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Hum Mol Genet. 2018 Dec 1;27(23):4077-4093. doi: 10.1093/hmg/ddy301.

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome.

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Department of Medical Microbiology and Immunology, UC Davis School of Medicine, University of California, Davis, CA, USA.
UC Davis Genome Center, University of California, Davis, CA, USA.
UC Davis MIND Institute, University of California, Davis, CA, USA.
Department of Psychiatry and Behavioral Sciences, UC Davis School of Medicine, University of California, Davis, CA, USA.
Department of Public Health Sciences, UC Davis School of Medicine, University of California, Davis, CA, USA.
Department of Molecular Biosciences, UC Davis School of Veterinary Medicine, University of California, Davis, CA, USA.


Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1-deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2. However, RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory and gastrointestinal phenotypes. Consequently, we conducted a longitudinal assessment of symptom development in MeCP2-e1 mutant females and males. A delayed and progressive onset of motor impairments was observed in both female and male MeCP2-e1 mutant mice, including hind limb clasping and motor deficits in gait and balance. Because these motor impairments were significantly impacted by age-dependent increases in body weight, we also investigated metabolic phenotypes at an early stage of disease progression. Both male and female MeCP2-e1 mutants exhibited significantly increased body fat compared to sex-matched wild-type littermates prior to weight differences. Mecp2e1-/y males exhibited significant metabolic phenotypes of hypoactivity, decreased energy expenditure, increased respiratory exchange ratio, but decreased food intake compared to wild-type. Untargeted analysis of lipid metabolites demonstrated a distinguishable profile in MeCP2-e1 female mutant liver characterized by increased triglycerides. Together, these results demonstrate that MeCP2-e1 mutation in mice of both sexes recapitulates early and progressive metabolic and motor phenotypes of human RTT.

[Available on 2019-12-01]
[Indexed for MEDLINE]

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