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.

中文翻译：

---

异常细胞分选是PCDH19癫痫病独特X连锁遗传的基础。

与X连锁的疾病通常在男性中表现出比女性更严重的表型。相比之下，原钙粘蛋白19（PCDH19）突变会导致杂合子雌性癫痫，而多余的半合子雄性癫痫。导致这种X连锁遗传的独特模式的细胞机制尚不清楚。我们显示PCDH19以一种组合方式有助于粘附特异性，使得杂合雌性小鼠中Pcdh19的镶嵌表达导致在发展中的皮层中表达野生型（WT）PCDH19和无效PCDH19的细胞之间的惊人分类，与改变的网络活动相关。杂合小鼠中PCDH19的完全删除消除了异常的细胞分选并恢复了正常的网络活动。此外，我们在PCDH19癫痫患者中发现了可变的皮质畸形。