{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T07:53:04Z","timestamp":1788335584372,"version":"build-2803163510"},"reference-count":175,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Campania Region","award":["POR Campania FSE 2014\u20132020"],"award-info":[{"award-number":["POR Campania FSE 2014\u20132020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Down syndrome (DS), a complex disorder that is caused by the trisomy of chromosome 21 (Hsa21), is a major cause of congenital heart defects (CHD). Interestingly, only about 50% of individuals with Hsa21 trisomy manifest CHD. Here we review the genetic basis of CHD in DS, focusing on genes that regulate extracellular matrix (ECM) organization. The overexpression of Hsa21 genes likely underlies the molecular mechanisms that contribute to CHD, even though the genes responsible for CHD could only be located in a critical region of Hsa21. A role in causing CHD has been attributed not only to protein-coding Hsa21 genes, but also to genes on other chromosomes, as well as miRNAs and lncRNAs. It is likely that the contribution of more than one gene is required, and that the overexpression of Hsa21 genes acts in combination with other genetic events, such as specific mutations or polymorphisms, amplifying their effect. Moreover, a key function in determining alterations in cardiac morphogenesis might be played by ECM. A large number of genes encoding ECM proteins are overexpressed in trisomic human fetal hearts, and many of them appear to be under the control of a Hsa21 gene, the RUNX1 transcription factor.<\/jats:p>","DOI":"10.3390\/ijms24032918","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T02:35:10Z","timestamp":1675391710000},"page":"2918","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation"],"prefix":"10.3390","volume":"24","author":[{"given":"Nunzia","family":"Mollo","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Scognamiglio","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2054-7375","authenticated-orcid":false,"given":"Anna","family":"Conti","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5332-6774","authenticated-orcid":false,"given":"Simona","family":"Paladino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Nitsch","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy"},{"name":"Institute of Experimental Endocrinology and Oncology, National Research Council, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Izzo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1016\/j.jacc.2011.08.025","article-title":"Birth Prevalence of Congenital Heart Disease Worldwide: A Systematic Review and Meta-Analysis","volume":"58","author":"Konings","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1161\/CIRCRESAHA.112.300853","article-title":"Genetics of Congenital Heart Disease: The Glass Half Empty","volume":"112","author":"Fahed","year":"2013","journal-title":"Circ. Res."},{"key":"ref_3","unstructured":"Urbano, R. (2012). Health Issues in Persons with Down Syndrome, Academic Press."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.ejmg.2015.11.003","article-title":"Associated congenital anomalies among cases with Down syndrome","volume":"58","author":"Stoll","year":"2015","journal-title":"Eur. J. Med. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1002\/ajmg.a.31494","article-title":"CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome","volume":"140","author":"Maslen","year":"2006","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12041-021-01296-0","article-title":"Congenital heart defects among Down\u2019s syndrome cases: An updated review from basic research to an emerging diagnostics technology and genetic counselling","volume":"100","author":"Asim","year":"2021","journal-title":"J. Genet."},{"key":"ref_7","first-page":"e29176","article-title":"Congenital Heart Disease and Its Association in Children with Down Syndrome","volume":"14","author":"Rehman","year":"2022","journal-title":"Cureus"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5958","DOI":"10.1073\/pnas.86.15.5958","article-title":"Critical role of the D21S55 region on chromosome 21 in the pathogenesis of Down syndrome","volume":"86","author":"Rahmani","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0888-7543(89)90065-7","article-title":"Molecular genetic approach to the characterization of the \u201cDown syndrome region\u201d of chromosome 21","volume":"5","author":"McCormick","year":"1989","journal-title":"Genomics"},{"key":"ref_10","first-page":"236","article-title":"Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype","volume":"47","author":"Korenberg","year":"1990","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","first-page":"294","article-title":"Down syndrome: Molecular mapping of the congenital heart disease and duodenal stenosis","volume":"50","author":"Korenberg","year":"1992","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1159\/000472398","article-title":"Molecular Mapping of Twenty-Four Features of Down Syndrome on Chromosome 21","volume":"1","author":"Delabar","year":"1993","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4997","DOI":"10.1073\/pnas.91.11.4997","article-title":"Down syndrome phenotypes: The consequences of chromosomal imbalance","volume":"91","author":"Korenberg","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","first-page":"91","article-title":"Down syndrome congenital heart disease: A narrowed region and a candidate