AI Article Synopsis
- X-linked diseases usually affect males more severely, but PCDH19 mutations cause epilepsy primarily in females, sparing males, which is unusual and not fully understood.
- Research shows that PCDH19 contributes to how cells stick to each other in the brain, and when there's a mix of normal and mutated PCDH19 in female mice, it causes abnormal cell sorting that changes network activity.
- Deleting PCDH19 in these mice restores normal cell sorting and network function, and patients with PCDH19 epilepsy show varying brain malformations, pointing to PCDH19's crucial role in brain development and the unique way this epilepsy is inherited.
Article Abstract
X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy.
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| http://dx.doi.org/10.1016/j.neuron.2017.12.005 | DOI Listing |
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