Vall dHebron Research Institute VHIR

Barcelona, Spain

Vall dHebron Research Institute VHIR

Barcelona, Spain
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Corominas-Roso M.,Hospital Universitari Vall dHebron | Corominas-Roso M.,Biomedical Network Research Center on Mental Health | Ramos-Quiroga J.A.,Hospital Universitari Vall dHebron | Ramos-Quiroga J.A.,Biomedical Network Research Center on Mental Health | And 14 more authors.
International Journal of Neuropsychopharmacology | Year: 2013

It has been hypothesized that brain-derived neurotrophic factor (BDNF) is involved in the pathogenesis of attention-deficit hyperactivity disorder (ADHD), although experimental data regarding the contribution of BDNF gene polymorphisms to this psychiatric disorder are controversial. Recently, changes in BDNF serum levels have been reported in children with ADHD, but there are no studies about the possible role of this neurotrophin in adults. A total of 54 Caucasoid ADHD adults, including the predominantly inattentive and combined types (aged 33.43 ±Â 8.99 yr) and 59 Caucasoid unrelated healthy controls (aged 35.52 ±Â 9.37 yr) were included in a study to evaluate BDNF levels in serum. Medical, neurological and psychiatric co-morbidities were excluded. Clinical data concerning ADHD diagnosis and blood samples for patients and controls were collected. BDNF serum levels were significantly lower in adults with ADHD compared to healthy controls (p < 0.0001). Although the combined type of ADHD subgroup displayed lower BDNF serum levels than the inattentive type, the differences did not reach statistical significance. No significant correlations were found between serum BDNF levels and scores on the Conners' Adult ADHD Rating Subscales. These results suggest a role for BDNF in ADHD, at least in those patients whose disorder persists throughout life. Low BDNF levels may contribute to the neurodevelopmental deficits of ADHD and to the persistence of the disorder into adulthood. BDNF differences between ADHD subtypes should be further studied. © CINP 2013.


Docampo E.,CIBER ISCIII | Ribases M.,Vall dHebron Research Institute VHIR | Ribases M.,Biomedical Network Research Center on Mental Health | Ribases M.,Hospital Universitari Vall dHebron | And 13 more authors.
Genes, Brain and Behavior | Year: 2012

The Neurexin 3 gene (NRXN3) has been associated with dependence on various addictive substances, as well as with the degree of smoking in schizophrenic patients and impulsivity among tobacco abusers. To further evaluate the role of NRXN3 in nicotine addiction, we analyzed single nucleotide polymorphisms (SNPs) and a copy number variant (CNV) within the NRXN3 genomic region. An initial study was carried out on 157 smokers and 595 controls, all of Spanish Caucasian origin. Nicotine dependence was assessed using the Fagerström index and the number of cigarettes smoked per day. The 45 NRXN3 SNPs genotyped included all the SNPs previously associated with disease, and a previously described deletion within NRXN3. This analysis was replicated in 276 additional independent smokers and 568 controls. Case-control association analyses were performed at the allele, genotype and haplotype levels. Allelic and genotypic association tests showed that three NRXN3 SNPs were associated with a lower risk of being a smoker. The haplotype analysis showed that one block of 16 Kb, consisting of two of the significant SNPs (rs221473 and rs221497), was also associated with lower risk of being a smoker in both the discovery and the replication cohorts, reaching a higher level of significance when the whole sample was considered [odds ratio = 0.57 (0.42-0.77), permuted P = 0.0075]. By contrast, the NRXN3 CNV was not associated with smoking behavior. Taken together, our results confirm a role for NRXN3 in susceptibility to smoking behavior, and strongly implicate this gene in genetic vulnerability to addictive behaviors. © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.


Jacobsen K.K.,University of Bergen | Halmoy A.,University of Bergen | Sanchez-Mora C.,Hospital Universitari Vall dHebron | Sanchez-Mora C.,Vall dHebron Research Institute VHIR | And 9 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2013