gene","volume":"3","author":"Barlow","year":"2001","journal-title":"Anesth. Analg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12031","DOI":"10.1073\/pnas.0813248106","article-title":"The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies","volume":"106","author":"Korbel","year":"2009","journal-title":"Proc. Natl. Acad Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.ygeno.2017.06.004","article-title":"Genotype-phenotype correlation for congenital heart disease in Down syndrome through analysis of partial trisomy 21 cases","volume":"109","author":"Pelleri","year":"2017","journal-title":"Genomics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/ejhg.2008.214","article-title":"Genotype\u2013phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21","volume":"17","author":"Lyle","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1093\/hmg\/ddq179","article-title":"A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions","volume":"19","author":"Yu","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1159\/000329422","article-title":"Mouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities","volume":"33","author":"Liu","year":"2011","journal-title":"Dev. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/s00439-013-1407-z","article-title":"Engineered chromosome-based genetic mapping establishes a 3.7 Mb critical genomic region for Down syndrome-associated heart defects in mice","volume":"133","author":"Liu","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e11614","DOI":"10.7554\/eLife.11614","article-title":"Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel","volume":"5","author":"Slender","year":"2016","journal-title":"eLife"},{"key":"ref_22","first-page":"2734","article-title":"New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease","volume":"12","author":"Sigcho","year":"2022","journal-title":"Front. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1186\/1471-2164-8-268","article-title":"Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy","volume":"8","author":"Conti","year":"2007","journal-title":"BMC Genom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.1073\/pnas.81.8.2426","article-title":"Increased adhesiveness of Down syndrome fetal fibroblasts in vitro","volume":"81","author":"Wright","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/ajmg.1320200222","article-title":"Increased adhesiveness of trisomy 21 cells and atrioventricular canal malformations in down syndrome: A stochastic model","volume":"20","author":"Kurnit","year":"1985","journal-title":"Am. J. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1006\/bbrc.2001.4420","article-title":"DSCAM, a Highly Conserved Gene in Mammals, Expressed in Differentiating Mouse Brain","volume":"281","author":"Agarwala","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1093\/cvr\/cvq193","article-title":"Down\u2019s syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse","volume":"88","author":"Dunlevy","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/j.1469-1809.1995.tb00746.x","article-title":"Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down\u2019s syndrome)","volume":"59","author":"Davies","year":"1995","journal-title":"Ann. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1002\/ar.a.10126","article-title":"Collagen type VI expression during cardiac development and in human fetuses with trisomy 21","volume":"275","author":"Groot","year":"2003","journal-title":"Anat. Rec."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S1097-2765(00)80003-9","article-title":"The Discoidin Domain Receptor Tyrosine Kinases Are Activated by Collagen","volume":"1","author":"Vogel","year":"1997","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S0945-053X(03)00053-2","article-title":"An extracellular matrix-specific microarray allowed the identification of target genes downstream of discoidin domain receptors","volume":"22","author":"Faraci","year":"2003","journal-title":"Matrix Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1017\/S1431927605050518","article-title":"Expression of Discoidin Domain Receptor 2 (DDR2) in the Developing Heart","volume":"11","author":"Morales","year":"2005","journal-title":"Microsc. Microanal."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Grossman, T.R., Gamliel, A., Wessells, R.J., Taghli-Lamallem, O., Jepsen, K., Ocorr, K., Korenberg, J.R., Peterson, K.L., Rosenfeld, M.G., and Bodmer, R. (2011). Over-Expression of DSCAM and COL6A2 Cooperatively Generates Congenital Heart Defects. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002344"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/j.1741-4520.2005.00065.x","article-title":"Refining chromosomal region critical for Down syndrome-related heart defects with a case of cryptic 21q22.2 duplication","volume":"45","author":"Kosaki","year":"2005","journal-title":"Congenit. Anomalies"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/nature04678","article-title":"NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21","volume":"441","author":"Arron","year":"2006","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S0092-8674(01)00396-8","article-title":"Signals Transduced by Ca2+\/Calcineurin and NFATc3\/c4 Pattern the Developing Vasculature","volume":"105","author":"Graef","year":"2001","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1093\/hmg\/9.11.1681","article-title":"DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways","volume":"9","author":"Fuentes","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13367","DOI":"10.1074\/jbc.273.22.13367","article-title":"Regulation