Fiche publication
Date publication
janvier 2024
Journal
Science translational medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann
Tous les auteurs :
Lana-Elola E, Aoidi R, Llorian M, Gibbins D, Buechsenschuetz C, Bussi C, Flynn H, Gilmore T, Watson-Scales S, Haugsten Hansen M, Hayward D, Song OR, Brault V, Herault Y, Deau E, Meijer L, Snijders AP, Gutierrez MG, Fisher EMC, Tybulewicz VLJ
Lien Pubmed
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 () gene, encoding a serine/threonine protein kinase, are associated with congenital heart disease pathology. In embryos from Dp1Tyb mice, reducing 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.
Mots clés
Animals, Humans, Mice, Down Syndrome, genetics, Heart Defects, Congenital, genetics, Trisomy, Genes, Mitochondrial, Disease Models, Animal, Myocytes, Cardiac
Référence
Sci Transl Med. 2024 01 24;16(731):eadd6883