The DISC1 gene was named after its discovery in a Scottish pedigree with schizophrenia (SCZ) patients. However, subsequent studies have shown association of DISC1 variants with a range of different neurocognitive phenotypes and psychiatric disorders, including bipolar disorder (BPD), and major depression. Attention-deficit/hyperactivity disorder (ADHD) shares some symptoms with BPD and ADHD patients often suffer from comorbid affective disorders. We wanted to examine the role of DISC1 in ADHD, and with comorbid symptoms of mood disorders. Eleven single nucleotide polymorphisms (SNPs) previously implicated in SCZ and BPD, and a DISC1 duplication involving exon 1, were genotyped in 561 adult ADHD cases and 713 controls of Norwegian ancestry. The intronic SNP rs1538979 was associated with ADHD in the Norwegian sample [odds ratio (OR): 1.33, 95% confidence interval (CI) 1.03-1.73, P=0.03] and replicated in a Spanish adult ADHD sample of 694 cases and 735 controls, using the tagging SNP rs11122330 (meta-analysis: P=0.008, OR 1.25, 95% CI 1.06-1.47). In the Norwegian ADHD sample we also observed an association between the Phe607-variant of rs6675281 and a positive score on the Mood Disorder Questionnaire (MDQ; OR=1.44, 95% CI 1.08-1.93, P=0.01). To our knowledge, this is the first study to show an association between DISC1 variants and ADHD. Our study suggests that further studies are warranted to resolve if DISC1 variation is involved in several common neurodevelopmental disorders including ADHD. © 2013 Wiley Periodicals, Inc.


Corominas-Roso M.,Autonomous University of Barcelona | Roncero C.,Autonomous University of Barcelona | Roncero C.,Hospital Universitari Vall dHebron | Eiroa-Orosa F.J.,Autonomous University of Barcelona | And 11 more authors.
European Neuropsychopharmacology | Year: 2013

Preclinical studies indicate that brain-derived neurotrophic factor (BDNF) is involved in neuroplastic changes underlying enduring cocaine-seeking following withdrawal. However, little is known about temporal changes in serum BDNF levels or the involvement of BDNF in craving and abstinence in early-abstinent cocaine-dependent patients. Twenty-three cocaine-dependent individuals (aged 33.65±6.85 years) completed a two-week detoxification program at an inpatient facility. Two serum samples were collected for each patient at baseline and at the end of the protocol. Serum samples were also collected for 46 healthy controls (aged 35.52±9.37 years). Demographic, consumption and clinical data were recorded for all patients. Significantly lower serum BDNF levels (p <0001) were observed for cocaine-dependent patients at baseline compared to healthy controls. Serum BDNF levels increased significantly across 12 days of early abstinence (p=030). Baseline BDNF levels correlated with craving (p=034). Post-detoxification BDNF levels correlated with craving (p=018), loss of control (p <000), abstinence measures (p=0.031), depression (p=0.036), and anxiety (p=0.036). Post-detoxification BDNF levels also had predictive value for the loss of control measure of craving. Chronic cocaine use is associated with decreased serum BDNF. A progressive increase in serum BDNF levels during early abstinence correlates with cocaine craving and abstinence symptoms and may reflect increasing BDNF levels in different brain regions. These findings suggest that serum BDNF may be a biomarker for cocaine addiction. © 2012 Elsevier B.V. and ECNP.


Pujol-Borrell R.,Vall dHebron Research Institute VHIR | Pujol-Borrell R.,Hospital Universitari Vall dHebron | Pujol-Borrell R.,Autonomous University of Barcelona | Gimenez-Barcons M.,Vall dHebron Research Institute VHIR | And 4 more authors.
Hormone and Metabolic Research | Year: 2015

As most autoimmune diseases, inherited predisposition to Graves' disease (GD) is polygenic with the main contributory genes being located in the HLA region. Also, as in other autoimmune diseases, family linkage, candidate gene association, and GWAS studies have identified an expanding number of predisposing genes (CTLA4, CD40, PTPN22...) and 2 of them, TG and TSHR, are thyroid specific. In spite of this expanding number of associated genes, it has been estimated that all together they account for only a 20% of the heritability of GD. TSHR is of special interest as it codes for the target of TSHR stimulating antibodies (TSAbs), which are unequivocally pathogenic and an exception in autoimmunity by being stimulating rather than neutral, blocking, or cytotoxic. This is surprising because the generation of stimulating TSHR antibodies by immunisation of laboratory animals has been remarkably difficult, suggesting an underlying mechanism that favours stimulating over neutral or blocking anti-TSHR antibodies must be operating in GD patients. Besides, after HLA, TSHR is the gene most tightly associated to GD. The TSHR polymorphisms conferring susceptibility are located in the unusually large intron 1. Two mechanisms have been already put forward to explain its association with GD. According to one, the risk alleles determine an increase in the expression of TSHR mRNA splice variants that code for a soluble form of the receptor. The wider distribution of soluble TSHR would favour its immunogenicity and the development of an autoimmune response to it. It does not explain why it becomes immunogenic, as immunogenicity and distribution are not necessarily connected, nor why the immune response focus to the production of stimulating antibodies. According to the second mechanism proposed, the risk alleles determine a lower TSHR expression in the thymus and this would favour the escape of more TSHR reactive T cells, that is, central tolerance failure. The unexpected finding that thymocytes express TSHR and that TSAbs stimulate them lead to postulate that this would accelerate their egress from the thymus and a less efficient deletion of the TSHR self-reactive T cells. It can be envisaged that these autoreactive T cells may enhance the production of TSHR-Abs in the germinal centres of the thyroid draining lymph nodes, especially of those capable of further stimulating the egress of autoreactive T cells from the thymus. This mechanism, which does not exclude the former, provides and insight of the way in which TSAbs are favoured over neutral or blocking antibodies. Finally this would explain the frequent finding of thymic hyperplasia in GD patients. © Georg Thieme Verlag KG Stuttgart New York.


