美国哈佛医学院Hisashi Umemori研究组揭示了原钙粘蛋白19（PCDH19）突变小鼠模型中雌性特异性突触的功能障碍和认知障碍。2021年4月16日出版的《科学》发表了这项成果。

研究人员发现细胞粘附分子PCDH19在海马出芽苔藓纤维突触中富集。Pcdh19杂合雌性（PCDH19HET♀）小鼠而非Pcdh19半合子雄性（PCDH19HEMI♂）鼠显示出苔藓纤维突触结构和生理功能受损。与此一致，Pcdh19HET 3而非Pcdh19HEMI 3小鼠表现出降低的模式完成和分离能力，而该功能需要苔藓纤维突触。

此外，PCDH19似乎在出芽苔藓纤维突触中与N-钙黏连蛋白相互作用。在Pcdh19HET♀条件下，PCDH19与N-钙黏连蛋白之间的不匹配减弱了N-钙黏连蛋白依赖性信号传导，并损害了苔藓纤维突触的发育。N-钙黏连蛋白的过表达可以挽救Pcdh19HET♀的表型。这些结果揭示了雌性特异性PCDH19疾病未知的潜在分子和细胞机制。

据悉，PCDH19突变会引起早发性癫痫和认知障碍。PCDH19基因位于X染色体。与大多数X染色体连锁疾病不同，PCDH19突变影响PCDH19HET♀，但不影响PCDH19HEMI♂个体。但是，其原因尚待阐明。

附：英文原文

Title: Female-specific synaptic dysfunction and cognitive impairment in a mouse model of PCDH19 disorder

Author: Naosuke Hoshina, Erin M. Johnson-Venkatesh, Miyuki Hoshina, Hisashi Umemori

Issue&Volume: 2021/04/16

Abstract: 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 (PCDH19HET♀) but not hemizygous males (PCDH19HEMI♂); however, the reason why remains to be elucidated. We demonstrate that PCDH19, a cell-adhesion molecule, is enriched at hippocampal mossy fiber synapses. Pcdh19HET♀ but not Pcdh19HEMI♂ mice show impaired mossy fiber synaptic structure and physiology. Consistently, Pcdh19HET♀ but not Pcdh19HEMI♂ 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 Pcdh19HET♀ conditions, mismatch between PCDH19 and N-cadherin diminishes N-cadherin–dependent signaling and impairs mossy fiber synapse development; N-cadherin overexpression rescues Pcdh19HET♀ phenotypes. These results reveal previously unknown molecular and cellular mechanisms underlying the female-specific PCDH19 disorder phenotype.

DOI: 10.1126/science.aaz3893

Source: https://science.sciencemag.org/content/372/6539/eaaz3893