Effect of PCDH19 missense mutations on cell-to-cell proximity and neuronal development under heterotypic conditions.
Nami MotosugiAkiko SugiyamaAsako OtomoYuka SakataTakuma ArakiShinji HadanoNatushiko KumasakaAtsushi FukudaPublished in: PNAS nexus (2024)
The mutation of the X-linked protocadherin (PCDH) 19 gene in heterozygous females causes epilepsy. However, because of the erosion of X-chromosome inactivation (XCI) in female human pluripotent stem cells, precise disease modeling often leads to failure. In this study, using a mathematical approach and induced pluripotent stem cells retaining XCI derived from patients with PCDH19 missense mutations, we found that heterotypic conditions, which are composed of wild-type and missense PCDH19, led to significant cell-to-cell proximity and impaired neuronal differentiation, accompanied by the aberrant accumulation of doublecortin, a microtubule-associated protein. Our findings suggest that ease of adhesion between cells expressing either wild-type or missense PCDH19 might lead to aberrant cell aggregation in early embryonic phases, causing poor neuronal development.
Keyphrases
- single cell
- wild type
- cell therapy
- intellectual disability
- induced pluripotent stem cells
- endothelial cells
- gene expression
- stem cells
- escherichia coli
- oxidative stress
- induced apoptosis
- mesenchymal stem cells
- autism spectrum disorder
- cell death
- cystic fibrosis
- transcription factor
- signaling pathway
- copy number
- early onset
- bone marrow
- cell cycle arrest
- genome wide identification