ORCID Profile
0000-0003-3457-1410
Current Organisation
Humanitas University
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Publisher: Springer Science and Business Media LLC
Date: 18-04-2015
Publisher: American Thoracic Society
Date: 05-2013
Publisher: Public Library of Science (PLoS)
Date: 22-03-2013
Publisher: Wiley
Date: 25-01-2012
DOI: 10.1002/MDS.24927
Publisher: Elsevier BV
Date: 03-2012
Publisher: Oxford University Press (OUP)
Date: 28-10-2011
DOI: 10.1093/HMG/DDR493
Publisher: Wiley
Date: 03-10-2016
DOI: 10.1002/ANA.24777
Abstract: The objective of this work was to investigate survival, dementia, and genotype‐phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene ( GBA ). We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild‐p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group. Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [HR] = 3.16 p 0.001) and death (HR = 1.85 p = 0.002) than noncarriers. When dementia was introduced in the model as a time‐dependent covariate, the mortality risk remained greater in carriers (HR = 1.65 p = 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination, GBA carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations ( p 0.001), but similar mortality risk. Consistent with clinical data, GBA carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB. Survival is reduced in GBA carriers compared to noncarriers this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016 :662–673
Publisher: Springer Science and Business Media LLC
Date: 20-12-2019
DOI: 10.1038/S41598-019-56047-0
Abstract: Acute myocardial infarction is primarily due to coronary atherosclerotic plaque rupture and subsequent thrombus formation. Platelets play a key role in the genesis and progression of both atherosclerosis and thrombosis. Since platelets are anuclear cells that inherit their mRNA from megakaryocyte precursors and maintain it unchanged during their life span, gene expression profiling at the time of an acute myocardial infarction provides information concerning the platelet gene expression preceding the coronary event. In ST-segment elevation myocardial infarction (STEMI), a gene-by-gene analysis of the platelet gene expression identified five differentially expressed genes: FKBP5, S100P, SAMSN1, CLEC4E and S100A12. The logistic regression model used to combine the gene expression in a STEMI vs healthy donors score showed an AUC of 0.95. The same five differentially expressed genes were externally validated using platelet gene expression data from patients with coronary atherosclerosis but without thrombosis. Platelet gene expression profile highlights five genes able to identify STEMI patients and to discriminate them in the background of atherosclerosis. Consequently, early signals of an imminent acute myocardial infarction are likely to be found by platelet gene expression profiling before the infarction occurs.
Publisher: Wiley
Date: 10-2017
DOI: 10.1002/ANA.25048
Abstract: Biallelic DNAJC12 mutations were described in children with hyperphenylalaninemia, neurodevelopmental delay, and dystonia. We identified DNAJC12 homozygous null variants (c.187A>T .K63* and c.79-2A>G .V27Wfs*14) in two kindreds with early-onset parkinsonism. Both probands had mild intellectual disability, mild nonprogressive, motor symptoms, sustained benefit from small dose of levodopa, and substantial worsening of symptoms after levodopa discontinuation. Neuropathology (Proband-A) revealed no alpha-synuclein pathology, and substantia nigra depigmentation with moderate cell loss. DNAJC12 transcripts were reduced in both patients. Our results suggest that DNAJC12 mutations (absent in 500 early-onset patients with Parkinson's disease) rarely cause dopa-responsive nonprogressive parkinsonism in adulthood, but broaden the clinical spectrum of DNAJC12 deficiency. Ann Neurol 2017 :640-646.
Publisher: Springer Science and Business Media LLC
Date: 07-05-2021
DOI: 10.1007/S00259-021-05371-7
Abstract: The objectives of our study were to assess the association of radiomic and genomic data with histology and patient outcome in non-small cell lung cancer (NSCLC). In this retrospective single-centre observational study, we selected 151 surgically treated patients with adenocarcinoma or squamous cell carcinoma who performed baseline [18F] FDG PET/CT. A subgroup of patients with cancer tissue s les at the Institutional Biobank ( n = 74/151) was included in the genomic analysis. Features were extracted from both PET and CT images using an in-house tool. The genomic analysis included detection of genetic variants, fusion transcripts, and gene expression. Generalised linear model (GLM) and machine learning (ML) algorithms were used to predict histology and tumour recurrence. Standardised uptake value (SUV) and kurtosis (among the PET and CT radiomic features, respectively), and the expression of TP63 , EPHA10 , FBN2 , and IL1RAP were associated with the histotype. No correlation was found between radiomic features/genomic data and relapse using GLM. The ML approach identified several radiomic/genomic rules to predict the histotype successfully. The ML approach showed a modest ability of PET radiomic features to predict relapse, while it identified a robust gene expression signature able to predict patient relapse correctly. The best-performing ML radiogenomic rule predicting the outcome resulted in an area under the curve (AUC) of 0.87. Radiogenomic data may provide clinically relevant information in NSCLC patients regarding the histotype, aggressiveness, and progression. Gene expression analysis showed potential new biomarkers and targets valuable for patient management and treatment. The application of ML allows to increase the efficacy of radiogenomic analysis and provides novel insights into cancer biology.