of the Calmodulin-stimulated Protein Phosphatase, Calcineurin","volume":"273","author":"Klee","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/352803a0","article-title":"Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A","volume":"352","author":"Flanagan","year":"1991","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1016\/S0092-8674(02)00699-2","article-title":"NFAT Signaling: Choreographing the Social Lives of Cells","volume":"109","author":"Crabtree","year":"2002","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/32419","article-title":"Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum","volume":"392","author":"Timmerman","year":"1998","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/32426","article-title":"The transcription factor NF-ATc is essential for cardiac valve formation","volume":"392","author":"Ranger","year":"1998","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.cell.2004.08.010","article-title":"A Field of Myocardial-Endocardial NFAT Signaling Underlies Heart Valve Morphogenesis","volume":"118","author":"Chang","year":"2004","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0925-4773(00)00583-9","article-title":"Dscr1, a novel endogenous inhibitor of calcineurin signaling, is expressed in the primitive ventricle of the heart and during neurogenesis","volume":"101","author":"Casas","year":"2001","journal-title":"Mech. Dev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.ydbio.2003.10.036","article-title":"DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice","volume":"266","author":"Lange","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.bbrc.2006.10.169","article-title":"MNB\/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins","volume":"351","author":"Adayev","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/S0166-2236(00)01930-5","article-title":"The dephosphins: Dephosphorylation by calcineurin triggers synaptic vesicle endocytosis","volume":"24","author":"Cousin","year":"2001","journal-title":"Trends Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/s41419-018-0410-7","article-title":"Alteration of endosomal trafficking is associated with early-onset parkinsonism caused by SYNJ1 mutations","volume":"9","author":"Fasano","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"673","DOI":"10.3389\/fnins.2019.00673","article-title":"PERK-Mediated Unfolded Protein Response Activation and Oxidative Stress in PARK20 Fibroblasts","volume":"13","author":"Amodio","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"136288","DOI":"10.1016\/j.neulet.2021.136288","article-title":"Mini-review: Synaptojanin 1 and its implications in membrane trafficking","volume":"765","author":"Choudhry","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3156","DOI":"10.1093\/hmg\/dds142","article-title":"Trisomy for Synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes","volume":"21","author":"Cossec","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"867989","DOI":"10.3389\/fgene.2022.867989","article-title":"Down Syndrome Fetal Fibroblasts Display Alterations of Endosomal Trafficking Possibly due to SYNJ1 Overexpression","volume":"13","author":"Fasano","year":"2022","journal-title":"Front. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fphys.2015.00034","article-title":"Endosome-based protein trafficking and Ca2+ homeostasis in the heart","volume":"6","author":"Curran","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1093\/cvr\/cvn062","article-title":"Recycling endosomes supply cardiac pacemaker channels for regulated surface expression","volume":"79","author":"Hardel","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"18148","DOI":"10.1074\/jbc.RA120.015216","article-title":"The endosomal trafficking regulator LITAF controls the cardiac Nav1.5 channel via the ubiquitin ligase NEDD4-2","volume":"295","author":"Turan","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1101\/gr.147991.112","article-title":"The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome","volume":"23","author":"Sailani","year":"2013","journal-title":"Genome Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Calcagni, G., Pugnaloni, F., Digilio, M., Unolt, M., Putotto, C., Niceta, M., Baban, A., Sparascio, F.P., Drago, F., and De Luca, A. (2021). Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights. Genes, 12.","DOI":"10.3390\/genes12071047"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Balistreri, C.R., Ammoscato, C.L., Scola, L., Fragapane, T., Giarratana, R.M., Lio, D., and Piccione, M. (2020). Susceptibility to Heart Defects in Down Syndrome Is Associated with Single Nucleotide Polymorphisms in HAS 21 Interferon Receptor Cluster and VEGFA Genes. Genes, 11.","DOI":"10.3390\/genes11121428"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1086\/374319","article-title":"Missense Mutations in CRELD1 Are Associated with Cardiac Atrioventricular Septal Defects","volume":"72","author":"Robinson","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.ajhg.2012.08.017","article-title":"An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects","volume":"91","author":"Ackerman","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.gene.2017.10.044","article-title":"CRELD1 gene variants and atrioventricular septal defects in Down syndrome","volume":"641","author":"Asim","year":"2018","journal-title":"Gene"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.gendis.2019.06.007","article-title":"Molecular mechanisms of congenital heart disease in down syndrome","volume":"6","author":"Zhang","year":"2019","journal-title":"Genes Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1007\/s007750050387","article-title":"Redox regulation of calcineurin in T-lymphocytes","volume":"4","author":"Reiter","year":"1999","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1093\/molehr\/8.9.855","article-title":"Microarray analysis of VEGF-responsive genes in myometrial endothelial cells","volume":"8","author":"Weston","year":"2002","journal-title":"Mol. Hum. Reprod."