Protocadherin-19 (PCDH19) mutations cause early-onset seizures and cognitive impairment. The PCDH19 gene is on the X-chromosome. Unlike most X-linked disorders, PCDH19 mutations affect heterozygous females (PCDH19^HET♀) but not hemizygous males (PCDH19^HEMI♂); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. Pcdh19^HET♀ but not Pcdh19^HEMI♂ mice show impaired mossy fiber synaptic structure and physiology. Consistently, Pcdh19^HET♀ but not Pcdh19^HEMI♂ mice exhibit reduced pattern completion and separation abilities, which require mossy fiber synaptic function. Furthermore, PCDH19 appears to interact with N-cadherin at mossy fiber synapses. In Pcdh19^HET♀ conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin–dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues Pcdh19^HET♀ phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype.

Protocadherin-19 ( PCDH19 ) 突变导致早发性癫痫发作和认知障碍。PCDH19基因位于X 染色体上。与大多数 X 连锁疾病不同，PCDH19突变影响杂合子女性 ( PCDH19 ^HET♀ ) 但不影响半合子男性 ( PCDH19 ^HEMI♂ )；然而，其原因仍有待阐明。我们证明 PCDH19 是一种细胞粘附分子，在海马苔藓纤维突触中富集。Pcdh19 ^HET♀而不是Pcdh19 ^HEMI♂小鼠显示受损的苔藓纤维突触结构和生理学。一致地，Pcdh19 ^HET♀但不是Pcdh19^HEMI♂小鼠表现出模式完成和分离能力降低，这需要苔藓纤维突触功能。此外，PCDH19 似乎与苔藓纤维突触处的 N-钙粘蛋白相互作用。在Pcdh19 ^HET♀条件下，PCDH19 和 N-钙粘蛋白之间的不匹配会减少 N-钙粘蛋白依赖性信号传导并损害苔藓纤维突触的发育；N-钙粘蛋白过表达挽救了Pcdh19 ^HET♀表型。这些结果揭示了女性特异性PCDH19疾病表型之前未知的分子和细胞机制