Related Experiment Video
Updated: May 2, 2026
A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Published on: May 22, 2019
Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X
J M Bissonnette1, L R Schaevitz2, S J Knopp3
1Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, USA; Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA.
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.
Insights
Respiratory issues in Rett syndrome (RTT) vary by mutation type. Different methyl-CpG-binding protein 2 (MeCP2) mutations in mouse models show distinct breathing patterns, impacting RTT research.
Area of Science:
- Neuroscience
- Genetics
- Respiratory Physiology
Background:
- Respiratory disturbances are a key feature of Rett syndrome (RTT), a neurological disorder linked to mutations in the methyl-CpG-binding protein 2 (MeCP2) gene.
- While null mutations in Mecp2 recapitulate some RTT respiratory phenotypes in mice, common point mutations are less understood.
- This study investigates respiratory function in mouse models of specific RTT point mutations.
Purpose of the Study:
- To characterize and compare the respiratory phenotypes in mouse models carrying missense (T158A) and nonsense (R168X) mutations in the Mecp2 gene.
- To explore how these distinct mutations, affecting MeCP2 protein function differently, influence respiratory control.
- To provide insights into the pathophysiology of Rett syndrome based on varying mutation effects.
Main Methods:
- Generation and analysis of heterozygous female mouse models for Mecp2 missense (Mecp2(T158A/+)) and nonsense (Mecp2(R168X/+)) mutations.
- Assessment of hypoxic ventilatory responses and hypercapnic responses in mutant and wild-type mice.
- Quantification of apnea incidence in both mutant mouse models.
Main Results:
- Both Mecp2(T158A/+) and Mecp2(R168X/+) heterozygotes exhibited augmented hypoxic ventilatory responses and depressed hypercapnic responses compared to controls.
- The Mecp2(R168X/+) model showed a significantly higher incidence of apnea (189/hour) compared to the Mecp2(T158A/+) model (41/hour).
- Functional differences in MeCP2 protein (DNA binding vs. transcriptional repression) correlate with distinct respiratory phenotypes.
Conclusions:
- Different Rett syndrome-associated mutations in MeCP2 lead to distinct respiratory phenotypes in mouse models.
- The severity and type of respiratory abnormalities, including apnea, vary depending on the specific mutation.
- Detailed characterization of respiratory phenotypes can reveal functional differences between MeCP2 mutations and aid understanding of RTT pathophysiology.
Related Concept Videos
02:23Master Transcription Regulators
01:39Epistasis
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:27Background and Environment Affect Phenotype
An example of how genetic background affects phenotype can be seen in horses. The Extension gene in horses is responsible for their coat color. A wild-type gene (EE) produces black pigment in the coat, while a mutant gene (ee) produces red pigment. A...