Effect of PCDH19 missense mutations on cell-to-cell proximity and neuronal development under heterotypic conditions
Nami Motosugi1, Akiko Sugiyama1, Asako Otomo1,2,3
1Division of Basic Medical Science and Molecular Medicine, Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
PNAS Nexus
|March 22, 2024
Summary
Mutations in the protocadherin (PCDH) 19 gene cause epilepsy in females. This study reveals that altered PCDH19 cell adhesion impairs neuronal development, offering insights into epilepsy pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Epilepsy in heterozygous females is linked to X-linked protocadherin (PCDH) 19 gene mutations.
- Challenges in modeling PCDH19 epilepsy arise from X-chromosome inactivation (XCI) erosion in female pluripotent stem cells.
Purpose of the Study:
- To investigate the impact of PCDH19 mutations on neuronal development using patient-derived induced pluripotent stem cells (iPSCs) that retain XCI.
- To understand the cellular mechanisms underlying PCDH19-related epilepsy.
Main Methods:
- Utilized a mathematical approach combined with iPSCs derived from patients with PCDH19 missense mutations.
- Maintained XCI in iPSCs for accurate disease modeling.
- Analyzed cell-to-cell interactions and neuronal differentiation under heterotypic conditions (wild-type and mutant PCDH19).
Main Results:
- Heterotypic conditions (co-culture of wild-type and mutant PCDH19 cells) resulted in increased cell-to-cell proximity.
- Neuronal differentiation was impaired in these conditions.
- Aberrant accumulation of doublecortin, a neuronal development marker, was observed.
Conclusions:
- Enhanced cell adhesion between wild-type and mutant PCDH19-expressing cells may cause aberrant cell aggregation during early embryonic development.
- This aggregation potentially leads to impaired neuronal development and contributes to PCDH19 epilepsy pathogenesis.
