Biomedical Network Research Center on Rare Diseases

Spain

Biomedical Network Research Center on Rare Diseases

Spain
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Camacho-Garcia R.J.,University of Seville | Hervas A.,Mutua Of Terrassa University Hospital | Toma C.,University of Barcelona | Toma C.,Biomedical Network Research Center on Rare Diseases | And 5 more authors.
Psychiatric Genetics | Year: 2013

Neurexins are synaptic plasma membrane proteins encoded by three genes (NRXN1, -2, -3) with alternative promoters. Mutations in neurexin genes have been identified in different neurodevelopmental disorders, including autism. Recently, two point mutations altering the translation initiation site of NRXN1β (c.-3G>T and c.3G>T) have been described in patients with autism and mental retardation. In this study, we analyzed the NRXN1β gene in a sample of 153 patients with autism. We report the identification of a novel mutation, c.3G>A (p.Met1), affecting the translation initiation site. Expression analysis showed that the c.3G>A mutation switches the translation start site of NRXN1β to an in-frame downstream methionine and decreases synaptic levels of the mutant protein in cultured neurons. These data reinforce a role for synaptic defects of NRXN1β in neurodevelopmental disorders. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.


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.


Franke B.,Radboud University Nijmegen | Faraone S.V.,New York University | Asherson P.,King's College London | Buitelaar J.,Radboud University Nijmegen | And 11 more authors.
Molecular Psychiatry | Year: 2012

The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood. © 2012 Macmillan Publishers Limited All rights reserved.


Toma C.,University of Barcelona | Toma C.,Biomedical Network Research Center on Rare Diseases | Torrico B.,University of Barcelona | Torrico B.,Biomedical Network Research Center on Rare Diseases | And 11 more authors.
Molecular Psychiatry | Year: 2014

Autism is a severe neurodevelopmental disorder, the aetiology of which remains mainly unknown. Family and twin studies provide strong evidence that genetic factors have a major role in the aetiology of this disease. Recently, whole exome sequencing (WES) efforts have focused mainly on rare de novo variants in singleton families. Although these studies have provided pioneering insights, de novo variants probably explain only a small proportion of the autism risk variance. In this study, we performed exome sequencing of 10 autism multiplex families with the aim of investigating the role of rare variants that are coinherited in the affected sibs. The pool of variants selected in our study is enriched with genes involved in neuronal functions or previously reported in psychiatric disorders, as shown by Gene Ontology analysis and by browsing the Neurocarta database. Our data suggest that rare truncating heterozygous variants have a predominant role in the aetiology of autism. Using a multiple linear regression model, we found that the burden of truncating mutations correlates with a lower non-verbal intelligence quotient (NVIQ). Also, the number of truncating mutations that were transmitted to the affected sibs was significantly higher (twofold) than those not transmitted. Protein-protein interaction analysis performed with our list of mutated genes revealed that the postsynaptic YWHAZ is the most interconnected node of the network. Among the genes found disrupted in our study, there is evidence suggesting that YWHAZ and also the X-linked DRP2 may be considered as novel autism candidate genes. © 2014 Macmillan Publishers Limited All rights reserved.


Legan P.K.,University of Sussex | Goodyear R.J.,University of Sussex | Morin M.,Ramon y Cajal Institute of Health Research IRYCIS | Morin M.,Biomedical Network Research Center on Rare Diseases | And 16 more authors.
Human Molecular Genetics | Year: 2014

Tecta is a modular, non-collagenous protein of the tectorial membrane (TM), an extracellular matrix of the cochlea essential for normal hearing. Missense mutations in Tecta cause dominant forms of non-syndromic deafness and a genotype-phenotype correlation has been reported in humans, with mutations in different Tecta domains causing mid- or high-frequency hearing impairments that are either stable or progressive. Three mutant mice were created as models for human Tecta mutations; the Tecta. L1820F, G1824D/+ mouse for zona pellucida (ZP) domain mutations causing stable mid-frequency hearing loss in a Belgian family, the Tecta. C1837G/+ mouse for a ZP-domain mutation underlying progressive mid-frequency hearing loss in a Spanish family and the Tecta. C1619S/+ mouse for a zonadhesin-like (ZA) domain mutation responsible for progressive, high-frequency hearing loss in a French family. Mutations in the ZP and ZA domains generate distinctly different changes in the structure of the TM. Auditory brainstem response thresholds in the 8-40 kHz range are elevated by 30-40 dB in the ZP-domain mutants, whilst those in the ZA-domain mutant are elevated by 20-30 dB. The phenotypes are stable and no evidence has been found for a progressive deterioration in TM structure or auditory function. Despite elevated auditory thresholds, the Tecta mutant mice all exhibit an enhanced tendency to have audiogenic seizures in response to white noise stimuli at low sound pressure levels (≤84 dB SPL), revealing a previously unrecognised consequence of Tecta mutations. These results, together with those from previous studies, establish an allelic series for Tecta unequivocally demonstrating an association between genotype and phenotype. © The Author 2013. Published by Oxford University Press. All rights reserved.