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/onc.2011.272","article-title":"Anti-angiogenic and tumor-suppressive roles of candidate tumor-suppressor gene, Fibulin-2, in nasopharyngeal carcinoma","volume":"31","author":"Law","year":"2012","journal-title":"Oncogene"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ydbio.2004.10.013","article-title":"Frzb modulates Wnt-9a-mediated \u03b2-catenin signaling during avian atrioventricular cardiac cushion development","volume":"278","author":"Person","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1161\/01.RES.0000141146.95728.da","article-title":"Heart Valve Development: Endothelial Cell Signaling and Differentiation","volume":"95","author":"Armstrong","year":"2004","journal-title":"Circ. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.cell.2004.08.022","article-title":"Sculpting Heart Valves with NFATc and VEGF","volume":"118","author":"Lambrechts","year":"2004","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"C1367","DOI":"10.1152\/ajpcell.2001.280.6.C1367","article-title":"Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis","volume":"280","author":"Dor","year":"2001","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.3181\/0806-RM-186","article-title":"Cardiac Malformations Are Associated with Altered Expression of Vascular Endothelial Growth Factor and Endothelial Nitric Oxide Synthase Genes in Embryos of Diabetic Mice","volume":"233","author":"Kumar","year":"2008","journal-title":"Exp. Biol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5197","DOI":"10.1242\/dev.01393","article-title":"A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels","volume":"131","author":"Hallaq","year":"2004","journal-title":"Development"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1161\/CIRCRESAHA.107.157859","article-title":"Mutation of the HEXIM1 Gene Results in Defects During Heart and Vascular Development Partly Through Downregulation of Vascular Endothelial Growth Factor","volume":"102","author":"Montano","year":"2008","journal-title":"Circ. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3941","DOI":"10.1242\/dev.127.18.3941","article-title":"Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression","volume":"127","author":"Miquerol","year":"2000","journal-title":"Development"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1161\/CIRCGENETICS.111.960872","article-title":"Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population","volume":"5","author":"Li","year":"2012","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1007\/s00246-018-1951-3","article-title":"Targeted Next-Generation Sequencing of 406 Genes Identified Genetic Defects Underlying Congenital Heart Disease in Down Syndrome Patients","volume":"39","author":"Alharbi","year":"2018","journal-title":"Pediatr. Cardiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1093\/hmg\/dds529","article-title":"Chronic pro-oxidative state and mitochondrial dysfunctions are more pronounced in fibroblasts from Down syndrome foeti with congenital heart defects","volume":"22","author":"Piccoli","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/cvr\/cvq237","article-title":"Mitochondrial morphology and cardiovascular disease","volume":"88","author":"Ong","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Liu, Y., Huang, Y., Xu, C., An, P., Luo, Y., Jiao, L., Luo, J., and Li, Y. (2022). Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232416053"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1093\/hmg\/ddu157","article-title":"NRIP1\/RIP140 siRNA-mediated attenuation counteracts mitochondrial dysfunction in Down syndrome","volume":"23","author":"Izzo","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_80","first-page":"1056","article-title":"Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in Down syndrome cells","volume":"26","author":"Izzo","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"606","DOI":"10.3389\/fgene.2019.00606","article-title":"Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells","volume":"10","author":"Mollo","year":"2019","journal-title":"Front. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Mollo, N., Cicatiello, R., Aurilia, M., Scognamiglio, R., Genesio, R., Charalambous, M., Paladino, S., Conti, A., Nitsch, L., and Izzo, A. (2020). Targeting Mitochondrial Network Architecture in Down Syndrome and Aging. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093134"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s10020-018-0004-y","article-title":"Mitochondrial dysfunction in down syndrome: Molecular mechanisms and therapeutic targets","volume":"24","author":"Izzo","year":"2018","journal-title":"Mol. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/S0012-1606(03)00385-3","article-title":"Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart","volume":"262","author":"Stennard","year":"2003","journal-title":"Dev. