On the mechanisms governing Rett syndrome severity

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in Methyl-CpG Binding Protein 2 (MECP2). While defined clinical features are present in all cases, a spectrum of disease severity exists across individuals with RTT. The work presented here seeks to increase understanding of the mechanisms governing phenotypic severity in RTT and the implications these factors hold for potential therapeutic interventions. These efforts are broadly divided between two investigations. The first centers upon a dissection of the underlying causes of variation in phenotypic severity amongst common RTT causing nonsense mutations in MECP2. Included in this investigation is an assessment of nonsense suppression therapy viability in a novel mouse model of the common R294X mutation. The second study explores the contribution of individual genetic variation to clinical severity in people with RTT. To identify genetic modifiers of RTT severity, we performed exome sequencing on affected individuals from both ends of a clinical severity distribution. Subsequent analysis revealed variants in cholesterol and terpenoid synthesis related genes are associated with phenotypic severity in RTT