopp, Marnie, Duketis, Eftichia, Bacchelli, Elena, Minopoli, Fiorella, Ruta, Liliana, Battaglia, Agatino, Mazzone, Luigi, Maestrini, Elena, Sequeira, Ana F., Oliveira, Barbara, Vicente, Astrid M., Oliveira, Guiomar, Pinto, Dalila, Scherer, Stephen W., Zelenika, Diana, Delepine, Marc, Lathrop, Mark, Bonneau, Dominique, Guinchat, Vincent, Devillard, Françoise, Assouline, Brigitte, Mouren, Marie-Christine, Leboyer, Marion, Gillberg, Christopher, Böckers, Tobias M., and Bourgeron, Thomas
- Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
- Published
- 2012
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.