神经发育障碍PittHopkins综合征(PTHS)引起与Rett综合征(RTT)患者相似的临床症状。然而,RTT由MECP2突变引起,而TCF4基因中的突变导致PTHS。这两种疾病背后的机械共性是未知的,但是他们的共同症状表明,趋同通路水平的破坏可能存在。我们将患者皮肤来源的成纤维细胞重编程为诱导的神经元祖细胞。有趣的是,我们发现,与健康对照组相比,PTHS患者iNPC中MeCP2水平降低,iNPC和i星形胶质细胞均以突变特异性方式显示功能和分化缺陷.当Tcf4+/-小鼠与过表达MeCP2的小鼠遗传杂交时,分子和表型缺陷显着改善,MeCP2在PTHS病理中的强调和重要作用。重要的是,出生后脑室内基因替代疗法,使用表达9型腺相关病毒载体(AAV9)的MeCP2(AAV9。P546.MeCP2)显着改善了iNPC和i星形胶质细胞的功能,并有效改善了Tcf4/-小鼠的组织学和行为缺陷。合并,我们的数据提示MeCP2在PTHS病理和常见通路中的作用之前未知,可能在多种神经发育障碍中受到影响.我们的工作突出了PTHS的潜在新治疗靶点,包括上调MeCP2表达或其下游靶标,潜在的,基于MeCP2的基因治疗。
The neurodevelopmental disorder Pitt Hopkins syndrome (PTHS) causes clinical symptoms similar to Rett syndrome (RTT) patients. However, RTT is caused by MECP2 mutations whereas mutations in the TCF4 gene lead to PTHS. The mechanistic commonalities underling these two disorders are unknown, but their shared symptomology suggest that convergent pathway-level disruption likely exists. We reprogrammed patient skin derived fibroblasts into induced neuronal progenitor cells. Interestingly, we discovered that MeCP2 levels were decreased in PTHS patient iNPCs relative to healthy controls and that both iNPCs and iAstrocytes displayed defects in function and differentiation in a mutation-specific manner. When Tcf4+/- mice were genetically crossed with mice overexpressing MeCP2, molecular and phenotypic defects were significantly ameliorated, underlining and important role of MeCP2 in PTHS pathology. Importantly, post-natal intracerebroventricular gene replacement therapy with adeno-associated viral vector serotype 9 (AAV9)-expressing MeCP2 (AAV9.P546.MeCP2) significantly improved iNPC and iAstrocyte function and effectively ameliorated histological and behavioral defects in Tcf4+/- mice. Combined, our data suggest a previously unknown role of MeCP2 in PTHS pathology and common pathways that might be affected in multiple neurodevelopmental disorders. Our work highlights potential novel therapeutic targets for PTHS, including upregulation of MeCP2 expression or its downstream targets or, potentially, MeCP2-based gene therapy.