Characterization of respiration in mice with Rett syndrome mutations T158A and R168X.

The X-linked disorder, Rett syndrome (RTT), is caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). A featuring phenotype of RTT is abnormal respiration characterized by frequent apnea and an irregular interbreath pattern. Mice with a large deletion of Mecp2 show similar breathing abnormalities to RTT. Here we characterize respiration in two mouse models that genetically mimic common RTT mutations, heterozygous females with a missense mutation, T158A (Mecp2T158A/+) or a nonsense mutation R168X (Mecp2R168X/+). Previous studies demonstrated that MeCP2 T158A protein shows impaired binding to methylated DNA and MeCP2 R168X retains the methyl-DNA binding domain but lacks the large C-terminus of the protein including the transcription repression domain. Oregon Health & Science University IACUC approved the protocol that was in agreement with the National Institutes of Health "Guide for the Care and Use of Laboratory Animals". Mice were 7.7 to 12.5 months old when studied, un-anaesthetized, in a body plethysmograph. We found that both mutant strains show abnormal breathing consisting of a slower frequency, frequent apnea and an irregular inter-breath interval, compared to their respective wild type littermates (Mecp2+/+) (Table 1). The breathing phenotype in Mecp2R168X/+ mice, however, varies significantly among individuals as might be expected in an X-linked disorder. For comparison, we classified Mecp2R168X/+ mice into a mild group and a severe group based on phenotypic severity. Mecp2T158A/+ mice fall between these two groups. Our findings demonstrate that there is considerable inter animal symptom variability in mouse models of RTT, reflecting the fact that RTT is a spectrum disorder. This is likely due to a combination of random X-chromosome inactivation and the different types of mutations on MeCP2. These heterozygous females are well suited for preclinical treatment trials that utilize respiration as an outcome measure, but classification of individual animal respiratory severity is necessary prior to treatment trials. In addition the varied respiratory phenotype in these mutant mice affords an opportunity to further define mechanisms that underlie abnormal breathing in Rett syndrome. [ABSTRACT FROM AUTHOR]

Copyright of Proceedings of the Physiological Society is the property of Physiological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)