Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome - Archive ouverte HAL
Article Dans Une Revue Science Translational Medicine Année : 2024

Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome

Eva Lana-Elola
Rifdat Aoidi
Miriam Llorian
Helen Flynn
Tegan Gilmore
Darryl Hayward
Ok-Ryul Song
Emmanuel Deau
Laurent Meijer
Victor Tybulewicz

Résumé

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). DS is a gene dosage disorder that results in multiple phenotypes including congenital heart defects. This clinically important cardiac pathology is the result of a third copy of one or more of the approximately 230 genes on Hsa21, but the identity of the causative dosage–sensitive genes and hence mechanisms underlying this cardiac pathology remain unclear. Here, we show that hearts from human fetuses with DS and embryonic hearts from the Dp1Tyb mouse model of DS show reduced expression of mitochondrial respiration genes and cell proliferation genes. Using systematic genetic mapping, we determined that three copies of the dual-specificity tyrosine phosphorylation–regulated kinase 1A ( Dyrk1a ) gene, encoding a serine/threonine protein kinase, are associated with congenital heart disease pathology. In embryos from Dp1Tyb mice, reducing Dyrk1a gene copy number from three to two reversed defects in cellular proliferation and mitochondrial respiration in cardiomyocytes and rescued heart septation defects. Increased dosage of DYRK1A protein resulted in impairment of mitochondrial function and congenital heart disease pathology in mice with DS, suggesting that DYRK1A may be a useful therapeutic target for treating this common human condition.
Fichier principal
Vignette du fichier
Lana-Elola Aoidi STM rev 3 Main Supp VT021223 CLEAN (2).pdf (96.31 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-04747430 , version 1 (20-11-2024)

Identifiants

Citer

Eva Lana-Elola, Rifdat Aoidi, Miriam Llorian, Dorota Gibbins, Callan Buechsenschuetz, et al.. Increased dosage of DYRK1A leads to congenital heart defects in a mouse model of Down syndrome. Science Translational Medicine, 2024, 16 (731), pp.eadd6883. ⟨10.1126/scitranslmed.add6883⟩. ⟨hal-04747430⟩
11 Consultations
0 Téléchargements

Altmetric

Partager

More