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.ydbio.2011.09.023","article-title":"Myocardial Tbx20 regulates early atrioventricular canal formation and endocardial epithelial\u2013mesenchymal transition via Bmp2","volume":"360","author":"Cai","year":"2011","journal-title":"Dev. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature03817","article-title":"Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis","volume":"436","author":"Zhao","year":"2005","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12929-022-00820-3","article-title":"SRF: A seriously responsible factor in cardiac development and disease","volume":"29","author":"Deshpande","year":"2022","journal-title":"J. Biomed. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.scr.2013.11.008","article-title":"Cardiomyogenesis is controlled by the miR-99a\/let-7c cluster and epigenetic modifications","volume":"12","author":"Coppola","year":"2014","journal-title":"Stem Cell Res."},{"key":"ref_89","first-page":"11","article-title":"Down syndrome and microRNAs (Review)","volume":"8","author":"Rodrigues","year":"2018","journal-title":"Biomed. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1152\/physiolgenomics.90254.2008","article-title":"MicroRNA and Cardiac Pathologies","volume":"34","author":"Latronico","year":"2008","journal-title":"Physiol. Genom."},{"key":"ref_91","first-page":"8737649","article-title":"Overexpression of Chromosome 21 miRNAs May Affect Mitochondrial Function in the Hearts of Down Syndrome Fetuses","volume":"2017","author":"Izzo","year":"2017","journal-title":"Int. J. Genom."},{"key":"ref_92","unstructured":"Mollo, N., Izzo, A., Nitti, M., Paladino, S., Cal\u00ec, G., Genesio, R., Bonfiglio, F., Cicatiello, R., Conti, A., and Nitsch, L. (2017). Down Syndrome, SM Group."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.bbadis.2015.04.004","article-title":"Chromosome 21-derived hsa-miR-155-5p regulates mitochondrial biogenesis by targeting Mitochondrial Transcription Factor A (TFAM)","volume":"1852","author":"Blanco","year":"2015","journal-title":"Biochim. et Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1111\/j.1742-4658.2011.08090.x","article-title":"MicroRNAs and cardiovascular diseases","volume":"278","author":"Ono","year":"2011","journal-title":"FEBS J."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1161\/01.RES.0000257913.42552.23","article-title":"MicroRNAs Play an Essential Role in the Development of Cardiac Hypertrophy","volume":"100","author":"Sayed","year":"2007","journal-title":"Circ. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1534\/g3.115.019943","article-title":"Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects","volume":"5","author":"Ramachandran","year":"2015","journal-title":"G3 Genes Genomes Genet."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.bbrc.2016.06.088","article-title":"The mediator complex subunit Med10 regulates heart valve formation in zebrafish by controlling Tbx2b-mediated Has2 expression and cardiac jelly formation","volume":"477","author":"Just","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1369\/0022155420952902","article-title":"Aggrecan in Cardiovascular Development and Disease","volume":"68","author":"Koch","year":"2020","journal-title":"J. Histochem. Cytochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"H1687","DOI":"10.1152\/ajpheart.00631.2018","article-title":"Extracellular matrix in cardiovascular pathophysiology","volume":"315","author":"Bloksgaard","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1002\/dvdy.20922","article-title":"MEKK4 regulates developmental EMT in the embryonic heart","volume":"235","author":"Stevens","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.ydbio.2006.09.047","article-title":"Tbx20 regulation of endocardial cushion cell proliferation and extracellular matrix gene expression","volume":"302","author":"Shelton","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1186\/1471-2164-12-229","article-title":"Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes","volume":"12","author":"Vilardell","year":"2011","journal-title":"BMC Genom."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1242\/bio.20134408","article-title":"An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21","volume":"2","author":"Vilardell","year":"2013","journal-title":"Biol. Open"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"De Toma, I., Sierra, C., and Dierssen, M. (2021). Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome. PLoS Comput. Biol., 17.","DOI":"10.1371\/journal.pcbi.1009317"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"4587","DOI":"10.1242\/jcs.114.24.4587","article-title":"Fibulin-1 suppression of fibronectin-regulated cell adhesion and motility","volume":"114","author":"Twal","year":"2001","journal-title":"J. Cell Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1002\/dvdy.20838","article-title":"Proteolytic cleavage of versican during cardiac cushion morphogenesis","volume":"235","author":"Kern","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/dvdy.21059","article-title":"Versican proteolysis mediates myocardial regression during outflow tract development","volume":"236","author":"Kern","year":"2007","journal-title":"Dev. Dyn."