title: Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X.
abstract: Respiratory disturbances are a primary phenotype of the neurological disorder, Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). Mouse models generated with null mutations in Mecp2 mimic respiratory abnormalities in RTT girls. Large deletions, however, are seen in only ∼10% of affected human individuals. Here we characterized respiration in heterozygous females from two mouse models that genetically mimic common RTT point mutations, a missense mutation T158A (Mecp2(T158A/)(+)) or a nonsense mutation R168X (Mecp2(R168X/+)). MeCP2 T158A shows decreased binding to methylated DNA, while MeCP2 R168X retains the capacity to bind methylated DNA but lacks the ability to recruit complexes required for transcriptional repression. We found that both Mecp2(T158A/+) and Mecp2(R168X/+) heterozygotes display augmented hypoxic ventilatory responses and depressed hypercapnic responses, compared to wild-type controls. Interestingly, the incidence of apnea was much greater in Mecp2(R168X/+) heterozygotes, 189 per hour, than Mecp2(T158A/+) heterozygotes, 41 per hour. These results demonstrate that different RTT mutations lead to distinct respiratory phenotypes, suggesting that characterization of the respiratory phenotype may reveal functional differences between MeCP2 mutations and provide insights into the pathophysiology of RTT.
authors.affiliation: Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, USA; Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA. Electronic address: bissonne@ohsu.edu.
authors.forename: J M
authors.initials: JM
authors.lastname: Bissonnette
authors.affiliation: Department of Biology, Tufts University, Medford, MA 02155, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Schaevitz
authors.affiliation: Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Knopp
authors.affiliation: Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000367:Age Factors; D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010991:Plethysmography; D012120:Respiration Disorders / Q000209:etiology* / Q000235:genetics; D015518:Rett Syndrome / Q000150:complications* / Q000235:genetics*; D013990:Tidal Volume / Q000235:genetics
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D002245:Carbon Dioxide
keywords: MeCP2; Rett syndrome; apnea; hypercapnia; hypoxia; transcriptional repression domain