Browsing by Author "Santos, J.X."
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- An integrative system biology approach for dissecting Autism Spectrum DisorderPublication . Asif, M.; Rasga, C.; Martiniano, H.; Santos, J.X.; Marques, A.R.; Couto, F.M .; Vicente, A.M.Autism Spectrum Disorder (ASD) is characterized by a wide spectrum of behavioral presentation. Many genetic factors are implicated in ASD, however their role in the heterogeneous ASD phenotype remains elusive. Using data mining-based integrative approaches, we seek to identify patterns of association between ASD phenotypic subgroups and altered biological processes inferred from CNVs targeting brain genes.
- Autism Spectrum Disorder: gene variants involved in the nonsense-mediated mRNA decay pathwayPublication . Marques, Ana Rita; Martiniano, H.; Santos, J.X.; Vilela, J.; Rasga, C.; Oliveira, G.; Romão, L.; Vicente, A.M.No abstract available
- Autism Spectrum Disorder: gene variants involved in the nonsense-mediated mRNA decay pathwayPublication . Marques, Ana Rita; Martiniano, Hugo; Santos, J.X.; Vilela, Joana; Asif, M.; Rasga, C.; Oliveira, G.; Romão, Luísa; Vicente, AstridGenetic factors account for 50-80% of the familial risk of Autism Spectrum Disorder (ASD), but most of the genetic determinants are still unknown and a role for other regulatory mechanisms is likely. The nonsense-mediated decay (NMD) pathway is essential to control mRNA quality and has an important role in the regulation of the transcriptome. Mutations in genes involved in the NMD pathway, such as the UPF3B gene, a core component of this pathway, were previously linked to ASD. In this study we explored the potential role of NMD factors in ASD. We generated a list of 153 genes involved in the NMD pathway using AmiGO, Reactome and a systematic literature review. To identify potentially pathogenic variants in the NMD genes, we analyzed whole exome sequencing data (WES) data from 1338 ASD subjects. We also searched for Copy Number Variants (CNVs) targeting NMD genes in ASD patients (n=3570) and checked their frequency in controls (n=9649). We identified 43 high impact variants in 28 NMD genes, including the UPF3B and ACE, two genes previously implicated in ASD. Importantly, 11 were novel candidate genes that carry loss-of-function and missense (deleterious and damaging) variants with a frequency of 1 to 5% in this ASD dataset. Additionally, 5 NMD genes were found to be targeted by CNVs in 12 ASD subjects but none of the controls. The discovery of 33 NMD genes that are intriguing candidates for ASD in large patient genomic datasets provides evidence supporting the involvement of the NMD pathway in ASD pathophysiology.
- CNVs targeting genes that regulate exposure to toxicants in Autism Spectrum Disorder (ASD): a role for gene-environment interactionsPublication . Santos, J.X.; Rasga, C.; Asif, M.; Marques, A.R.; Vicente, A.M.Objective: Our overall goal is to identify genes involved in detoxification and regulation of barrier permeability processes that can mediate the effect of exposure to toxicants in individuals with ASD. For this purpose, we screened large ASD and control datasets for CNVs targeting selected detoxification and barrier permeability genes.
- Evidence for a role of nonsense-mediated mRNA decay pathway genes in Autism Spectrum DisorderPublication . Marques, Ana Rita; Martiniano, H.; Santos, J.X.; Vilela, J.; Asif, M.; Oliveira, G.; Romão, L.; Vicente, A.M.Autism Spectrum Disorder (ASD): is a neurodevelopmental disorder characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests.
- Evidence for a role of nonsense-mediated mRNA decay pathway genes in Autism Spectrum DisorderPublication . Marques, Ana; Martiniano, Hugo; Santos, J.X.; Vilela, J.; Asif, M.; Oliveira, G.; Romão, Luísa; Vicente, AstridIntroduction: Autism Spectrum Disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with an unclear etiology. Genetic factors are estimated to account for 50 to 80% of the familial ASD risk, but most of the genetic determinants are still not known and a role for other regulatory mechanisms is likely. The nonsense-mediated decay (NMD) pathway controls mRNA quality and plays an important role in the regulation of the transcriptome. Mutations in genes involved in the NMD pathway have been linked to neurodevelopmental disorders, with intriguing evidence for an involvement of mutations in the UPF3B gene, a core component of the NMD pathway, in ASD.
- miRNA and lncRNA gene variants in Autism Spectrum DisorderPublication . Marques, Ana Rita; Martiniano, H.; Santos, J.X.; Vilela, J.; Asif, M.; Oliveira, G.; Enguita, F.J.; Romão, L.; Vicente, A.M.Introduction: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder: Characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests; Median estimated prevalence worldwide is 17/10000; Male to female ratio: ~4:1; Comorbidities: intellectual disability, anxiety, epilepsy, (…).
- miRNA and lncRNA gene variants in Autism Spectrum DisorderPublication . Marques, Ana Rita; Martiniano, Hugo; Santos, J.X.; Vilela, Joana; Asif, M.; Oliveira, G.; Romão, Luísa; Vicente, AstridAutism Spectrum Disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder. Genetic factors are estimated to account for 50 to 80% of the familial ASD risk, but most of the genetic determinants are still not known and a role for epigenetic factors is likely. In this study we explored the potential role of noncoding RNAs in ASD by comparing the frequency of Copy Number Variants (CNVs) targeting microRNA (miRNA) or long noncoding (lncRNA) genes in ASD patients (n=3570) with control subjects (n=9649), using the Fisher’s exact test corrected for multiple testing. We found 22 miRNA genes exclusively targeted by CNVs in ASD subjects and 14 miRNA genes more frequently disrupted by CNVs in ASD patients than in controls. Two miRNA were previously associated with ASD in serum miRNA profiling studies, while 5 novel miRNAs for ASD have been described in schizophrenia, a disorder that phenotypically and genetically overlaps with ASD. Many putative targets of these 36 miRNAs are reported ASD risk genes. Gene-target enrichment analysis identified 6 significant pathways, 2 of which, the PI3K-Akt and MAPK signalling pathways, have been implicated in ASD. We further identified 102 novel lncRNA genes more frequently targeted by CNVs in ASD, 3 of which are antisense to ASD candidate genes. These results support our hypothesis that genetic variants targeting noncoding regulatory RNAs are involved in ASD pathophysiology. This systems biology integrative strategy will provide a better understanding of the biological processes underlying ASD, and contribute to biomarker and drug target discovery.
- Regulatory RNA genes are targeted by Copy Number Variation in Autism Spectrum DisorderPublication . Marques, A.R.; Martiniano, H.; Santos, J.X.; Vilela, J.; Asif, M.; Oliveira, G.; Romão, L.; Vicente, A.M.Autism Spectrum Disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with an unclear etiology. Genetic factors are estimated to account for 50 to 80% of the familial ASD risk, but most of the genetic determinants are still not known and a role for epigenetic factors is likely. The involvement of noncoding RNAs in ASD is, so far, insufficiently explored. MicroRNA (miRNA) and long noncoding RNA (lncRNA) are regulatory molecules, abundantly expressed in the brain, that play an important role during early stages of neural development. In this work we sought to address their potential role as ASD candidates, by identifying Copy Number Variants (CNVs) targeting miRNA and lncRNA genes in a large cohort of ASD patients, and examined their target genes and biological pathways.
- Regulatory RNAs in Autism Spectrum DisorderPublication . Marques, Ana Rita; Martiniano, H.; Santos, J.X.; Vilela, J.; Asif, M.; Oliveira, G.; Enguita, F.J.; Romão, L.; Vicente, A.M.Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder: Characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests.