Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X.

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.