Abstract: Dual specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A), a phosphorylation kinase, is localized within the central nervous system and is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of DYRK1A leads to ASD-related phenotypes in mice and human, however, the key pathological mechanisms remain unclear, particularly in human. Here, we generated human induced pluripotent stem cell (iPSC) lines from two patients with de novo missense mutations and differentiated these lines into cortical neurons. We found that DYRK1A-mutant neurons exhibited small soma size with increased soma circularity. Besides, DYRK1A-mutant neurons showed decreased dendritic branching and immature synaptic formations. Transcriptomic analysis revealed reduced expression of multiple ion channel genes, particularly calcium channels, in DYRK1A-mutant neurons. Electrophysiological results showed that DYRK1A-mutant neurons exhibited an increased action potential half-width and decreased calcium currents. Overall, these findings indicate that DYRK1A deficiency disrupts calcium channels, suggesting calcium channels modulators as potential therapeutics for diseases with DYRK1A deficiency.
Funding Source: National Natural Science Foundation
