Year: 2018
Type: article
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddy301
Institution: University of California, Davis
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: International Rett Syndrome Foundation, University of California, National Alliance for Research on Schizophrenia and Depression, MIND Institute, University of California, Davis, National Institutes of Health, University of California, Davis, Intellectual and Developmental Disabilities Research Center, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1359208854, G1488703235, G156123175, G2578633385, G2578853757, G2594562258, Mouse Metabolic Phenotyping Center (MMPC) at UC Davis, G2719456613, G2817276033, West Coast Central Comprehensive Metabolomics Resource Core (WC3MRC), G3056480490, G3073890309, G3305947724, MIND Institute Intellectual and Developmental Disabilities Research Center, G4096623411, G477963360, G522538789, G530069377, Coordinating and Bioinformatics Unit for the MMPC/DiaComp, G6577422614, G6597090951, Coordinating Unit for DiaComp, G7513379028, G9000005033, G9000006656, G9000025022, G9000033486, G9000036510, G9000078454, G9000111834, G9000166011, G9000234988, G9000243758, G9000331382
OpenAlex ID: W2952491028