Publisher: Georg Thieme Verlag KG
Date: 05-2015
DOI: 10.1160/TH14-07-0629
Abstract: Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aα, Bβ, and γ, encoded by the FGA, FGB, and FGG gene, respectively). Congenital afibrinogenaemia and hypofibrinogenaemia are rare bleeding disorders characterised by abnormally low levels of functional and immunoreactive fibrinogen in plasma, associated with haemorrhagic manifestations of variable severity. While afibrinogenaemia is caused by mutations in the homozygous or compound heterozygous state in one of the three fibrinogen genes, hypofibrinogenaemia is generally due to heterozygous mutations, and is usually characterised by a milder phenotype. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations often affecting fibrinogen assembly and/or secretion. Here we report the clinical and molecular characterisation of 13 unrelated afibrinogenaemic and eight hypofibrino - genaemic patients, leading to the identification of 17 different mutations (10 hitherto unknown). All the newly-identified missense and splicing mutations were in vitro expressed to verify their pathogenic role. Our data increase the number of mutations causing quantitative fibrinogen deficiencies by about 7 %. The high number of private mutations identified in the analysed probands indicates that the full mutational screening of the three fibrinogen genes is still required for molecular diagnosis.
Publisher: Springer Science and Business Media LLC
Date: 11-2001
Abstract: Genes coding for the alpha5, alpha3, and beta4 subunits (CHRNA5, CHRNA3, and CHRNB4) of the neuronal nicotinic acetylcholine receptors (nAChRs) are clustered on chromosome 15q24. Linkage of this chromosomal region to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), an idiopathic partial epilepsy, was reported in one family. Moreover, mutations in other neuronal nAChR subunit genes coding for the alpha4 (CHRNA4) and the beta2 (CHRNB2) subunits were associated with ADNFLE. Apart from the exon-intron structure of CHRNA3, the genomic organization of this gene cluster was unknown, making comprehensive mutational analyses impossible. The genomic structure of CHRNA5 and CHRNB4 is here reported. Moreover, two hitherto unknown introns were identified within the 3' untranslated region of CHRNA3, causing a partial tail-to-tail overlap with CHRNA5. Four novel intragenic polymorphisms were identified and characterized in the cluster.
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.GENE.2004.12.005
Abstract: Natural antisense transcripts, because of their potential to form double-stranded RNA (dsRNA) molecules, recently emerged as a mechanism acting on eukaryotic gene regulation at multiple levels. CHRNA3 and CHRNA5, coding for alpha3 and alpha5 subunits of the neuronal nicotinic acetylcholine receptor, have been reported to overlap at their 3'ends in human and bovine genomes. In the present paper, four CHRNA3 and three CHRNA5 human transcripts were characterised, leading to the identification of different antisense complementary regions. Since the two genes are coexpressed in some neuronal and non-neuronal tissues, we ventured on the in vivo identification of RNA-RNA duplexes in both humans and cattle. Using an RNase protection-based approach, CHRNA3/CHRNA5 duplexes were detected in human neuroblastoma SY5Y cells, but not in bovine cerebellum. A semi-quantitative analysis of overlapping transcript levels was performed by real-time RT-PCR. Possible consequences of sense-antisense interaction are discussed.
Publisher: Wiley
Date: 10-05-2018
Publisher: American Society of Hematology
Date: 25-11-2021
Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among in iduals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In in iduals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2020
DOI: 10.1158/0008-5472.CAN-19-2843
Abstract: Tumor-derived PGE2-mediated induction of nuclear p50 NF-κB epigenetically reprograms the response of monocytic cells to IFNγ toward an immunosuppressive phenotype, thus retrieving the anticancer properties of IFNγ.
