Effect of PCDH19 missense mutations on cell-to-cell proximity and neuronal development under heterotypic conditions

• Published in: PNAS nexus Vol. 3; no. 3; p. pgae060
• Main Authors: Motosugi, Nami, Sugiyama, Akiko, Otomo, Asako, Sakata, Yuka, Araki, Takuma, Hadano, Shinji, Kumasaka, Natsuhiko, Fukuda, Atsushi
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.03.2024
• Subjects: Brief Report; Epilepsy; Genetic aspects; Neurons; Stem cells; Japan
• ISSN: 2752-6542; 2752-6542
• DOI: 10.1093/pnasnexus/pgae060

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.