Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation

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 regul...

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Bibliographic Details
Published in:International journal of molecular sciences 2023-02, Vol.24 (3), p.2918
Main Authors: Mollo, Nunzia, Scognamiglio, Roberta, Conti, Anna, Paladino, Simona, Nitsch, Lucio, Izzo, Antonella
Format: Article
Language:English
Subjects:
Animals
Cell adhesion & migration
Chromosome 21
Chromosomes
Chromosomes, Human, Pair 21 - genetics
Collagen
congenital heart defects
Disease Models, Animal
Down syndrome
Down Syndrome - complications
Down Syndrome - genetics
Down's syndrome
Extracellular matrix
Extracellular Matrix - genetics
Fetuses
Genes
Genotype & phenotype
Heart
Heart Defects, Congenital - genetics
Humans
Kinases
MicroRNAs - genetics
Molecular modelling
Morphogenesis
Mutation
Pathogenesis
Phosphatase
Phosphorylation
Proteins
Review
RUNX1
Runx1 protein
Stem cells
Trisomy
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms24032918