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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.

Author information

1
Department of Medical Microbiology and Immunology, UC Davis School of Medicine, University of California, Davis, CA, USA.
2
UC Davis Genome Center, University of California, Davis, CA, USA.
3
UC Davis MIND Institute, University of California, Davis, CA, USA.
4
Department of Psychiatry and Behavioral Sciences, UC Davis School of Medicine, University of California, Davis, CA, USA.
5
Department of Public Health Sciences, UC Davis School of Medicine, University of California, Davis, CA, USA.
6
Department of Molecular Biosciences, UC Davis School of Veterinary Medicine, University of California, Davis, CA, USA.

Abstract

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.

PMID:
30137367
PMCID:
PMC6240741
[Available on 2019-12-01]
DOI:
10.1093/hmg/ddy301
[Indexed for MEDLINE]

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