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

Annie Vogel Ciernia, Dag H. Yasui, Michael C. Pride, Blythe Durbin-Johnson, Adriana B. Noronha, Alene Chang, Trina A. Knotts, Jennifer R. Rutkowsky, Jon J Ramsey, Jacqueline Crawley, Janine M LaSalle

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4077-4093
Number of pages17
JournalHuman Molecular Genetics
Volume27
Issue number23
DOIs
StatePublished - Dec 1 2018

Fingerprint

Rett Syndrome
Protein Isoforms
Phenotype
Exons
Mutation
X-Linked Genes
Symptom Assessment
Gait
Energy Metabolism
Nervous System
Disease Progression
Adipose Tissue
Triglycerides
Extremities
Eating
Body Weight
Lipids
Weights and Measures
Liver

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Vogel Ciernia, A., Yasui, D. H., Pride, M. C., Durbin-Johnson, B., Noronha, A. B., Chang, A., ... LaSalle, J. M. (2018). MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome. Human Molecular Genetics, 27(23), 4077-4093. https://doi.org/10.1093/hmg/ddy301

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome. / Vogel Ciernia, Annie; Yasui, Dag H.; Pride, Michael C.; Durbin-Johnson, Blythe; Noronha, Adriana B.; Chang, Alene; Knotts, Trina A.; Rutkowsky, Jennifer R.; Ramsey, Jon J; Crawley, Jacqueline; LaSalle, Janine M.

In: Human Molecular Genetics, Vol. 27, No. 23, 01.12.2018, p. 4077-4093.

Research output: Contribution to journalArticle

Vogel Ciernia, A, Yasui, DH, Pride, MC, Durbin-Johnson, B, Noronha, AB, Chang, A, Knotts, TA, Rutkowsky, JR, Ramsey, JJ, Crawley, J & LaSalle, JM 2018, 'MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome', Human Molecular Genetics, vol. 27, no. 23, pp. 4077-4093. https://doi.org/10.1093/hmg/ddy301
Vogel Ciernia A, Yasui DH, Pride MC, Durbin-Johnson B, Noronha AB, Chang A et al. MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome. Human Molecular Genetics. 2018 Dec 1;27(23):4077-4093. https://doi.org/10.1093/hmg/ddy301
Vogel Ciernia, Annie ; Yasui, Dag H. ; Pride, Michael C. ; Durbin-Johnson, Blythe ; Noronha, Adriana B. ; Chang, Alene ; Knotts, Trina A. ; Rutkowsky, Jennifer R. ; Ramsey, Jon J ; Crawley, Jacqueline ; LaSalle, Janine M. / MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 23. pp. 4077-4093.
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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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AU - Chang, Alene

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