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.devcel.2007.11.018","article-title":"Endocardial Brg1 Represses ADAMTS1 to Maintain the Microenvironment for Myocardial Morphogenesis","volume":"14","author":"Stankunas","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1002\/bdra.20810","article-title":"Extracellular matrix and heart development","volume":"91","author":"Lockhart","year":"2011","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.gep.2009.02.006","article-title":"Adamts5, the gene encoding a proteoglycan-degrading metalloprotease, is expressed by specific cell lineages during mouse embryonic development and in adult tissues","volume":"9","author":"McCulloch","year":"2009","journal-title":"Gene Expr. Patterns"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1006\/geno.1997.4866","article-title":"Genomic Organization, Alternative Splicing, and Expression Patterns of the DSCR1 (Down Syndrome Candidate Region 1) Gene","volume":"44","author":"Fuentes","year":"1997","journal-title":"Genomics"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1093\/hmg\/7.13.2135","article-title":"Collagen VI deficiency induces early onset myopathy in the mouse: An animal model for Bethlem myopathy","volume":"7","author":"Bonaldo","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/(SICI)1097-0177(199803)211:3<248::AID-AJA6>3.0.CO;2-H","article-title":"Expression of Type VI Collagen in the Developing Mouse Heart","volume":"211","author":"Klewer","year":"1998","journal-title":"Dev. Dyn."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.ydbio.2006.09.024","article-title":"Atrioventricular valve development during late embryonic and postnatal stages involves condensation and extracellular matrix remodeling","volume":"302","author":"Kruithof","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1093\/hmg\/ddh213","article-title":"Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line","volume":"13","author":"Utriainen","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/dvdy.20556","article-title":"Collagen XVIII\/endostatin is associated with the epithelial-mesenchymal transformation in the atrioventricular valves during cardiac development","volume":"235","author":"Carvalhaes","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/nature09106","article-title":"Tumour angiogenesis is reduced in the Tc1 mouse model of Down\u2019s syndrome","volume":"465","author":"Reynolds","year":"2010","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1534\/genetics.116.188045","article-title":"Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier","volume":"203","author":"Li","year":"2016","journal-title":"Genetics"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0925-4773(01)00537-8","article-title":"Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis","volume":"109","author":"Levanon","year":"2001","journal-title":"Mech. Dev."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/S0002-9440(10)63467-0","article-title":"NCAM(CD56) and RUNX1(AML1) Are Up-Regulated in Human Ischemic Cardiomyopathy and a Rat Model of Chronic Cardiac Ischemia","volume":"163","author":"Waller","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.stem.2011.08.013","article-title":"Oncostatin M Is a Major Mediator of Cardiomyocyte Dedifferentiation and Remodeling","volume":"9","author":"Kubin","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature11739","article-title":"Functional screening identifies miRNAs inducing cardiac regeneration","volume":"492","author":"Eulalio","year":"2012","journal-title":"Nature"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s11427-013-4604-z","article-title":"Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart","volume":"57","author":"Wang","year":"2014","journal-title":"Sci. China Life Sci."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.yjmcc.2015.07.021","article-title":"Hematopoietic progenitors are required for proper development of coronary vasculature","volume":"86","author":"Lluri","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"G\u00f3rnikiewicz, B., Ronowicz, A., Krzemi\u0144ski, M., and Sachadyn, P. (2016). Changes in gene methylation patterns in neonatal murine hearts: Implications for the regenerative potential. BMC Genom., 17.","DOI":"10.1186\/s12864-016-2545-1"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1161\/CIRCULATIONAHA.117.028911","article-title":"Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction","volume":"137","author":"McCarroll","year":"2018","journal-title":"Circulation"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/dvdy.20051","article-title":"Development of heart valve leaflets and supporting apparatus in chicken and mouse embryos","volume":"230","author":"Lincoln","year":"2004","journal-title":"Dev. Dyn."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1073\/pnas.94.5.1852","article-title":"Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development","volume":"94","author":"Liu","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.3389\/fgene.2022.941364","article-title":"Genetic Diagnostic Yield and Novel Causal Genes of Congenital Heart Disease","volume":"13","author":"Tan","year":"2022","journal-title":"Front. Genet."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"53331","DOI":"10.1074\/jbc.M409622200","article-title":"Type V Collagen Controls the Initiation of Collagen Fibril Assembly","volume":"279","author":"Wenstrup","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1073\/pnas.98.3.1194","article-title":"Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice","volume":"98","author":"Eklund","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0945-053X(01)00187-1","article-title":"Developmentally regulated expression of type XV collagen correlates with abnormalities in Col15a1\u2212\/\u2212 mice","volume":"21","author":"Muona","year":"2002","journal-title":"Matrix Biol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1161\/CIRCRESAHA.110.222133","article-title":"Collagen XV Is Necessary for Modeling of the Extracellular Matrix and Its Deficiency Predisposes to Cardiomyopathy","volume":"107","author":"Rasi","year":"2010","journal-title":"Circ. Res."