PubMed | Hospital Universitari Vall dHebron and Vall dHebron Research Institute VHIR
Type: Journal Article | Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | Year: 2015

As most autoimmune diseases, inherited predisposition to Graves disease (GD) is polygenic with the main contributory genes being located in the HLA region. Also, as in other autoimmune diseases, family linkage, candidate gene association, and GWAS studies have identified an expanding number of predisposing genes (CTLA4, CD40, PTPN22...) and 2 of them, TG and TSHR, are thyroid specific. In spite of this expanding number of associated genes, it has been estimated that all together they account for only a 20% of the heritability of GD. TSHR is of special interest as it codes for the target of TSHR stimulating antibodies (TSAbs), which are unequivocally pathogenic and an exception in autoimmunity by being stimulating rather than neutral, blocking, or cytotoxic. This is surprising because the generation of stimulating TSHR antibodies by immunisation of laboratory animals has been remarkably difficult, suggesting an underlying mechanism that favours stimulating over neutral or blocking anti-TSHR antibodies must be operating in GD patients. Besides, after HLA, TSHR is the gene most tightly associated to GD. The TSHR polymorphisms conferring susceptibility are located in the unusually large intron 1. Two mechanisms have been already put forward to explain its association with GD. According to one, the risk alleles determine an increase in the expression of TSHR mRNA splice variants that code for a soluble form of the receptor. The wider distribution of soluble TSHR would favour its immunogenicity and the development of an autoimmune response to it. It does not explain why it becomes immunogenic, as immunogenicity and distribution are not necessarily connected, nor why the immune response focus to the production of stimulating antibodies. According to the second mechanism proposed, the risk alleles determine a lower TSHR expression in the thymus and this would favour the escape of more TSHR reactive T cells, that is, central tolerance failure. The unexpected finding that thymocytes express TSHR and that TSAbs stimulate them lead to postulate that this would accelerate their egress from the thymus and a less efficient deletion of the TSHR self-reactive T cells. It can be envisaged that these autoreactive T cells may enhance the production of TSHR-Abs in the germinal centres of the thyroid draining lymph nodes, especially of those capable of further stimulating the egress of autoreactive T cells from the thymus. This mechanism, which does not exclude the former, provides and insight of the way in which TSAbs are favoured over neutral or blocking antibodies. Finally this would explain the frequent finding of thymic hyperplasia in GD patients.


Blanco A.,University of Santiago de Compostela | Gutierrez-Enriquez S.,Autonomous University of Barcelona | Santamarina M.,University of Santiago de Compostela | Montalban G.,Autonomous University of Barcelona | And 7 more authors.
Breast Cancer Research and Treatment | Year: 2014

BRCA1 and BRCA2 are the most well-known breast and ovarian cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. Recently, RAD51C, a new Fanconi Anemia gene, essential for homologous recombination repair, has been reported to be a rare hereditary breast and ovarian cancer susceptibility gene. Indeed, several pathogenic mutations have been identified in BRCA1/BRCA2-negative hereditary breast and ovarian cancer families. Here, we present the results of the screening of RAD51C mutations in a large series of 516 BRCA1/BRCA2-negative Spanish patients from breast and/or ovarian cancer families, and the evaluation of these results in the context of all RAD51C carriers. RAD51C mutation screening was performed by DNA analysis for all index cases. All the genetic variants identified were analyzed in silico for splicing and protein predictions. cDNA analysis was performed for three selected variants. All previous RAD51C mutation studies on breast and/or ovarian cancer were reviewed. We identified three inactivating RAD51C mutations. Two mutations were found in breast and ovarian cancer families and one mutation in a site-specific breast cancer family. Based on the mean age of ovarian cancer diagnosis in RAD51C carriers, we would recommend prophylactic bilateral salpingo-ophorectomy in premenopausal RAD51C mutation carriers. Our results support that RAD51C is a rare breast and ovarian cancer susceptibility gene and may contribute to a small fraction of families including breast and ovarian cancer cases and families with only breast cancer. Thus, RAD51C testing should be offered to hereditary breast and/or ovarian cancer families without selecting for specific cancer origin. © 2014 Springer Science+Business Media.


