Abstract
Rett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Mecp2 deficient rodents used to model RTT pathophysiology in most prior studies have been male. Thus, we utilized a patient-relevant mouse model of RTT to longitudinally profile the gut microbiome and metabolome across disease progression in both sexes. Fecal metabolites were altered in Mecp2e1 mutant females before onset of neuromotor phenotypes and correlated with lipid deficiencies in brain, results not observed in males. Females also displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males. These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp2 animal models.
Highlights
Rett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism
Neurological phenotyping scores were assigned based on a system previously used to assess disease progression in RTT mouse models[40,44], motor phenotyping of gait was performed by footprint analysis, and gross metabolic phenotype was assessed by body weight measurements
Since IFNγ is mainly associated with T helper 1 (Th1) cell and IL-4 associated with T helper 2 (Th2) cell immune responses, these results indicate that female Mecp2-e1 mutants exhibited a shift towards a Th2 response at 18 weeks of age
Summary
Rett syndrome (RTT) is a regressive neurodevelopmental disorder in girls, characterized by multisystem complications including gut dysbiosis and altered metabolism. While RTT is known to be caused by mutations in the X-linked gene MECP2, the intermediate molecular pathways of progressive disease phenotypes are unknown. Females displayed altered gut microbial communities and an inflammatory profile that were more consistent with RTT patients than males These findings identify new molecular pathways of RTT disease progression and demonstrate the relevance of further study in female Mecp[2] animal models. RTT is an X-linked dominant disorder that is predominantly caused by mutations in MECP22, a gene encoding Methyl-CpG Binding Protein 2. Well characterized, generelevant female Mecp[2] mosaic mouse models are needed to uncover underlying molecular, cellular, and physiological intermediate phenotypes in the pathophysiology of RTT in order to provide insights into potential therapies
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