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/0012-1606(92)90186-K","article-title":"Fibulin is localized at sites of epithelial-mesenchymal transitions in the early avian embryo","volume":"151","author":"Spence","year":"1992","journal-title":"Dev. Biol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.ydbio.2008.04.029","article-title":"Fibulin-1 is required for morphogenesis of neural crest-derived structures","volume":"319","author":"Cooley","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0012-1606(87)90206-5","article-title":"Myocardial specificity for initiating endothelial-mesenchymal cell transition in embryonic chick heart correlates with a particulate distribution of fibronectin","volume":"119","author":"Mjaatvedt","year":"1987","journal-title":"Dev. Biol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1242\/dev.106.2.375","article-title":"Alternative splicing of fibronectin is temporally and spatially regulated in the chicken embryo","volume":"106","author":"Hynes","year":"1989","journal-title":"Development"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00211822","article-title":"Effects of injecting fibronectin and antifibronectin antibodies on cushion mesenchyme formation in the chick","volume":"185","author":"Icardo","year":"1992","journal-title":"Anat. Embryol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ydbio.2007.07.005","article-title":"Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin","volume":"311","author":"Astrof","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/jcb.22744","article-title":"Differentiation of cardiomyocytes from human embryonic stem cells is accompanied by changes in the extracellular matrix production of versican and hyaluronan","volume":"111","author":"Chan","year":"2010","journal-title":"J. Cell. Biochem."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1477-5956-7-31","article-title":"Transchromosomic cell model of Down syndrome shows aberrant migration, adhesion and proteome response to extracellular matrix","volume":"7","author":"Delom","year":"2009","journal-title":"Proteome Sci."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/0753-3322(93)90056-Q","article-title":"Congenital heart disease in patients with Down\u2019s Syndrome: Anatomic and genetic aspects","volume":"47","author":"Marino","year":"1993","journal-title":"Biomed. Pharmacother."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/ajmg.10413","article-title":"Beta 1 integrin activation mediates adhesive differences between trisomy 21 and non-trisomic fibroblasts on type VI collagen","volume":"109","author":"Jongewaard","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1042\/bst0190843","article-title":"Cell Adhesion to Type-VI Collagen","volume":"19","author":"Aumailley","year":"1991","journal-title":"Biochem. Soc. Trans."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"3861","DOI":"10.1242\/jcs.00059","article-title":"Fibronectin at a glance","volume":"115","author":"Pankov","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1242\/dev.119.4.1079","article-title":"Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin","volume":"119","author":"George","year":"1993","journal-title":"Development"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"34796","DOI":"10.1074\/jbc.M506980200","article-title":"Fibulin-1 Acts as a Cofactor for the Matrix Metalloprotease ADAMTS-1","volume":"280","author":"Lee","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"824922","DOI":"10.3389\/fgene.2022.824922","article-title":"Overexpression of the Hsa21 Transcription Factor RUNX1 Modulates the Extracellular Matrix in Trisomy 21 Cells","volume":"13","author":"Mollo","year":"2022","journal-title":"Front. Genet."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"R64","DOI":"10.1186\/gb-2010-11-6-r64","article-title":"A mouse embryonic stem cell bank for inducible overexpression of human chromosome 21 genes","volume":"11","author":"Romito","year":"2010","journal-title":"Genome Biol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"4211","DOI":"10.1038\/sj.onc.1207670","article-title":"Structure and regulated expression of mammalian RUNX genes","volume":"23","author":"Levanon","year":"2004","journal-title":"Oncogene"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1182\/blood-2014-04-572958","article-title":"RUNX1 positively regulates a cell adhesion and migration program in murine hemogenic endothelium prior to blood emergence","volume":"124","author":"Marinopoulou","year":"2014","journal-title":"Blood"},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Michaud, J., Simpson, K.M., Escher, R., Buchet-Poyau, K., Beissbarth, T., Carmichael, C., Ritchie, M.E., Sch\u00fctz, F., Cannon, P., and Liu, M. (2008). Integrative analysis of RUNX1 downstream pathways and target genes. BMC Genom., 9.","DOI":"10.1186\/1471-2164-9-363"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"5856","DOI":"10.1038\/onc.2008.195","article-title":"Gene array analysis reveals a common Runx transcriptional programme controlling cell adhesion and survival","volume":"27","author":"Wotton","year":"2008","journal-title":"Oncogene"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.bbagrm.2016.08.003","article-title":"RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells","volume":"1859","author":"Barutcu","year":"2016","journal-title":"Biochim. et Biophys. Acta (BBA)-Gene Regul. Mech."