Cursiefen C.,University of Cologne | Colin J.,Center Hospitalier University Pellegrin | Dana R.,Massachusetts Eye and Ear Infirmary | Diaz-Llopis M.,University of Valencia | And 13 more authors.
British Journal of Ophthalmology | Year: 2012

The cornea is the clear window at the front of the eye and is the eye's main refractive medium. Its transparency is essential for vision. Corneal neovascularisation is a common clinical problem with serious consequences for vision; it can compromise corneal transparency and plays a major role in corneal graft rejection by breaching corneal immune privilege. In this review, we formulate a consensus on the unmet medical needs in the management of corneal neovascularisation and outline a framework for the clinical research that is needed to identify suitable agents to meet these needs.


Garcia-Gimenez J.L.,Biomedical Network Research Center on Rare Diseases | Garcia-Gimenez J.L.,Universitario Of Valencia | Sanchis-Gomar F.,University of Valencia | Sanchis-Gomar F.,Universitario Of Valencia | And 3 more authors.
Movement Disorders | Year: 2011

Clinical evidence and the recent decisions of the European Medicines Agency and the Food and Drug Administration challenge the safety of thiazolidinediones treatment. Recently, this treatment has been suggested for Friedreich's ataxia because thiazolidinediones improve neurological symptoms. Hypertrophic cardiomyopathy is the most prevalent cardiac feature and the cause of premature death in Friedreich's ataxia patients. We recommend that therapy with peroxisome proliferator-activated receptor-gamma agonists like thiazolidinediones be taken with caution, as they cause a decrease in the number of fast fibers and an increase in mitochondrial biogenesis in cardiac muscle because of the induction of peroxisome proliferator-activated receptor-gamma coactivator-1α. Furthermore, the incidence of heart failure may increase when thiazolidinediones are combined with insulin, and moreover, they produce cyclooxygenase 2 inhibition, inducing a thrombotic response. Thus, patients are predisposed to adverse cardiovascular outcomes. In our opinion, the possible fatal consequences must be taken into account when peroxisome proliferator-activated receptor-gamma agonist drugs are considered as possible therapeutic agents for Friedreich's ataxia patients. © 2011 Movement Disorder Society.


Sanchis-Gomar F.,University of Valencia | Sanchis-Gomar F.,Fundacion Investigacion Hospital Clinico Universitario | Garcia-Gimenez J.L.,University of Valencia | Garcia-Gimenez J.L.,Fundacion Investigacion Hospital Clinico Universitario | And 7 more authors.
International Journal of Cardiology | Year: 2014

Erythropoietin (Epo) has been thought to act exclusively on erythroid progenitor cells. The identification of Epo receptor (EpoR) in non-haematopoietic cells and tissues including neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells, as well as cells of myocardium, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle indicates that Epo has pleiotropic actions. Epo shows signals through protein kinases, anti-apoptotic proteins and transcription factors. In light of interest of administering recombinant human erythropoietin (rhEpo) and its analogues for limiting infarct size and left ventricular (LV) remodelling after acute myocardial infarction (AMI) in humans, the foremost studies utilising rhEpo are reviewed. The putative mechanisms involved in Epo-induced cardioprotection are related to the antiapoptotic, anti-inflammatory and angiogenic effects of Epo. Thus, cardioprotective potentials of rhEpo are reviewed in this article by focusing on clinical applicability. An overview of non-haematopoietic Epo analogues, which are a reliable alternative to the classic EpoR agonists and may prevent undesired side effects, is also provided. © 2013 Published by Elsevier Ireland Ltd.


Sanchis-Gomar F.,University of Valencia | Garcia-Gimenez J.L.,Biomedical Network Research Center on Rare Diseases | Garcia-Gimenez J.L.,Academic Hospital of Parma | Perez-Quilis C.,Biomedical Network Research Center on Rare Diseases | And 6 more authors.
Journal of Strength and Conditioning Research | Year: 2012

Physical exercise as an epigenetic modulator: Eustress, the "positive stress" as an effector of gene expression. J Strength Cond Res 26(12): 3469-3472, 2012-Physical exercise positively influences epigenetic mechanisms and improves health. Several issues remain unclear concerning the links between physical exercise and epigenetics. There is growing concern about the negative influence of excessive and persistent physical exercise on health. How an individual physically adapts to the prevailing environmental conditions might influence epigenetic mechanisms and modulate gene expression. In this article, we put forward the idea that physical exercise, especially longterm repetitive strenuous exercise, positively affects health, reduces the aging process, and decreases the incidence of cancer through induced stress and epigenetic mechanisms. We propose herein that stress may stimulate genetic adaptations through epigenetics that, in turn, modulate the link between the environment, human lifestyle factors, and genes. © 2012 National Strength and Conditioning Association.


Urbizu A.,Autonomous University of Barcelona | Toma C.,University of Barcelona | Toma C.,Biomedical Network Research Center on Rare Diseases | Poca M.A.,Autonomous University of Barcelona | And 5 more authors.
PLoS ONE | Year: 2013

Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A) considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI. © 2013 Urbizu et al.

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