DYRK1A - a gene dose paradox

The DYRK1A (Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A) gene is located on human chromosome 21 (HSA21) within the Down Syndrome Critical Region (DSCR). As a protein kinase, DYRK1A is involved in the regulation of the cell cycle, cell growth, transcription, and cellular communication. It also plays essential roles in embryonic and neuronal development, and in disease pathogenesis. Dysregulation of DYRK1A has been associated with several human disorders, including DYRK1A syndrome, caused by DYRK1A haploinsufficiency (i.e., one functional copy of the gene) and Down syndrome (DS), caused by trisomy 21 (i.e., three functional copies of the gene). DYRK1A is an extremely dosage-sensitive gene and is considered one of the "Goldilocks" genes, for which both increased and decreased gene dosage can lead to pathological phenotypes. Interestingly, these two syndromes share several overlapping clinical features. This apparent paradox represents/highlights a major gap in our current understanding of DYRK1A function and raises important biological questions. In this review, we summarise the most important findings related to both DYRK1A syndrome and Down syndrome, as well as the available human cellular and animal models that provide valuable platforms for future research. To obtain a comprehensive understanding of DYRK1A role, it is necessary to integrate data from multiple experimental systems and sources. Such an integrated approach will facilitate the identification of novel therapeutic targets and support the development of treatments that may ultimately advance to clinical trials.