Castellana B.,University of Barcelona | Castellana B.,Vall dHebron Research Institute VHIR | Marin-Juez R.,University of Barcelona | Marin-Juez R.,ZF Screens B.V. | Planas J.V.,University of Barcelona
Fish and Shellfish Immunology | Year: 2013

Interleukin-6 (IL-6) has been identified and characterized from several fish species and its mRNA expression is induced by pathogen-associated molecular patterns (PAMPs) and cytokines in immune cells and tissues. However, the transcriptional regulation of the IL-6 gene in fish is not well understood. In the present study, we have cloned and sequenced a 1028bp 5'-flanking DNA region from the IL-6 gene in seabream (Sparus aurata). Sequence analysis of the seabream IL-6 promoter (sbIL-6P) evidenced the presence of a conserved TATA motif and conserved response elements for NF-κB, C/EBPβ (NF-IL6), AP-1 and GRE, similar to other vertebrate IL-6 promoters. Functional characterization of sbIL-6P was performed by cloning sbIL-6P into a luciferase expression vector and by transfecting it into L6 muscle cells, a mammalian cell line shown previously to express IL-6 in response to pro-inflammatory stimuli. We show here that the activity of sbIL-6P was significantly induced by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα), IL-6 and IL-2, as well as by lipopolysaccharide (LPS), but significantly repressed by dexamethasone. In addition, the stimulatory effects of TNFα on sbIL-6P activity appeared to be mediated by the NF-κB, p38 MAPK and JNK signaling pathways. Deletion analyses of sbIL-6P suggested that activation of sbIL-6P by TNFα and IL-6 required the presence of binding motifs present in the proximal promoter (-171 to-84) whereas activation by IL-2 required binding motifs present in the distal promoter (-1024 to-864). The results from this study indicate, for the first time in fish, that pro-inflammatory cytokines, LPS and glucocorticoids can regulate the activity of the IL-6 gene at a transcriptional level and identify important regions in its response to cytokines. © 2013 Elsevier Ltd.


De Groot N.S.,Laboratory of Molecular Biology Medical Research Council | De Groot N.S.,Autonomous University of Barcelona | Burgas M.T.,Laboratory of Molecular Biology Medical Research Council | Burgas M.T.,Autonomous University of Barcelona | Burgas M.T.,Vall dHebron Research Institute VHIR
Cellular and Molecular Life Sciences | Year: 2015

Systemic inflammation and infections are associated with neurodegenerative diseases. Unfortunately, the molecular bases of this link are still largely undiscovered. We, therefore, review how inflammatory processes can imbalance membrane homeostasis and theorize how this may have an effect on the aggregation behavior of the proteins implicated in such diseases. Specifically, we describe the processes that generate such imbalances at the molecular level, and try to understand how they affect protein folding and localization. Overall, current knowledge suggests that microglia pro-inflammatory mediators can generate membrane damage, which may have an impact in terms of triggering or accelerating disease manifestation. © 2015 Springer Basel.


PubMed | Max Planck Institute for Chemistry, Center for Research in Agricultural Genomics, Barcelona Supercomputing Center, University of Rome La Sapienza and 2 more.
Type: Journal Article | Journal: PloS one | Year: 2015

Couplings between protein sub-structures are a common property of protein dynamics. Some of these couplings are especially interesting since they relate to function and its regulation. In this article we have studied the case of cavity couplings because cavities can host functional sites, allosteric sites, and are the locus of interactions with the cell milieu. We have divided this problem into two parts. In the first part, we have explored the presence of cavity couplings in the natural dynamics of 75 proteins, using 20 ns molecular dynamics simulations. For each of these proteins, we have obtained two trajectories around their native state. After applying a stringent filtering procedure, we found significant cavity correlations in 60% of the proteins. We analyze and discuss the structure origins of these correlations, including neighbourhood, cavity distance, etc. In the second part of our study, we have used longer simulations (100 ns) from the MoDEL project, to obtain a broader view of cavity couplings, particularly about their dependence on time. Using moving window computations we explored the fluctuations of cavity couplings along time, finding that these couplings could fluctuate substantially during the trajectory, reaching in several cases correlations above 0.25/0.5. In summary, we describe the structural origin and the variations with time of cavity couplings. We complete our work with a brief discussion of the biological implications of these results.

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