Publisher: Elsevier BV
Date: 02-2014
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-05-2017
DOI: 10.1126/SCITRANSLMED.AAD9157
Abstract: Annexin A11 mutations, implicated in ALS, prevent binding to calcyclin and induce the formation of cytoplasmic inclusions.
Publisher: American Society of Hematology
Date: 11-03-2010
DOI: 10.1182/BLOOD-2009-09-245092
Abstract: Alternative splicing of pre-mRNAs is a central process to the generation of proteome complexity. However, many alternative mRNA isoforms carry premature termination codons (PTCs) rendering them possible targets for the nonsense-mediated mRNA decay (NMD) pathway. The F11 gene consists of 15 exons spanning approximately 23 kb on chromosome 4q35 and codes for coagulation factor XI (FXI), a 160-kDa dimeric zymogen composed of 4 apple domains and a serine protease domain. Here, we characterized the F11 splicing pattern in human liver and platelets identifying multiple in-frame and out-of-frame splicing events. Inhibition of NMD resulted in the up-regulation of all unproductively spliced F11 transcripts, thus providing evidence that these PTC-containing mRNAs are under the control of NMD. Among in-frame alternatively spliced transcripts, the one skipping exons 6 and 7 would lead to the synthesis of a FXI protein lacking 1 apple domain (FXI-Δ6/7). Ex vivo expression in mammalian cells demonstrated that FXI-Δ6/7 is mostly retained intracellularly, and secreted only in low amounts. Traces of this FXI isoform were detectable in human plasma. Our results suggest that the coupling of alternative splicing and NMD may play a role in regulating F11 expression, and point to the existence of a novel FXI isoform.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-10-2020
DOI: 10.1212/NXG.0000000000000523
Abstract: To provide a variant-specific estimate of incidence, penetrance, sex distribution, and association with dementia of the 4 most common Parkinson disease (PD)-associated GBA variants, we analyzed a large cohort of 4,923 Italian unrelated patients with primary degenerative parkinsonism (including 3,832 PD) enrolled in a single tertiary care center and 7,757 ethnically matched controls. The p.E326K, p.T369M, p.N370S, and p.L444P variants were screened using an allele-specific multiplexed PCR approach. All statistical procedures were performed using R or Plink v1.07. Among the 4 analyzed variants, the p.L444P confirmed to be the most strongly associated with disease risk for PD, PD dementia (PDD), and dementia with Lewy bodies (DLB) (odds ratio [OR] for PD 15.63, 95% confidence interval [CI] = 8.04–30.37, p = 4.97*10 −16 OR for PDD 29.57, 95% CI = 14.07–62.13, p = 3.86*10 −19 OR for DLB 102.7, 95% CI = 31.38–336.1, p = 1.91*10 −14 ). However, an unexpectedly high risk for dementia was conferred by p.E326K (OR for PDD 4.80, 95% CI = 2.87–8.02, p = 2.12*10 −9 OR for DLB 12.24, 95% CI = 4.95–30.24, p = 5.71*10 −8 ), which, on the basis of the impact on glucocerebrosidase activity, would be expected to be mild. The 1.5–2:1 male sex bias described in sporadic PD was lost in p.T369M carriers. We also showed that PD penetrance for p.L444P could reach the 15% at age 75 years. We report a large monocentric study on GBA -PD assessing mutation-specific data on the sex distribution, penetrance, incidence, and association with dementia of the 4 most frequent deleterious variants in GBA .
