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Publication
MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett
syndrome.
Authors Vogel Ciernia A, Yasui DH, Pride MC, Durbin-Johnson B, Noronha AB, Chang A,
Knotts TA, Rutkowsky JR, Ramsey JJ, Crawley JN, LaSalle JM
Submitted By Submitted Externally on 2/22/2019
Status Published
Journal Human molecular genetics
Year 2018
Date Published 12/1/2018
Volume : Pages 27 : 4077 - 4093
PubMed Reference 30137367
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.




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