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 inter-breath 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 pre-clinical 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.