Cooperation to amplify gene-dosage-imbalance effects

Abstract

Trisomy 21, also known as Down syndrome (DS), is a complex developmental disorder that affects many organs, including the brain, heart, skeleton and immune system. A working hypothesis for understanding the consequences of trisomy 21 is that the overexpression of certain genes on chromosome 21, alone or in cooperation, is responsible for the clinical features of DS. There is now compelling evidence that the protein products of two genes on chromosome 21, Down syndrome candidate region 1 (DSCR1) and dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), interact functionally, and that their increased dosage cooperatively leads to dysregulation of the signaling pathways that are controlled by the nuclear factor of activated T cells (NFAT) family of transcription factors, with potential consequences for several organs and systems that are affected in DS individuals.