Publisher: Oxford University Press (OUP)
Date: 30-07-2014
DOI: 10.1093/HMG/DDU392
Abstract: The protein kinase C alpha (PRKCA) gene, encoding a Th17-cell-selective kinase, was repeatedly associated with multiple sclerosis (MS), but the underlying pathogenic mechanism remains unknown. We replicated the association in Italians (409 cases, 723 controls), identifying a protective signal in the PRKCA promoter (P = 0.033), and a risk haplotype in intron 3 (P = 7.7 × 10(-4) meta-analysis with previously published data: P = 4.01 × 10(-8)). Expression experiments demonstrated that the protective signal is associated with alleles conferring higher PRKCA expression levels, well fitting our observation that MS patients have significantly lower PRKCA mRNA levels in blood. The risk haplotype was shown to be driven by a GGTG ins/del polymorphism influencing the heterogeneous nuclear ribonucleoprotein H-dependent inclusion/skipping of a PRKCA alternative exon 3*. Indeed, exon 3* can be present in two different versions in PRKCA mRNAs (out-of-frame 61 bp or in-frame 66 bp long), and is preferentially included in transcripts generated through a premature polyadenylation event. The GGTG insertion downregulates 3* inclusion and shifts splicing towards the 66 bp isoform. Both events reduce the nonsense-mediated mRNA-decay-induced degradation of exon 3*-containing mRNAs. Since we demonstrated that the protein isoform produced through premature polyadenylation aberrantly localizes to the plasma membrane and/or in cytoplasmic clusters, dysregulated PRKCA 3* inclusion may represent an additional mechanism relevant to MS susceptibility.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Elsevier BV
Date: 11-2018
Publisher: Oxford University Press (OUP)
Date: 19-12-2018
DOI: 10.1093/HMG/DDY438
Abstract: Long non-coding RNAs (lncRNAs) are post-transcriptional and epigenetic regulators, whose implication in neurodegenerative and autoimmune diseases remains poorly understood. We analyzed publicly available microarray data sets to identify dysregulated lncRNAs in multiple sclerosis (MS), a neuroinflammatory autoimmune disease. We found a consistent upregulation in MS of the lncRNA MALAT1 (2.7-fold increase meta-analysis, P = 1.3 × 10−8 190 cases, 182 controls), known to regulate alternative splicing (AS). We confirmed MALAT1 upregulation in two independent MS cohorts (1.5-fold increase P & 0.01 59 cases, 50 controls). We hence performed MALAT1 overexpression/knockdown in cell lines, demonstrating that its modulation impacts on endogenous expression of splicing factors (HNRNPF and HNRNPH1) and on AS of MS-associated genes (IL7R and SP140). Minigene-based splicing assays upon MALAT1 modulation recapitulated IL7R and SP140 isoform unbalances observed in patients. RNA-sequencing of MALAT1-knockdown Jurkat cells further highlighted MALAT1 role in splicing (approximately 1100 significantly-modulated AS events) and revealed its contribution to backsplicing (approximately 50 differentially expressed circular RNAs). Our study proposes a possible novel role for MALAT1 dysregulation and the consequent AS alteration in MS pathogenesis, based on anomalous splicing/backsplicing profiles of MS-relevant genes.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2014
Publisher: Frontiers Media SA
Date: 10-10-2018
Publisher: Springer Science and Business Media LLC
Date: 05-10-2017
DOI: 10.1038/S41598-017-12973-5
Abstract: Mutations in the GBA gene, encoding lysosomal glucocerebrosidase, represent the major predisposing factor for Parkinson’s disease (PD), and modulation of the glucocerebrosidase activity is an emerging PD therapy. However, little is known about mechanisms regulating GBA expression. We explored the existence of a regulatory network involving GBA , its expressed pseudogene GBAP1 , and microRNAs. The high level of sequence identity between GBA and GBAP1 makes the pseudogene a promising competing-endogenous RNA (ceRNA), functioning as a microRNA sponge. After selecting microRNAs potentially targeting both transcripts, we demonstrated that miR-22-3p binds to and down-regulates GBA and GBAP1 , and decreases their endogenous mRNA levels up to 70%. Moreover, over-expression of GBAP1 3′-untranslated region was able to sequester miR-22-3p, thus increasing GBA mRNA and glucocerebrosidase levels. The characterization of GBAP1 splicing identified multiple out-of-frame isoforms down-regulated by the nonsense-mediated mRNA decay, suggesting that GBAP1 levels and, accordingly, its ceRNA effect, are significantly modulated by this degradation process. Using skin-derived induced pluripotent stem cells of PD patients with GBA mutations and controls, we observed a significant GBA up-regulation during dopaminergic differentiation, paralleled by down-regulation of miR-22-3p. Our results describe the first microRNA controlling GBA and suggest that the GBAP1 non-coding RNA functions as a GBA ceRNA.
