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

ABSTRACT: 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.

SUBMITTER: Motosugi N 

PROVIDER: S-EPMC10957236 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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

Motosugi Nami N   Sugiyama Akiko A   Otomo Asako A   Sakata Yuka Y   Araki Takuma T   Hadano Shinji S   Kumasaka Natsuhiko N   Fukuda Atsushi A  

PNAS nexus 20240208 3

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  ...[more]