Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy

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. •The cis interaction of PCDH19 with other PCDHs determines cell-cell adhesion affinities•Mosaic expression of PCDH19 leads to abnormal network activity•Wild-type and null PCDH19 cells segregate during cortical development•Cortical malformations are present in patients with PCDH19 mutations Pederick et al. report a cellular mechanism explaining the unique X-linked inheritance pattern of PCDH19 epilepsy. PCDH19 specifies binding affinities such that mosaic expression in females leads to striking segregation of WT and null cortical progenitors and abnormal network activity.