Single-nucleus profiling reveals a core disease signature and cell-type-specific vulnerabilities in early Rett syndrome

Like other X-linked disorders, RTT patients have sex-specific differences in clinical presentation due to distinct cellular environments, where females have ~50% of cells expressing either a mutant or wild-type copy of MECP2 (mosaic) and males have 100% of cells expressing a mutant MECP2 (non-mosaic). Typical RTT females have a short window of normal early development until ~6-18 months, followed by regression and progressive decline, whereas neonatal encephalopathy is more likely in RTT males.

How these sex-specific differences in cellular context contribute molecularly to RTT pathogenesis, particularly in the presymptomatic stages of RTT females, remains poorly understood. Here, we profiled the hippocampal transcriptomes of female (Mecp2+/-) and male (Mecp2-/y) RTT mice at early timepoints using both bulk and single-nucleus RNA-seq, including sorted MeCP2 positive (MeCP2+) and MeCP2 negative (MeCP2-) neurons in female mice.