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

• DOI: 10.1126/scitranslmed.add6883
• Publication Date: 2024-01-24T18:58:53Z
• Authors: Eva Lana-Elola; Rifdat Aoidi; Miriam Llorian; Dorota Gibbins; Callan Buechsensc...; Claudio Bussi; Helen Flynn; Tegan Gilmore; Sheona Watson-Scales; Marie Haugsten Ha...; Darryl Hayward; Ok-Ryul Song; Véronique Brault; Yann Herault; Emmanuel Deau; Laurent Meijer; Ambrosius P. Snij...; Maximiliano G. Gu...; Elizabeth M. C. F...; Victor L. J. Tybu...
• Keywords: Heart Defects, Congenital; Myocytes; Animal; Trisomy; Article; Mitochondrial; Congenital; Mice; Disease Models, Animal; Genes, Mitochondrial; Genes; Disease Models; Animals; Humans; Myocytes, Cardiac; Down Syndrome; Cardiac; Heart Defects

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, reducingDyrk1agene 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.