Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

• Published in: European journal of human genetics : EJHG Vol. 20; no. 1; pp. 69 - 76
• Main Authors: KERR, Bredford, SOTO C, Jessica, SAEZ, Mauricio, ABRAMS, Alexander, WALZ, Katherina, YOUNG, Juan I
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.01.2012
• Subjects: Age; Age Factors; Alternative Splicing; Animals; Ataxia; Behavior, Animal; Biological and medical sciences; Brain; Complementation; CpG islands; Crosses, Genetic; Cytomegalovirus - genetics; Cytomegalovirus - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; E2 protein; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Developmental; General aspects. Genetic counseling; Genes, X-Linked; Genetic Complementation Test; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Hypotheses; Intellectual disabilities; Isoforms; Language; Longevity; Male; MeCP2 protein; Medical genetics; Medical sciences; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - deficiency; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Mice, Transgenic; Molecular and cellular biology; Mutation; N-Terminus; Neurology; Neurons - cytology; Neurons - metabolism; Phenotype; Phenotypes; Promoter Regions, Genetic; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; Quantitative genetics; Rett syndrome; Rett Syndrome - genetics; Rett Syndrome - metabolism; Rodents; Seizures; Sleep; Transcription; Transgenes; Transgenic animals; Weight Gain; Chile; United States > US; Alternative splicing; Animal model; Rescue; MeCP2; Nervous system diseases; mouse model; Deficiency; Rodentia; Transgene; Genetic disease; Cerebral disorder; Vertebrata; Phenotype; Mammalia; Mouse; Animal; Central nervous system disease; Rett syndrome; Genetics; Degenerative disease; Complementation
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2011.145

Rett syndrome (RTT) is a disorder that affects patients' ability to communicate, move and behave. RTT patients are characterized by impaired language, stereotypic behaviors, frequent seizures, ataxia and sleep disturbances, with the onset of symptoms occurring after a period of seemingly normal development. RTT is caused by mutations in methyl-CpG binding protein 2 (MECP2), an X-chromosome gene encoding for MeCP2, a protein that regulates gene expression. MECP2 generates two alternative splice variants encoding two protein isoforms that differ only in the N-terminus. Although no functional differences have been identified for these splice variants, it has been suggested that the RTT phenotype may occur in the presence of a functional MeCP2-e2 protein. This suggests that the two isoforms might be functionally distinct. Supporting this notion, the two variants show regional and age-related differences in transcript abundance. Here, we show that transgenic expression of either the MeCP2-e1 or MeCP2-e2 splice variant results in prevention of development of RTT-like phenotypic manifestations in a mouse model lacking Mecp2. Our results indicate that the two MeCP2 splice variants can substitute for each other and fulfill the basic functions of MeCP2 in the mouse brain.