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"7113","DOI":"10.1007\/s12035-019-1585-3","article-title":"Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions","volume":"56","author":"Sobol","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1083\/jcb.200211089","article-title":"Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte\u2013specific expression in vivo","volume":"162","author":"Zheng","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1002\/art.24243","article-title":"Identification of the core element responsive to runt-related transcription factor 2 in the promoter of human type x collagen gene","volume":"60","author":"Higashikawa","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1016\/j.cell.2015.05.029","article-title":"Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation","volume":"161","author":"Wei","year":"2015","journal-title":"Cell"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13046-020-01650-7","article-title":"COL4A1 promotes the growth and metastasis of hepatocellular carcinoma cells by activating FAK-Src signaling","volume":"39","author":"Wang","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1030226","DOI":"10.3389\/fmolb.2022.1030226","article-title":"Exploring the cardiac ECM during fibrosis: A new era with next-gen proteomics","volume":"9","author":"Sarohi","year":"2022","journal-title":"Front. Mol. Biosci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1186\/s13046-019-1330-9","article-title":"RUNX1 promotes tumour metastasis by activating the Wnt\/\u03b2-catenin signalling pathway and EMT in colorectal cancer","volume":"38","author":"Li","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"972","DOI":"10.4161\/cc.23963","article-title":"The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion","volume":"12","author":"Keita","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.humpath.2010.01.025","article-title":"Matrix metalloproteinase-2 and matrix metalloproteinase-9 codistribute with transcription factors RUNX1\/AML1 and ETV5\/ERM at the invasive front of endometrial and ovarian carcinoma","volume":"42","author":"Alameda","year":"2011","journal-title":"Hum. Pathol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1007\/s10571-016-0456-y","article-title":"RUNX1 Regulates Migration, Invasion, and Angiogenesis via p38 MAPK Pathway in Human Glioblastoma","volume":"37","author":"Sangpairoj","year":"2017","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"3465","DOI":"10.1093\/hmg\/ddaa218","article-title":"Low-pass whole genome bisulfite sequencing of neonatal dried blood spots identifies a role for RUNX1 in Down syndrome DNA methylation profiles","volume":"29","author":"Laufer","year":"2020","journal-title":"Hum. Mol. Genet."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s12041-019-1152-8","article-title":"Hypermethylation of NRG1 gene correlates with the presence of heart defects in Down\u2019s syndrome","volume":"98","author":"Dobosz","year":"2019","journal-title":"J. Genet."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Mollo, N., Esposito, M., Aurilia, M., Scognamiglio, R., Accarino, R., Bonfiglio, F., Cicatiello, R., Charalambous, M., Procaccini, C., and Micillo, T. (2021). Human Trisomic iPSCs from Down Syndrome Fibroblasts Manifest Mitochondrial Alterations Early during Neuronal Differentiation. Biology, 10.","DOI":"10.3390\/biology10070609"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/iep.12329","article-title":"Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis","volume":"100","author":"Yamada","year":"2019","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Garcia, O., Torres, M., Helguera, P., Coskun, P., and Busciglio, J. (2010). A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down\u2019s Syndrome. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0014200"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/path.5735","article-title":"Prenatal histological, cellular, and molecular anomalies in Trisomy 21 lung","volume":"255","author":"Danopoulos","year":"2021","journal-title":"J. Pathol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s004290050123","article-title":"Morphological classification of nuchal skin in human fetuses with trisomy 21, 18, and 13 at 12\u201318 weeks and in a trisomy 16 mouse","volume":"197","author":"Krenn","year":"1998","journal-title":"Anat. Embryol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.ydbio.2007.07.041","article-title":"Cartilage link protein 1 (Crtl1), an extracellular matrix component playing an important role in heart development","volume":"310","author":"Wirrig","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function","volume":"38","author":"Donaldson","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"W60","DOI":"10.1093\/nar\/gky311","article-title":"GeneMANIA update 2018","volume":"46","author":"Franz","year":"2018","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2918\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:22:27Z","timestamp":1760120547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2918"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,2]]},"references-count":175,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032918"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032918","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,2]]}}}