Publisher: Oxford University Press (OUP)
Date: 13-08-2020
Publisher: Georg Thieme Verlag KG
Date: 2008
DOI: 10.1160/TH07-12-0723
Abstract: Severe factor XI (FXI) deficiency is a bleeding disorder generally inherited as an autosomal recessive trait and characterized by haemorrhagic symptoms mainly associated with injury or surgery. So far, more than 150 causative molecular defects have been identified throughout the F11 gene. In the present study, we investigated the molecular basis of FXI deficiency in two Italian patients. Mutational screening of the F|| gene disclosed a novel missense substitution (Arg184Gly) in exon 7 and two splicing mutations: a novel G A transition affecting the last nucleotide of exon 4 (325G A), and the already known IVS6+3A G. RT-PCR assays were performed on total RNA extracted from platelets and lymphocytes of each patient. Se- quencing of RT-PCR products demonstrated that both 325G A and IVS6+3A G mutations abolish the corresponding donor splice site, causing the skipping of the affected exon this in turn results in a frameshift introducing a premature termination codon. Expression of recombinant FXI-Arg184Gly revealed a 70% reduction in FXI activity, suggesting that the Arg184Gly mutation might cause a cross-reactive material positive (CRM+) deficiency. In conclusion, the functional consequences of two splicing mutations leading to FXI deficiency have been elucidated. Moreover, we report a novel missense mutation in the FIX-binding region of the FXI A3 domain leading to a CRM+ deficiency.
Publisher: Elsevier BV
Date: 08-2014
Publisher: Springer Science and Business Media LLC
Date: 04-08-2016
DOI: 10.1038/JHG.2016.101
Abstract: Despite extensive screening, 1-5% of cystic fibrosis (CF) patients lack a definite molecular diagnosis. Next-generation sequencing (NGS) is making affordable genetic testing based on the identification of variants in extended genomic regions. In this frame, we analyzed 23 CF patients and one carrier by whole-gene CFTR resequencing: 4 were previously characterized and served as controls 17 were cases lacking a complete diagnosis after a full conventional CFTR screening 3 were consecutive subjects referring to our centers, not previously submitted to any screening. We also included in the custom NGS design the coding portions of the SCNN1A, SCNN1B and SCNN1G genes, encoding the subunits of the sodium channel ENaC, which were found to be mutated in CF-like patients. Besides 2 novel SCNN1B missense mutations, we identified 22 previously-known CFTR mutations, including 2 large deletions (whose breakpoints were precisely mapped), and novel deep-intronic variants, whose role on splicing was excluded by ex-vivo analyses. Finally, for 2 patients, compound heterozygotes for a CFTR mutation and the intron-9c.1210-34TG
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.NEUROBIOLAGING.2009.12.016
Abstract: The Grb10-Interacting GYF Protein-2 (GIGYF2) gene has been proposed as the Parkinson-disease (PD) gene underlying the PARK11 locus. However, association of GIGYF2 with PD has been challenged and a functional validation of GIGYF2 mutations is lacking. In this frame, we performed a mutational screening of GIGYF2 in an Italian PD cohort. Exons containing known mutations were analyzed in 552 cases and 552 controls. Thereafter, a subset of 184 familial PD cases and controls were subjected to a full coding-exon screening. These analyses identified 8 missense variations in 9 in iduals (4 cases, 5 controls). Furthermore, we developed a zebrafish model of gigyf2 deficiency. Abrogation of gigyf2 function in zebrafish embryos did not lead to a drastic cell loss in diencephalic dopaminergic (DA) neuron clusters, suggesting that gigyf2 is not required for DA neuron differentiation. Notably, gigyf2 functional abrogation did not increase diencephalic DA neurons susceptibility to the PD-inducing drug MPP+. These data, together with those recently reported by other groups, suggest that GIGYF2 is unlikely to be the PARK11 gene.
Publisher: Public Library of Science (PLoS)
Date: 06-2017
Publisher: American Association for the Advancement of Science (AAAS)
Date: 27-03-2015
Abstract: Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig's disease,” is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Cirulli et al. sequenced the expressed genes of nearly 3000 ALS patients and compared them with those of more than 6000 controls (see the Perspective by Singleton and Traynor). They identified several proteins that were linked to disease in patients. One such protein, TBK1, is implicated in innate immunity and autophagy and may represent a therapeutic target. Science , this issue p. 1436 see also p. 1422
Publisher: Elsevier BV
Date: 10-2014
No related grants have been discovered for Stefano Duga.